Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Mar 11, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.

Dr Carolyn Lam:                So Greg, are ARNI's now going to be used for functional, mitral regurgitation and heart failure? Well, we're going to be chatting all about that with our feature paper, coming right up after these summaries.

                                                Greg, you've got a biggie to start with, haven't you?

Dr Greg Hundley:             Oh yes, Carolyn, I'm really excited about this paper. The senior author Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas and looking at high phosphate diets and their relationship to exercise intolerance. I really felt this was an exceptional study and combining that key that we have, for basic science papers and translation, where we're looking at data from both human and basic science, in both in a single manuscript.

                                                So, this study focuses on inorganic phosphates and they are present in 40-70 percent of the foods, really as a preservative enhancer, in western diets. We see it in colas, meats, dry food mixes, bakery products.

                                                For the human subject component of this study, the investigators examine the relationship between physical inactivity, assessed with ActiGraphs that were worn, and serum phosphate levels. They also obtained MRI measures of cardiac function and participants were recruited from the Dallas Heart Study too.

                                                In animals, they looked at the direct effects of dietary, inorganic phosphate on exercise capacity, oxygen uptake, serum non-esterified fatty acids, and glucose was measured during exercise treadmill tests in mice fed either high inorganic phosphate diets or normal in-organic phosphate diets. And they were on that for 12 weeks.

                                                To determine the direct effect of phosphate on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in the differentiated myotubes were conducted after subjecting those cells to media with high or low phosphate conditions.

Dr Carolyn Lam:                So, what did the study show?

Dr Greg Hundley:             In the human part, among 1603 participants, higher serum in-organic phosphate was independently associated with reduced time spent in moderate to vigorous physical activity and increased sedentary time. And interestingly, there was no association between serum phosphate levels and left ventricular ejection fraction or volumes.

                                                In the animal studies, mechanistic insight was obtained. Compared to controlled diets, consumption of high phosphate diet for 12 weeks did not alter body weight or left ventricular function, thereby confirming what we saw in the human subjects, but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, fatty acid levels, and led to down-regulations of genes involved in fatty acid synthesis.

                                                So, the take-home on this is that the results of this study demonstrate a detrimental effect of dietary, phosphate excess on skeletal muscle, fatty acid metabolism, and exercise capacity, which is independent of obesity and cardiac contractile function.

                                                And as such, dietary in-organic phosphate may represent a novel and modifiable target to reduce physical inactivity associated with the western diet. I think, Carolyn, we're going to see a large number of epidemiologic studies that are going to really look at this as something we might be able to modify in our diet to help impact some of these sedentary lifestyles and the harmful cardiovascular effects that we find associated with that lifestyle.

Dr Carolyn Lam:                Yikes. Remind me again, so phosphates in colas, meats, dried food mixes, and bakery products and so on, the preservative. Wow, you're right; big paper.

Dr Greg Hundley:             It's amazing. It's in 40-70 percent of the food products here in the United States. So, wow. Something really striking. So Carolyn, how about one of the papers that you liked?

Dr Carolyn Lam:                Moving to related cardio metabolic disease, we know that patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease, there is a tenfold variation in future cardiovascular risk in these patients. The current paper actually analyzes data from EMPA-REG OUTCOME where the authors, led by David Fitchett from St. Michael's Hospital in Toronto, sought to investigate whether the beneficial effects of Empagliflozin, observed in the EMPA-REG OUTCOME trial, varied across the spectrum of baseline, cardiovascular risk.

                                                What they found was that in patients with type 2 diabetes and atherosclerotic cardiovascular disease, the relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalizations with Empagliflozin versus placebo, were consistent in patients with and without a prior, myocardial infarction, with and without a prior stroke, and across sub-groups by the 10-point TIMI Risk Score for secondary prevention at baseline.

Dr Greg Hundley:             Does this suggest, Carolyn, that we use these inhibitors in all patients with type 2 diabetes?

Dr Carolyn Lam:                Remember the EMPA-REG OUTCOME; all patients had established atherosclerotic cardiovascular disease. This paper really adds to the understanding of the gradient of risk within these patients who had atherosclerotic cardiovascular disease and says Empagliflozin could be beneficial. But remember, there are patients with type 2 diabetes without established, cardiovascular disease and I think there's still equipoise in this primary prevention population.

Dr Greg Hundley:             That was great, Carolyn. Now I'm going to grab another sip of coffee and go onto my next paper.

Dr Carolyn Lam:                Sure, as long as it's not cola. No phosphates.

Dr Greg Hundley:             Right, thank you very much, Carolyn. I'm going to talk about screening for small and medium abdominal aortic aneurysms. This particular study comes from the surveillance of the National Health Service screening program by Dr Earnshaw. Basically, population screening for abdominal, aortic aneurysms has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have a AAA below 5.5 centimeters in diameter, and that's really our current referral threshold for treatment. When they have smaller diameter aneurysms they're entered into an ultrasound surveillance program.

                                                In this study, the investigators looked and reviewed those that had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up to 5.4 centimeter aneurysms, and they were followed. They were looking at the risk of rupture in these under surveillance.

                                                They had a total of 18,652 men and the risk of rupture overall per annum was 0.03% for men with small, abdominal aortic aneurysms and 0.28% for medium size. That was just below the threshold for the 5-5.4 centimeters, which was 0.4% over time. The risk of abdominal aortic aneurysm surveillance is below .5% per year and that is just below our current referral threshold for surgery, which is 5.5 centimeters.

                                                This is a study that really confirms, Carolyn, that the target mark or diameter that we've selected is appropriate.

Dr Carolyn Lam:                Nice. These just confirm the current guidelines?

Dr Greg Hundley:             Yeah, they do and Gil Upchurch from University of Florida, a surgeon, had a very nice editorial. The point he wants to make is yep, diameter of 5.5 is the threshold, but a couple key points. As patients are coming in for these visits, we need to continue to emphasize to them other factors related to growth of abdominal aortic aneurysms and their rupture. So, tobacco cessation, treatment of your lipids, management of your hypertension.

                                                The other point that he makes, is we really don't need to be operating on those individuals with an abdominal aortic aneurysm diameter of less than 5.5 centimeters. He makes an argument here that's in some countries with fee-for-service reimbursement, up to 30% of AAA repairs are for aneurysms less than this diameter of 5.5 centimeters. This over utilization of resources can add considerable costs to the healthcare system for managing this condition and is unlikely to increase the overall survival of these patients.

                                                A nice study confirming that what we're doing, really in terms of size and diameter, is correct, but also emphasizing this patient population often has a lot of other cardiovascular co-morbidities that we need to aggressively manage. How about your next paper?

Dr Carolyn Lam:                From one very clinically, applicable paper to another. This one answers the question, what's the optimal duration of emergency department and post-emergency department rhythm monitoring among patients with syncope. And the authors, led by Dr Thiruganasambandamoorthy and his colleagues from the Ottawa Hospital Research Institute, prospectively studied adults presenting within 24 hours of syncope at six emergency departments. They collected baseline characteristics, the time of syncope, the time of emergency department arrival, and the Canadian Syncope Risk Score, risk category. They followed subjects for 30 days and adjudicated the primary outcome, which was serious arrhythmic conditions and that includes arrhythmias or interventions for arrhythmias and unexplained death.

                                                Their results showed that the overall arrhythmia risk, and the risk after two hours of emergency department arrival from Canadian Syncope Risk Score, low-risk patients, was indeed very low. Similarly, the overall risk and after six hours of emergency department arrival for medium and high-risk patients was moderate and high, respectively. No low-risk patients suffered ventricular arrhythmia or unexplained death and most of the arrhythmias among the non-low-risk patients occurred within 15 days of the index syncope.

Dr Greg Hundley:             Carolyn, what's the take home message here?

Dr Carolyn Lam:                The results really support brief monitoring in the emergency department for two hours for Canadian Syncope Risk Score low-risk patients, and six hours for medium and high risk patients followed by selective admissions and the results also support a 15-day outpatient monitoring for medium-risk patients at a selected threshold and for all high-risk patients. So very practical advice.

Dr Greg Hundley:             Very good. Until next week, I'm going to watch out for phosphates.

Dr Carolyn Lam:                Indeed, and let's go on now to our featured discussion.

                                                For today's featured paper, we are discussing the results of the PRIME Study and that is Angiotensin Receptor Neprilysin Inhibitor, or ARNIs, for functional mitral regurgitation. A terribly interesting study. So pleased to have with us an author Dr Sung-Hee Shin from Inha University Medical center in Incheon, Korea as well as our associate editor Dr Victoria Delgado from University of Leiden in the Netherlands.

                                                Sung-Hee, what an interesting study. ARNI or Entresto for functional mitral regurgitation. Could you tell us what inspired this study and what did you find?

Dr Sung-Hee Shin:            Our study was the designed to tell if ARNI or functional mitral regurgitation because secondary functional mitral regurgitation was developed as a result of a reduced function. Guideline-directed medical therapy for heart failure would be a mainstay for a therapy.

                                                But despite use of the traditional drugs such as BETA blocker, ACE inhibitor or angiotensin receptor blockers, you know that the functional mitral regurgitation may be common and significant in the person having this functional mitral regurgitation would be related to increased morbidity and mortality.

                                                So, that trial showed that trans-catheter mitral valve repair effectively reduced the function mitral patient and resulted in lower rate of heart related mortality among patients with heart failure and function mitral regurgitation.

                                                In our blind trial, we also tried to tell whether an ARNI is more effective in improving function mitral regurgitation and randomly assigned 118 patients with heart failure and chronic secondary function mitral regurgitation lasting more than six months despite medical therapy and ejection fraction between 25% and 50% to receive either sacubitril/valsartan or valsartan in addition to standard medical therapy for heart failure.

                                                What happened with that change of mitral regurgitation after 12 months which was assessed by means of transthoracic area ways echo. What we observed was that transthoracic area as well as the volume of mitral regurgitation saw a decrease much more effective in the sacubitril/valsartan group than valsartan group.

                                                We also looked at the various other measures of the left ventricle remodeling and showed that the valsartan group had smaller left ventricle volume at 12 months and had a greater reduction of end-diastolic volume index.

                                                Also, among the completers ARNI, for the reduced left ventricle volume and the yearly time than the control group. So, what we think is that these factors might contribute to greater reduction of function mitral regurgitation in patients in the sacubitril/valsartan group.

                                                But our study was a mechanism study, but it was not designed to see outcomes. So further research and data would be necessary to check is this transthoracic echo end point can translate into better outcome in this population.

Dr Carolyn Lam:                Sung-Hee, this is just so interesting to have hypothesized this about functional mitral regurgitation. And not only that, I mean, to my mind, this is the largest echo-based studies of patients before and after Entresto that I can think of. It's nice to know, on top of knowing in paradigm that we can improve outcomes in heart failure reduced ejection fraction, that we now can look at the heart and see what happens in so many dimensions.

                                                So, congratulations.

                                                Victoria, were you surprised by these results? And do you agree with the mechanisms that Sung-Hee suggested?

Dr Victoria Delgado:        I think that this study is very important because in the field of functional mitral regurgitation, there is still a lack of consensus on how to treat these patients, which are very challenging.

                                                If the patient needs revascularization they will be referred for certain. But it still should be CBR mitral regurgitation and moderate and mile mitral regurgitation are not considered.

                                                I think that we discuss often which is the optimal medical therapy or the guidelines based medical therapy but it's not really consensus because the studies before have not been like this one. That large in order to answer a specifically that question.

                                                I think that this article brings an important message and brings more evidence to our field that there is not that much data. So, I think it's very important for that research, in particularly after the research of the co-op and the mitral trial where it seems that the selection of patients is very important in order to identify the patients that will really benefit from those therapies.

Dr Carolyn Lam:                That's such a good point. Going to that selection of patients, Sung-He, you mentioned very carefully the ejection fractions that you allowed up to 50% in these patients. Could you explain how you reasoned the selection of this patient cohort?

Dr Sung-Hee Shin:            The reason why we chose the patients we did, the range of ejection fraction condition, was that we thought the reversibility of the left ventricle mortality and function mitral regurgitation might be more pronounced in these patients.

                                                When we considered the fraction condition in mitral regurgitation with ejection fraction used under [inaudible 00:18:17] LV dysfunction, our inclusive criteria of ejection fraction between 25 to 50% might correspond to ejection fraction of 20 to 40% in patients with mitral regurgitation.

                                                We concluded that if a patient had ejection fraction less than 25% because the reversibility of mortality and function mitral regurgitation might be smaller when all the LV dilation is too extreme and advanced heart failure is already established.

                                                So, I just thing how it can be provided to the patient who have functional mitral regurgitation associated with too extreme LV dilation and LV ejection fraction too.

Dr Victoria Delgado:        I think, Carolyn, it's a very good point what she explained because we are used to select patients based on ejection fraction, in particularly patients with functional mitral regurgitation, ejection fraction is rather misleading because actually it's just a change of volume in the ventricles emptying in a low pressure chamber which is the left atrium.

                                                The moment that you correct that in mitral regurgitation sometimes then you face, or you see, the true ejection fraction of that ventricle. And if we wait too long, we may end up with ventricles that they don't have any more resource in order to improve ejection fraction after repair of the mitral valve.

                                                So, I think that this study is important to also realize that concept. That ejection fraction in patients with functional mitral regurgitation may not be the most accurate parameter to assess the function of that ventricle.

Dr Carolyn Lam:                Yeah. Exactly. And I thought that was a very clever part of the design. I'm glad you explained it and also so glad, Victoria, you invited the editorial by Dr Mullens, who also commented on that. So, just for the audience to understand that ejection fraction up to 50% was included and ejection fraction less than 25% was excluded.

                                                So also, again, very consistent to your prior point, Victoria.

                                                Could I ask you, I think Dr Mullens also spent quite some time talking about the potential mechanisms. What's your take of this Victoria? ARNI for functional regurgitation. How come?

Dr Victoria Delgado:        For me, I'm much more from the side of the imaging point of view. When we have patients with functional mitral regurgitation I always try to see which is the capability that that ventricle has to recover.

                                                Actually, first is always medical therapy, but we know that the [inaudible 00:20:59] only, for example, we just reduced the mitral regurgitation, but they don't really improve the function of that ventricle, while if you reduce the loading conditions of the ventricle in terms of blood pressure as well and favoring remodeling of the left ventricle, you can improve the condition of the mitral valve and reduce the mitral regurgitation.

                                                How valsartan plus sacubitril works differently than valsartan alone that I don't think that I have enough knowledge to explain why but it could be that in a way there is more effective with sacubitril on top of valsartan can improve the loading conditions of the ventricle and improve the, or facilitate, the reversing of morbidity of that ventricle, reducing the mitral regurgitation and that, by itself, could also lead to reversing morbidity.

                                                Like a little bit cardiac resynchronization we'd do, for example, in patients with an ejection fraction below 35% and based on the EEG you have the synchronous fraction of the papillary muscle or the walls of the ventricle which could lead to the mitral regurgitation at the moment that you resynchronize that mitral regurgitation can produce, you reduce part of the volume of the load of the ventricle and that can favor that reversing morbidity.

                                                So, I think that this study raises a lot of questions and I think that further research is needed in order to confirm or to know more how these treatments work.

Dr Carolyn Lam:                Goodness, that was so beautifully explained and in fact, many clues from Sung-Hee's study and the reversal of left ventricle end diastolic volume index greater with those treated with ARNI, the LA size and so on.

                                                But maybe I should ask you, Sung-Hee, in line with what Victoria said, what are the next steps? Do you already know what are the next studies that you're going to be looking at in PRIME?

Dr Sung-Hee Shin:            We're considering mark of monitoring such as NT pro-BNP or using auto imaging models such as echo and cardiac MRI to look at the change of mitral valve regurgitation in more detail.

                                                This kind of study might be very helpful in understanding [inaudible 00:23:15] ARNI in functional mitral patient.

Dr Carolyn Lam:                Yes, that's clever, too. And Victoria, before we end could you maybe give us some take home messages?

Dr Victoria Delgado:        I think that the take home message from this study is that when we have patients with functional mitral regurgitation, we need to think what we can offer to them. Not consider mitral regurgitation just as a base standard. That it's going to respond only to diuretics. No. We need to do something on that left ventricle to help it to improve the function and to avoid the progress to more reduced function.

                                                It's very important to understand the mechanism of the mitral regurgitation and to use the guidelines based medical therapy trying to go step by step in order to optimize the medication of that patient and later on, see all the potential treatments that are available right now such as cardiac synchronization therapy, which we should not forget, and then surgery if the patient needs catheterization and if the patient needs the benefit from mitral valve plasty or eventually, for example, trans catheter mitral valve therapies.

                                                But we should avoid that the patient goes further down into heart failure with very dilated ventricles and very poor function because then probably we may face a point of no return.

Dr Carolyn Lam:                Thank you so much, Victoria. Both you and Sung-Hee mentioned this is a mechanistic study. So many insights. But it's not saying that everybody with functional mitral regurgitation has to be treated this way now. It's calling for more work and it's certainly very, very important study.

                                                Thank you listeners, for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2019.


Mar 4, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Have you heard of long non-coding RNAs? Well, they are definitely the hot topic and our feature paper today discusses the first demonstration of the importance of a linked RNA in atherosclerotic lesions not just in mice but also in humans. You have to listen on, it's coming up right after our copy chat.

                                                Greg, what are your picks upon the journal this week?

Dr Greg Hundley:             The first paper I wanted to discuss comes from France, and it's basically looking at ambulance density and outcomes after out of hospital cardiac arrest from Florence Dumas from Hôpital Cochin in Paris, France. This manuscript addresses the geographic disparities and survivorship of out of hospital cardiac arrest and the relevance of the patients characteristics versus whether ambulances are equipped with those trained in basic or advanced cardiac life support. So, what they did they had nineteen neighborhoods in Paris, and the number of BLS trained versus ALS ambulances was collected, and the authors assessed that respective associations of socio-economic characteristics of the patient population and the ambulance resources of these neighborhoods and compared those with successful return of spontaneous circulation or risk as the primary end point and then survival of out of hospital discharge as the second end-point.

                                                So, they had 80754 non-traumatic out of hospital cardiac arrests across the Paris area. 42% at ROSK 9% head survival at discharge, and after accounting for the patient's socio-economic status, greater than one and a half advanced cardiac life support ambulances per neighborhood and greater than 4 basic cardiac support basic life support units per neighborhood were associated with ROSK, but only the 1.5 ALS units per neighborhood were associated with survival.

Dr Carolyn Lam:                Oh, interesting Greg. So does this we need more advanced life support units?

Dr Greg Hundley:             So, Paul Dorian from St. Micheal's Hospital in Toronto, Canada wrote an excellent editorial, and one point he made related to these ALS units is that it was really a very small 1.3 adjusted odd ratio for survival to hospital discharge, and it's important to note that although the increase in survival was associated with more ALS units, there were many other variables that were likely important and not recorded in this study. For example, including the time to collapse, to calling for EMS, the time from the call to the deployment of that ALS unit to the scene, the time from collapse to the defibrillation, the total "no flow time" sort of in quotation, which is the total duration of collapse until CPR is started and so I think one of the points in this observational study is there could've been many differences that would've associated with the findings, interesting findings how about one of the papers that you liked?

Dr Carolyn Lam:                So, the paper that I selected here is a first time that a targeted anti-inflammatory therapy has been shown to reduce hospitalization for heart failure and at-risk patients. So, you know that some clinical inflammation associates with an increased risk of heart failure and associates with the worst prognosis in patients with heart failure, and yet, so far, treatments specifically directed at reducing inflammation in patients with heart failure have not been shown to improve clinical outcomes. That's why today's paper is so special and it's from Dr Everett and colleagues from Brigham and Women's Hospital Harvard Medical School in Boston, and basically, the authors looked at CANTOS and tested the hypothesis that the interleukin -1β inhibitor can canakinumab would prevent heart failure hospitalizations and the composite of heart failure hospitalizations on heart failure related mortality in the CANTOS trial.

                                                Now, remember the CANTOS trial randomized more than 10 000 patients with a prior myocardial infarction and with high sensitivity C-reactive proteins at least two or greater, and they were randomized to canakinumab 50, 150, and 300 mg or placebos. Now, before randomization, these participated were asked if they had a history of heart failure and 22% said yes so the current paper actually looks at this stratification of patients who said they had heart failure, and during a meeting follow-up of 3.7 years, 385 patients had a new heart failure hospitalization event. Now, here's the key: the authors found a dose dependent reduction in the risk of hospitalization for heart failure as well as the composite of hospitalization for heart failure or heart failure related mortality among those allocated to Canakinumab.

Dr Greg Hundley:             So, how does this differ from prior attempts targeting inflammation and heart failure? I mean is this ready for prime time thing?

Dr Carolyn Lam:                So, we have to bear a few things in mind here you know. CANTOS was different from a previously published randomized controlled trials, which were basically neutral and that was like of infliximab and etanercept so the drug in CANTOS targets interleukin-1 beta whereas the prior ones targeted the TNF-alpha, and also very importantly, CANTOS did not specifically enroll patients with an established heart failure only. CANTOS patients had to have a history of myocardial infarction and there was no data on their ejection fraction or natriuretic peptides at the time of randomization nor at the time of heart failure hospitalization. So, by the way, we don't know whether there's a differentially effect on hep pef versus hep-ref. So, again difference from the heart failure focused trial previously that used an anti-inflammatory agents.

                                                The other thing: although there was a dose dependent reduction in the risk of hospitalization for heart failure no single dose of Canakinumab compared to the placebo had a statistically significant reduction in the risk of heart failure hospitalization. Only the trend was statistically significant so all in all, this was a pre-specified aim of CANTOS to look at heart failure, the data presented here should really be considered hypothesis generally, but really quite promising. And what about you Greg? What's your other paper?

Dr Greg Hundley:             We're going to switch gears a little bit and shift over to the Jackson heart study. The large longitudinal cohort from Jackson, Mississippi that's recruited to follow for cardiovascular events, and it's an area of the United States where we have some of the highest cardiovascular disease event rates really across the nation so this study focuses on sleep apnea and is the Jackson's heart sleep study. It's a sub-study of this larger Jackson's heart study that involves 913 patients, and the investigators were looking at the association between sleep apnea and blood pressure control among those of a Black race. So, Dayna Johnson of Emerald University is the first author on the paper. What's nice about this sub-study, this sleep sub-study is that there are objective measures using an in-home type III sleep apnea study. They had clinical blood pressure measurements and then anthropometry as opposed to questionnaire derived data that may have been performed in the larger cohort.

                                                And the study determined these associations between moderate or severe obstructed sleep apnea with controlled, uncontrolled and resistant hypertension. So the analytic sample of the individuals with hypertension was 664, and they had an average age of about 64 years. They were predominately women 69%, obese 58%, College-educated at 51%. Among the sample, about a quarter had obstructive sleep apnea, which was untreated and unrecognized in 94% of the participants. That's an interesting point, just right there.

                                                Overall, 48% of the participants had uncontrolled hypertension and 14% had resistant hypertension. So, multiple medications, often four and still unable to control the blood pressure. So the findings participants with moderate or severe obstructive sleep apnea had 2 times higher odds' ratio of resistant hypertension.

Dr Carolyn Lam:                Whoa Greg, that's a huge risk and very important finding. I mean if sleep apnea could be modifiable risk factor perhaps for very important issue among African Americans resistant hypertension. What do you think about clinical implication?

Dr Greg Hundley:             One of the things to be considering now is what are we going to do about that cause as you know CPAP is really the preferred treatment for resistant hypertension, but it's efficacy hasn't been really that well studied in African Americans and CPAP tolerance is low so this study highlights for us potentially new mechanisms for resistant hypertension, but we still got to be thinking about what would be our next therapeutic intervention for this particular patient population. And what about your next study?

Dr Carolyn Lam:                The next study is about Impella support for acute myocardial infarction complicated by cardiogenic shock. Now, we use it all the time, but did you know that to date, there is no large randomized study actually comparing the use of Impella to other contemporary cardiac support devices and medical treatment in stem related cardiogenic shock. So, Dirk Westermann and colleagues from University Heart Center in Hamburg tried to address this knowledge gap by using a multi-national database of patients with acute myocardial infarction complicated by cardiogenic shock and treated with the Impella device and compared in a matched fashion their outcomes to patients from the IABP Shock II trial, which you would recall is a randomized trial which demonstrated similar outcomes between IABP and medical treatment in myocardial infarction in cardiogenic shock.

                                                So, they looked at 237 matched-pairs so remember this was pairs from this registry of acute myocardial infarction with shock and using an Impella matched with IABP shock patients and what they found was that there was no significant difference in 30-day all-cause mortality. Instead, severe or life-threatening bleeding and peripheral vascular complications occurred significantly more often in the Impella group when they limited the analysis to the IABP treated group as controlled versus Impella that was still the same results.

Dr Greg Hundley:             So, Carolyn, there are trying to match patient population from two different studies and they may have confounders in there that we can't account for so why we not able to produce large randomized trials of Impella devices in studies of patients with acute myocardial infarction?

Dr Carolyn Lam:                The rate of acute myocardial infarction complicated by cardiogenic shock has really declined in the past decade. Furthermore, clinical signs of shock really appear in half to three quarter of cases several hours after hospital admission so making randomization before primary PCI of the AMI really very difficult. And finally, many interventional cardiologists believe that there's equipoise that has already been reached on the use of these cardiac assistive devices in patients with cardiogenic shock and this was from registry data, and so if interventionists believe this then they also believe its unethical to randomize these patients in trials. Still, I think that current study to date really causes us to pause and to acknowledge that we really need to evaluate this better and prospective randomize trials of Impella treatment are warranted.

                                                Let's now go to our featured discussion, shall we?

                                                For our featured paper discussion today, we are talking about a basic science paper, and we have none other than the best of the best Dr Charles Lowenstein, our associate editor from University of Rochester Medical Center joining us as well as the first author of a really fantastic paper on long non-coding RNA in a specific type involved in arthrosclerosis and plaque formation. This first author is Sebastian Creamer from Goethe University in Frankfurt.

                                                Charlie, could you start us off by telling us what is a long non-coding RNA? We've heard a lot about this in recent times. What's the big deal about them?

Dr Charlie Lowenstein:  So in the last decade, scientists have learned that your genome, your DNA inside you, every cell codes about 20,000 genes and those 20000 genes encode proteins, but there are another 20000 genes that encode RNA only, RNA that never turns into protein that leaves RNA are an amazing diversity of different kinds of RNA really short micro RNA, longer RNA that defends the host from viruses and long non-coding RNA that have a huge variety of effects regulating genes, turning genes on and off in proliferation and cell growth and inflammation so long non-coding RNAs are increasingly appreciated as an important part of the genome.

Dr Carolyn Lam:                What a perfect set up with that. Sebastian, could you tell us about your study please?

Dr Sebastian Creamer:   Our laboratory was interested in non-coding RNAs for some time and previously, we've found that this specific non-coding RNA MALAT1 regulates endothelial cell functions and because we were interested in analyzing this particular RNA in the disease setting it shows at a risk growth so it's because also we saw that when it's regulated by flow and end of previous cells and so we cross MALAT1 deficient mice to Apoe mice and set them on a high fat diet and analyzed and subtracted in both groups. And while we only saw a modest increase in plaque size in MALAT1 deficient mice, we could appreciate a higher amount of inflammatory cells in plaque of aortic roots in those mice, which let us hypothesize that inflammatory responses was appreciated and is a very important contributor to arthrosclerosis in MALAT1 deficient mice. And to test this, we decided to transplant MALAT1 deficient bone marrow in Apoe knockout mice with MALAT1 and interestingly, we saw that now plaques were significantly larger than compared to mice who received controlled MALAT1 white cell bone marrow, and also inflammatory cells were more prominent in those mice.

Dr Greg Hundley:             Sebastian, this is Greg Hundley. You also did some experiments in human subjects. Could you tell us a little bit about those too?

Dr Sebastian Creamer:   So, because we saw this interesting phenotype, we were very much interested if this also translates into the human setting. Luckily, we got a really nice collaboration receding in Stockholm access to high impact material from patients with arthrosclerosis and what we could see here that MALAT1 expression was down regulated in patients with arthrosclerosis and it also correlated with disease progression. Moreover, in another collaboration, we consolidated those findings with experiments, which showed that human cells have less MALAT1 compared to normal vasculature.

Dr Carolyn Lam:                It all sounds so sensible and logical and so on but let me just frame this for our audience. This is actually the first time that it's been demonstrated. The importance of long non-coding RNA in arthrosclerosis. Charlie, could you tell us a little bit about how significant these findings are?

Dr Charlie Lowenstein:  Sure. So, I'm really interested in the final figure in this paper because there are lots of interesting human data, showing that MALAT1 expressed more in normal than atherosclerotic arteries and also that MALAT1 expression is correlated with fewer major adverse cardiac events so the whole story is a very nice story saying that the expression of this anti-inflammatory link RNA not only has an effect in mice but it can be extended into the human field of arthrosclerosis and inflammation. It's particularly important because there's a lot of attention in the last decade that inflammation drives atherosclerosis, and in light of CANTO trial showing that anti-inflammatory therapy can actually decrease atherosclerosis and decrease cardiovascular events in humans. This is important cause it shows another pathway, which regulates inflammation. Not only in mice, but also in humans, and in the human atherosclerotic setting.

Dr Carolyn Lam:                Amazing. Sebastian, what are the next steps? How far are we away from clinical applications here? What are the next steps to get it in the clinic?

Dr Sebastian Creamer:   So, the very difficult thing is that MALAT1 is down-regulated in atherosclerosis and also therapeutic approaches is very difficult in such a complicated disease like atherosclerosis to actually increase the expression of such a long non-coding RNA. What we are currently working on is to decipher more than the clinical malade-1 is actually influencing atherosclerosis so we have lots of hints or some evidence that adhesion of inflammatory substances altered and the bone marrow activity, which is very important in atherosclerosis and also in other cardiovascular diseases like myocardial infarction is altered so we think that malade-1 might actually influence the resolution of inflammation and when it's lacking, inflammation can be resolved. So, we are now putting somewhat mechanistic studies and finally, we hope that we can find another downstream target like micron AB, we talked about in our paper, which we can directly target in the future.

Dr Charlie Lowenstein:  So, I agree with Sebastian. I think MALAT1 is going to turn out as one of those major link RNAs that controls inflammation possibly controlling the way in which the bone marrow reacts to systemic inflammation and produces cells and then have those cells home in on various inflammatory targets so I think this is an important observation that's going to have not only implications for atherosclerosis but also for other inflammatory diseases.

Dr Carolyn Lam:                Excellent. If you don't mind, I would love to switch tracks a little bit. We find it that very special and we can discuss basic papers with people who can explain it so well because we understand that there's so much work that goes in to these papers and so on. Charlie, could you take behind the scenes a little bit with the editors and tell us what is it that circulation looks for in basic science papers that makes us published?

Dr Charlie Lowenstein:  We get a lot of really good basic science papers, and it's a challenge for the associate editors, and the editors to figure out what's right for circulation and let me use this manuscript as a great example because this is a terrific paper. So, this paper is divided into four sections, and these sections are what we look for in any basic science paper that's going to reach an audience of clinicians who are interested in pathways and therapeutics so this paper has a section on mice. There's a gene in mice that's important then the paper delves into cells what's happening with cells and then a little bit of mechanisms and genes and proteins and then this paper takes the observation back into humans and shows that there's some human and clinical relevance so this is not only a great paper, but it is a classic example of what the associate editors are looking for in a basic science paper that's targeted towards clinicians.

Dr Charlie Lowenstein:  There's some in vivo work with mice, there's some mechanistic work then they take it back to the humans. Plus, of course like anything that comes into circulation, it's going to be novel, interesting and has some important relevance to human cardiovascular disease. This paper that we're discussing is a great example of a paper that we love to publish in a circulation and it's a real tribute to Dr Dimmeler and her team and to Sebastian that they put this paper together and submitted it to us.

Dr Carolyn Lam:                Thank you audience for joining Greg and I today. You've been listening to circulation on the run. Don't forget to tune in again next week.


Feb 25, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor and director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                So, Greg, are we any closer to the holy grail of safe ED discharge for acute heart failure based on a risk score? Well, we're going to be discussing that coming right up after Greg and I share about the papers that we'd like to discuss today. Lovely issue, isn't it?

Dr Greg Hundley:             Yup, and time to get your coffee and bring it up. My first paper, Carolyn, is from Michael Chu from London Health Sciences Center, and is really investigating the surgical management of thoracic aortic disease, and looking at the impact of gender or sex related differences. Sex related differences have not been thoroughly studied. This group looked at a total of 1653 patients, 30% were women, who underwent thoracic aortic surgery with hypothermic circulatory arrest between the years of 2002 and 2017 across Canada in 10 institutions.

                                                Well, women underwent less aortic root reconstruction, including aortic root replacement, Ross procedures, or valve sparing root operations. But, even with less invasive, the women experienced higher rates of mortality, 11% versus 7%, stroke, and that composite of the thoracic surgeons' adverse events. On multi variable analysis, female sex or women was an independent predictor of overall mortality, stroke, and those comorbidities.

Dr Carolyn Lam:                Greg, you know how much I love these papers, so I'm going to repeat that. You're saying the women received less ominous procedures and yet had worse outcomes, and this was independent of the clinical covariances, right?

Dr Greg Hundley:             Absolutely. Putting all this together, women underwent thoracic aortic surgery a little bit older, and with larger index aortic aneurysm size than men. Intraoperatively, women undergo fewer concomitant procedures, such as the aortic root repairs, and things that you just mentioned. But nevertheless, women experience significantly worse outcomes identified as an independent predictor of mortality, stroke, and that composite endpoint for mortality, morbidity, after multi variable analysis.

                                                What should we think about this? Well, sex specific considerations are important when considering thoracic aortic surgery and future research should focus on the development of a personalized approach to thoracic aortic surgery with respect to gender. For example, utilization of maybe lower size thresholds for women for aortic aneurysms should be considered, and for earlier interventions, and improved outcomes.

                                                Carolyn, tell me about one of your papers.

Dr Carolyn Lam:                All right, so I chose a paper looking at the stroke outcomes in the COMPASS trial. Now, let's remind everybody that the COMPASS trial, where patients with stable coronary artery disease or peripheral artery disease, and randomly assigned to receive aspirin 100 milligrams daily, rivaroxaban five milligrams twice daily, or the combination of rivaroxaban 2.5 milligrams twice daily plus aspirin. Patients requiring anticoagulation with a stroke within a month had a previous lacunar stroke or intracerebral hemorrhage were excluded.

                                                Now, in the current paper, and this is from Dr Sharma from Population Health Research Institute, and their colleagues, basically they looked at a detailed analysis of the stroke by type, predictors, and anti-thrombotic effects in the key subgroups. They found that the combination of low dose rivaroxaban and aspirin prevented stroke and disabling stroke better than aspirin in patients without atrial fibrillation and with stable vascular disease, and without an increasing risk of hemorrhagic stroke; which is really important. This effect was consistent across subgroups of baseline risk, and particularly marked in those with a history of previous stroke.

Dr Greg Hundley:             Carolyn, what about that rivaroxaban five milligrams twice daily alone?

Dr Carolyn Lam:                There was no significant difference in the occurrence of stroke in the rivaroxaban alone group compared with aspirin. But all of this simply says perhaps low dose rivaroxaban and aspirin may be a really important new anti-thrombotic option for primary and secondary stroke prevention in patients with clinical stable atherosclerosis.

Dr Greg Hundley:             Very interesting. I'm going to follow your lead and go into another sort of anticoagulant-related topic on iliofemoral deep vein thrombosis. This paper is by Suresh Vedantham from the Washington University of St. Louis.

                                                Let's talk about just what is the definition? This is a DVT that involves the iliac and/or the common femoral vein with or without involvement of additional veins. It basically obstructs the outflow of the veins. These patients are phenotypically distinct from patients with cath or femoral popliteal DVT because that totally obstructs flow, and they have more frequent recurrence of venous thromboembolic events, and more frequent post-thrombotic syndrome. Well, that's a horrible condition because of that obstruction, it leads to calf muscle dysfunction, edema, subcutaneous fibrosis, tissue hypoxia, and ulceration.

Dr Carolyn Lam:                Great background. What did this study show?

Dr Greg Hundley:             This is a sub-study of the ATTRACT trial. The ATTRACT trial basically is looking at anticoagulation plus perhaps mechanical intervention, or direct catheter directed thrombolysis therapy versus just anticoagulation alone. This sub-study is 391 patients with acute DVT involving just the iliac or the common femoral veins, and following these individuals for 24 months to compare short and long-term outcomes.

                                                What did the study show? Well, this interventional group did have a reduction in leg pain and swelling, and improvement in quality of life related to that lower extremity. But, no overall difference in overall quality of life, and very importantly, no difference in the occurrence of this post thrombotic syndrome.

Dr Carolyn Lam:                That's kind of disappointing. I understand that the ATTRACT study is not the first to look at this, though. That was in an editorial discussing this. Could you tell us about that?

Dr Greg Hundley:             Yeah, Carolyn. Jay Giri from University of Pennsylvania just had an incredible editorial. I think if you have an opportunity, listeners, to take a look at that, I highly recommend it. He reminded us of the CaVenT trial, which is basically performed as an open label randomized control trial of 209 patients across 20 hospitals in Norway.

                                                What was different in the CaVenT trial is that at 24 months of follow up, the intervention with thrombolysis and systemic anticoagulation improved iliofemoral patency. It reduced the incidence of this post thrombotic syndrome. In ATTRACT, in this sub-study, it was intravenous thrombolysis, systemic anticoagulation, and mechanical intervention on the vein versus in the other study from Norway, CaVenT, just the inter vein thrombolysis and the systemic anticoagulation.

                                                What Dr Giri points out is that maybe something related to intervention in that vein when you're stripping out thrombus, et cetera, are we damaging the veins in the vessel that prevents reflux, et cetera?

                                                I think really moving forward, you're going to have to personalize this decision in individual patients until we have more data on this subject.

Dr Carolyn Lam:                Great learning. I learned a lot from this next paper, too, because I actually chose a basic science paper. This is a paper that uncovers a new fine tuning factor that modulates myocardial infarction induced inflammation. That is a small GTPase called RhoE.

                                                In this study, Drs Chang from Texas A&M University College of Medicine, and Song from Fuwai Hospital in Beijing used three genetic mouse model lines. Those are the global knockout, the cardiomyocyte specific RhoE heterozygous mouse, and the cardiomyocyte specific RhoE over expression mouse. With this combination, they showed that RhoE deficiency causes excessive inflammatory response in infarct animal heart, resulting in enlarged heart, decreased contractility, and increased mortality. The mechanism is that RhoE binds to P65 and P50, which impedes their dimerization and blocks these two proteins from nuclear translocation. Now, over expression of cardiac RhoE inhibits NF-κB, restrains post MI inflammation, and improves cardiac function and survival.

                                                Importantly as you always say, Greg, there is human data. They found that the expression of RhoE was elevated in the infarct patient heart and that patients with a higher expression of RhoE exhibited a better prognosis and better cardiac function recovery.

Dr Greg Hundley:             Carolyn, tell me a little bit about the clinical significance of this.

Dr Carolyn Lam:                You just wanted to ask me a tough question. I can see it on your face. Basically, I think this is really exciting because RhoE may serve as a new potential biomarker for the assessment of myocardial infarction in patients, and manipulation of RhoE could be a potential therapeutic approach for MI. There.

Dr Greg Hundley:             Very good.

Dr Carolyn Lam:                That's all the time we have for our little discussion here. Now, let's go onto the feature paper. ...

                                                Over 80% of emergency department patients with acute heart failure are admitted to the hospital. Now, contrast this with the fact that over 80% of all emergency department visits result in discharge. So, why is that many other emergency department based cardiovascular disease processes like for acute coronary syndrome have evolved from high rates of admission to timely and safe discharge whereas decision making in acute heart failure has not experienced a similar evolution. Do we need perhaps a better acute heart failure prognostic score that's validated?

                                                Well, guess what? We're going to talk about this right now in our feature discussion, and a beautiful feature paper that we're so proud to have the corresponding author, Dr Douglas Lee from University of Toronto right here to discuss; along with the managing editor, Dr Justin Ezekowitz, who's associate editor from University of Alberta, and the editorialist, Dr Sean Collins from Vanderbilt University Medical Center. Welcome everyone, and Doug, please, could you just start by telling us about this great paper?

Dr Douglas Lee:                 We validated, and it's a tool, decision making tool, for acute heart failure patients in the emergency department. We, in this study, wanted to prospectively validate a decision making prognostic tool called the Emergency Heart Failure Mortality Risk Grade, or EHFMRG for short, to see how well it performed in the real world busy emergency department hospital setting.

                                                We studied just under 2,000 patients who came to emergency departments at multiple centers, and asked physicians to rate their prognostic estimation of what's going to happen to that patient in the next seven days. We compared that with the EHFMRG model, which predicts outcomes of seven days and 30 days. We were very careful to ask physicians to provide their prognostic estimates. This is their intuitive guesstimation of the risk of the patient before calculating the score because we didn't want the physicians to be influenced by the score.

                                                What we found was that when we looked at how well physicians' estimates performed, they actually performed quite well. The c-statistic for physician estimated risk was around .7, which is a reasonable discrimination. However, the physicians' estimates were not as good as the EHFMRG risk score, which had a C greater than .8. The mathematical model seemed to do better in terms of predicting what's going to happen to the patient than physicians' estimates.

                                                Interestingly, when we combined the physicians' estimates with the EHFMRG risk score, the c-statistic improved by another 1%, so there's some additive value of having both factors combined.

                                                The other interesting finding was that patients in the lowest risk groups had 0% mortality at seven days, and 0% mortality at 30 days. We may be able to identify, using the score, patients who have a very low risk of events in that seven to 30 day period after emergency department presentation.

Dr Carolyn Lam:                Thanks so much, Doug. I have to tell you, I am a fan of the EHFMRG score. In fact, we're trying to study how well it performs in our local situation even here in Singapore.

                                                Justin, you've been thinking a lot about this. I would love for you to share the reactions that we got when we discussed this among the editors.

Dr Justin Ezekowitz:        We had a lot of good discussion about this from a number of different aspects. First, it's an in-practice assessment, a physician-based risk assessment, as we survey hundreds of physicians in the ER, which is a busy environment, and get these types of information. That's a very unique piece of this study where, in addition to the just under 2,000 patients and collecting the other data in a robust way, this really does have a potential to contribute to the literature.

                                                A lot of the discussion was about how data rich this is, and that this is an area where unlike acute cardiovascular disease where there are good risk assessment tools and other therapies, it's a really need of a scoring system that was well validated, can be replicated, and both in clinical practice as well as in selective cohorts. Doug, my congrats to your and the other parts of the team that's helped put this together.

                                                One of the questions that came up when we were discussing it was the risk textiles and buckets were very important for people to think about the very low risk, as you mentioned, 0% all the way up through much higher percents for seven day mortality, but how discrepant the risk was of the physicians versus the mathematical model; and a very good reminder of the inaccuracy of sometimes our assessments of risk in practice, especially in acute care.

                                                I wonder if you could comment on what your fence was from the physicians who participated in the study, and then the data of those, the most striking findings of that piece about where physicians make judgements on risk in for that seven-day mortality. Just any comments you may have?

Dr Douglas Lee:                 We didn't know what to expect because there haven’t been many studies of this type before. What we found in our study was that physicians tended to overestimate the risk of lower risk patients. They thought bad things would happen to healthier patients, just to put it very simply. Physicians also underestimated the risk of the highest risk patients. They thought that the highest risk patients would do well.

                                                We were surprised about that finding, but also, we were not surprised in the fact that it seems to explain some of our earlier findings that in our earlier work, we found that low risk patients are hospitalized, and we think it's probably that physicians are admitting those patients because they want to ensure that they're making a safe decision; and no harm will fall in the patient. Maybe physicians are erring on the side of admitting those patients, even though they know they're a little bit low risk.

                                                At the other extreme, physicians underestimated risk in the highest risk patients. We think it might explain the observation that we made previously that sometimes high risk patients are discharged home, and they die at home after discharge. That may be because patients who look well to physicians, I think there's great value in the clinical experience of a seasoned physician looking at a patient and knowing that, that patient is sick or not sick. But in certain cases, patients may look relatively well, but their numbers would indicate that they're actually higher risk. I think it's that group where we found they're higher risk, but physicians thought that they were healthier than they were. It seems physicians' estimations really have great value, but it seems that they can be improved.

Dr Carolyn Lam:                Sean, you discussed this beautifully in your editorial. Share with us your thoughts, and especially thoughts on the question you posed: are we any closer to the holy grail of safe emergency department discharge based on acute heart failure risk rules?

Dr Sean Collins:                 Doug, kudos to you. Nearly 2,000 patients, nine different hospitals, prospective data collection, as Justin said. I don't think this can be overstated. From a data cleaning perspective, this is truly a labor of love, and to get this done, congratulations to you and your team.

                                                I think the most interesting part of this is this exact disconnect of patients look well who are high risk, and patients may look a little bit unwell who may be low risk, ironically. That's where a risk tool is much needed, as Carolyn said in her introduction to sort of change the dynamic of 80 to 90% of patients are admitted to the hospital. If we even chipped away at 10 to 15% to able to be discharged, it would be a huge win for partly for management for an emergency department perspective.

                                                I think that the importantly, the next steps will be now looking at implementing this in some sort of a randomized manner, somewhat like what you did with asking physicians gestalt about what their level of risk is, but really finding out how does a physician gestalt when it comes to nuance and heart failure. A relative amount of congestion, even when the tool says the patient may be low risk, can they go home? I think that will be the crucial next step to find out how much does this augment and/or detract from physician decision making? We have a long way to go, as Carolyn said. It's just the complete opposite at almost every other disease process, including chest pain, from a discharge perspective. Even a little bit improvement would be great, so I'm looking forward to seeing the next steps, and I'm wondering what your thoughts are about the next steps, Doug.

Dr Douglas Lee:                 There's actually great value in physicians' clinical judgment. It's been, I think relatively understudied. I'm hopeful that future studies where decision tools or prognostic tools are validated, we can see more potentially, more comparisons with clinicians because we don't have a real great understanding, I think, of how doctors think, especially in an acute setting. More research in this area, I think would be really helpful, especially as we ... As more and more clinical decision tools being published, it would be great to see how well they hold up against good clinician judgment.

                                                In terms of next steps and implementation, when we talk to our emergency colleagues, they have brought up an issue about it's great that patients are low risk, and that we could potentially discharge them from hospital; but where is the receptor to take that patient and to care for that patient once they've left the hospital? Are they going to get good care once they leave the hospital? Are there structures in place?

                                                We're now embarking on testing this in the clinical trial where we will be comparing two strategies. The first strategy will be using the risk score at a hospital-wide level, and then discharging home patients who are in the lower risk categories, and having them follow up, and receive their care in a rapid ambulatory follow up clinic within two to three days after discharge from the emergency. This will be compared to the control, which is not using the risk score, and having usual follow up care. This trial is called the Comparison of Outcomes and Access to Heart Failure Trial, or the COAHFT trial. It is currently ongoing.

Dr Sean Collins:                 Great point, Doug. As Carolyn suggested with chest pain and heart failure as the interesting dichotomy is that unlike chest pain, when we safely rule somebody out and send them home, we're sort of done with that acute episode. Heart failure, it doesn't end. We've found that they're safe enough to go home, but now they need great collaboration and outpatient support with their heart failure provider, which may be as equally heavy lift as externally validating the EHFMRG score. You bring up a great point, which is we need to have outpatient follow up and collaboration for this to be successful. Thanks.

Dr Carolyn Lam:                Awesome comments, guys. Could I switch tracks a bit and maybe just ask Justin to round up by sharing? Circulation, we get a lot of papers about risk scores and so on. There's a bit of fatigue, I think, about scores in all kinds of things. Now, could you maybe tell us, Justin, what makes us look at a paper twice, and in fact, feature this one with a good editorial? I mean it's clearly very clinically applicable. Could you share some thoughts there?

Dr Justin Ezekowitz:        Yes, that's a great point. The things that make a risk score like this kind of elevated into kind of a circulation level of manuscript is A) the data quality has to be excellent. There has to be lots of completeness of data, but also capture of elements that we think are quite important. Two, the data science about how it's analyzed and put together, and interpreted, it has to be to the bar that we feel would be robust, and be able ... if somebody could repeat it and replicate it without an obvious challenge to the quality.

                                                The third, I think is the clinical applicability. It's okay to write a data model and come up with all these great risk scores, but if they haven't been thought through about how either a patient will be seeing this, or clinicians behave, or the environment that it has to be deployed in that, that isn't necessarily going to be something that is going to be implemented. Then, the question is: why would somebody do the study in the first place?

                                                Now, it's okay if somebody's forward thinking and saying, 'Look, EMRs are coming, or other EHRs around, so this could be implemented if there was enough impetuous and it's a good enough quality.' That's actually okay, but in the reverse where if you try to implement a model that is too complex, and it's in a hand-off to the environment, it just won't work. We just want to make sure people have thought that next knowledge translation and dissemination approach through.

                                                The final part is things that have a very local impact are, that are very unique to the environment they're in, such as it only would work in your hometown or your own country because of some environment, that's okay. But under that, the much more global focus that, that is, it could be picked up and trans located to any major city, providence, state, or country, because vis vises are global. Those things have a much greater impact because the circulation leadership is global. The patients are global. The clinicians who care for them are also global. People are all looking for very similar situations and can adapt to their own environments.

Dr Carolyn Lam:                Awesome, Justin. I don't think any of us could have said it better. Those are the reasons that we're so grateful that you publish with us, Doug. Thank you so much, Sean, for your excellent editorial, too.

                                                Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Feb 18, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. And I am so privileged to be joined by Senior Associate Editors whom I respect and admire so much. And they are Dr Biykem Bozkurt from Baylor College of Medicine and Dr Sana Al-Khatib from Duke University. And we have three woman discussing the Go Red for Women issue. Yes!

                                The current issue is the third Go Red for Women issue and boy, is it a bonanza issue. It tackles a wide spectrum of topics relating to cardiovascular disease in women, including prevention, risk stratification, myocardial infarction, pregnancy, heart failure, cardiac arrest, sudden cardiac death, and in so many wonderful formats; from original papers to systematic reviews, state-of-the-art papers, in-depth reviews, a research letter, and even frame of reference papers.

                                So, let’s get digging into this issue, shall we? And Biykem, we could start with you because I'd like to start with three original papers that really set the scene. The first discussed temporal changes and the very contemporary data from 2001 to 2016, describing cardiovascular risk factors and their treatment. And then the second focuses on young females with acute myocardial infarction. And the third on older women. Could you take us through these papers Biykem?

Dr Biykem Bozkurt:         Lets first start looking at the sex differences through the Anne Haines Survey which enrolled more than 35000 patients. And they examined the trend all the way back from 2000 to 2016. Now the good news is the improvement in hypertension diabetes hyperlipidemia in woman were similar to men. So that's the good news. But BMI increased more in women than in men and overall, the ability to control blood pressure and diabetes hyperlipidemia appear to be a little bit better for women than in men.

                                But the concerning trend becomes apparent when we look at another paper that examined the twenty-year trend in young adults. Now, the first message is, and this is important for both genders, the proportion of the hospitalizations that are attributable to young patients, and young patients are defined as ages between 35 and 54 in this study, and this study was from Erik, increased from 1995 to 2014. So young patients appear to be having more in life compared to before, compared to 1990s and the 2000s. And that was actually partly due to the increasing prevalence of comorbidities, such as hypertension diabetes among young patients.

                                Now, interestingly among young patients, young women presenting with [inaudible] had a lower likelihood of receiving guideline directed therapy which, of course, sound familiar to our audience because we have the disparities of lower treatments and lower access to care in women with MI presentation compared to men. And unfortunately, again this will sound like the former news, the pre-hospital mortality was quite high in young women and has declined less in young women, compared to men.

                                So, the Erik study highlights the disparity for young women compared to young men. And then we have to recognize that most young patients in my hospitalization attributed to young patients is increasing. So this is probably a population that we need to be aware of. Regarding the older patients, there is a publication from the Opach Study looking at the sedentary behavior and cardiovascular disease in older women. And they looked at more than 5500 patients aged between 63 and all the way up until 97. And they looked at sedentary time and they looked at the duration of sedentary time all the way over eleven hours in some of the patients. And of course the higher the sedentary time was, the worse the cardiovascular disease risk was amongst the older women. So now we are recognizing that among older women, the post-menopausal or elderly women, the risk of cardiovascular disease rises with sedentary lifestyle.

                                And I think these three papers highlight the overall trend that we tend to see, maybe, better emphasis for comorbidity control. But at the same time we are now starting to recognize that in younger patients, especially in younger women the risk of MI is on the rise. And in older women, activity and remaining active and not having too much sedentary time are important to prevent cardiovascular disease.

Dr Carolyn Lam: Oh, Biykem, thank you for framing that so beautifully. So some good news, some bad news, and certainly some things we should be looking out for. You know, in another patient group that we always need to touch on when we talk about the Go Red for Women issue is pregnant women, or post-pregnancy. Could you comment, perhaps, on the systematic review that we have?

Dr Biykem Bozkurt: This is a very comprehensive, systematic review looking at the cardiovascular disease morbidity and mortality in women with a history of pregnancy complications. And they provide detailed systematic review and method analysis. It's becoming more apparent that the spectrum of cardiovascular disease ranges all the way from preeclampsia to arrythmia to pericardial myopathy. And we're recognizing this continuum both in the peripartum period, at the same time as the future risk. So those with preeclampsia and premature birth and delivery are associated with lifetime risk of cardiovascular disease. So, I think this paper is providing the right overview and a very comprehensive meta-analysis recognizing that pregnancy led to complications and morbidity and mortality in women.

Dr Carolyn Lam: Indeed. And it does just add so nicely to this issue, you know? Letting us know that we should watch out for the young women. We should watch out for the sedentary older women. And we should watch out for women with a history of pregnancy complications. But let’s switch tracks now. Sana, there was an amazing autopsy paper, actually, relating to sudden death in women. And as well as another original paper focusing on out of hospital cardiac arrest that is really very interesting. Would you like to tell us about those two?

Dr Sana Al-Khatib: Oh absolutely. I would love to. As someone who has devoted her life to the study of sudden cardiac death and you know, identifying factors, prevention. I really like that the paper looking at the risk of cardiac death in women and men. This study, Carolyn, was conducting in Finland, and the aim of the study was to determine autopsy findings and causes of death among women in a large population of sudden cardiac death.

                                They also were able to classify some EKG characteristics in men and women cardiac death victims. That really added helpful information. To do that, they systematically collected clinical and autopsy data from sudden cardiac death victims in Northern Finland between 1998 and 2017. So they actually had data on close to 5870 SCD victims. The findings were very interesting because they found that victims were significantly older than that. You know, so when they provided the median age it was 70 years for women versus 63 for men. So that was a significant difference there. And when they looked at the most frequently identified cause of death, they found that it was ischemic heart disease in both factions. Seventy two percent in women verses seventy six percent among men. And what was really striking about this was that the seventy two percent presence among women was higher than what had been reported in other theories.

                                They also reported that women were more likely to have lung ischemic cause of sudden cardiac death than men. It commented on the fact that primary myocardiac fibrosis was more likely to be found in woman victims rather than in men. And then they were able to identify some EKG factors stating that, in general, women were more likely to have a prior normal EKG than men. But that it increased the marker for sudden cardiac death with the presence of MDH with the polarization changes that were more commonly seen in women.

                                So, I thought that the findings were really interesting. They sure to be advance the field.

Dr Carolyn Lam: I couldn't agree more. Sex differences in sudden cardiac death. I don't think many people could tell you they knew much about it at all before this paper. And what about at a hospital cardiac arrest?

Dr Sana Al-Khatib: So, the other paper, which was really interesting, was a study that really looked at the public perception on why women receive less bystander CPR than men in out of hospital cardiac arrest. And this was an observation that was made a long time ago, Carolyn. So what's interesting for these investigators to be able to shed some light on this observation. What they did was they conducted a national survey of members of the public. And they were able to get 548 people to respond. Not a very high response rate, but pretty good for getting qualitative research studies. About fifty percent of the responders were women, so it was important to note that. And there was a good geographic distribution of the people; this was done in the U.S. And after they corrected their data, and they analyzed their data, the major thing emerged in terms of why the public perceived that women received less bystander CPR. The findings were really interesting.

                                The first finding was that people were concerned about being accused of sexual assault if they were to do CPR on the woman, which was interesting. Some actually were concerned that women were too weak or too frail. If they were to ever do CPR, might they cause any bone fractures, any injuries to the woman because they're more fragile, so to speak, than men. And their last theme was misperceptions about women in medical distress. What that meant was they felt that, well, you know, are women actually victims of sudden cardiac death? Yes, definitely, women can have sudden cardiac arrest and some people said, "Well, sometimes women can be overly dramatic and so maybe those presentations were not real presentations of sudden cardiac arrest," which I thought was really interesting.

                                I felt these were really interesting insights into why women don't receive CPR as much as men, and hopefully future interventions can be targeting these misconceptions or these concerns that the public has about doing CPR on women.

Dr Carolyn Lam: Isn't that so intriguing. The misconception that women are either too shy, too frail, or too dramatic. Oh my goodness. Anyway, that was all the original papers, which were fantastic. But I have to admit that one of the things that I love most about the Go Red for Women issues is that it talks about women in cardiology. And Biykem, you've always been such a huge mentor to me. And what I love about this issue is that there are a few papers, aren't there, that actually focus on the importance of this mentorship. Could you tell us about that?

Dr Biykem Bozkurt: It's a very important concept that I think is underlying a few papers in our issue. The first one is women in cardiology and perhaps the lack of increase in the representation of women in cardiology. Even though women make up about half of our medical graduates, among practicing cardiologists women comprise less than about twelve to fifteen percent of the population. That perhaps disparity hasn't changed in the last two decades. We tend to sometimes compare our profession to the surgical field, and I think gender inequality appears to be a little bit similar to general surgery and orthopedic.

                                But the paper by Ziman underlines the following: Even though our gender inequality is similar to the surgical field, to look at the temporal trends there has been a significant rise in female representation in general surgery. And actually, among medical trainees, about one third of the medical trainees, not fifty percent like us, one third of the medical trainees are in surgical fields after they go to medical school. But the female representation has been steadily increasing in the surgical fields; about three-fold out of cardiology. Whereas female representation cardiology has the main slot, so the surgical fields are doing a better job in either welcoming, supporting, and mentoring their female trainees than the cardiology field.

                                This is an important concept for us to recognize, and usually the disparity reasons are perceived to be gender and lifestyle and/or personal preferences. That doesn't appear to be the case. Perhaps the better role models and better mentorship could eliminate this disparity and this is underlined in the Olmein Mein paper by Ziman.

                                Another paper by Sharon Hunt also underlines this concept. She portrays the woman needed in cardiac transplantation from a historical and personal perspective, and underlines the following: We tend to have a large number of woman leaders in advance heart failure and cardiac transplantation. And part of this may be attributed to the fact that women have been part of the fabric, part of the readership, part of the group that has developed the field and has been practicing. And thus, there has not been a nation or incorporation of the women in the field. And thus, since they've been involved in the practice from the beginning, they have been seen as a natural partner. Even though cardiac transplantation is quite demanding, requires bedside presence, and hours which are usually used as a reason for women not to go into certain fields, such as interventional. In transplant, we don't seem to have that much disparity for women. Women tend to select this field on one of the reasons in Sharon Hunt's piece is identified as being part of the team from the beginning, and having good role models and mentors.

                                And finally, there is a research letter that identifies if the corresponding author is a female author. There is a large representation of co-authors. This is a very interesting finding by Ouyang stating that even though the female to male senior authorship rates have not been different over the years, if the senior author or the corresponding author is a female there tends to be a higher number of co-authors. This may suggest that female corresponding authors are able to mentor or include their partners or team members. Or vice versa, female co-authors may feel more invited and incorporated as a team. So, this paper also underlines that women in leadership positions connected to cardiology may serve as positive role models to recruit and retain talented junior female investigators.

Dr Carolyn Lam: Ah, indeed, indeed, indeed. So many topics that come close to my own heart. But Sana, among the numerous other papers here, we have two state of the art papers, two in-depth reviews, there are three frame of reference papers. Which one, or ones, stood out to you?

Dr San Al-Khatib: One important paper, Carolyn, you certainly mentioned is an online paper that was titled "Why are Young Black Women as High Risk for Cardiovascular Disease". I personally like this paper a lot because it highlights such an important issue that has great impact on public health. And sometimes the population of young black women may go unrecognized in terms of their risk of cardiovascular disease and what have you. So really the On My Mind paper tackles what are these things that are driving the worsening cardiovascular disease trends in this patient population. And what can we do about it? And they talk about how the awareness of heart disease and the leading cause of death among these women is actually more among black patients. And so, they talk about the need to really implement multi-level strategies to try to address this, raise awareness, identify disparities in care. They even also call for really investing in black women scientists.

                                And so, this was such a really good paper and I'm sure that the readers will enjoy it as much as I have.

Dr Carolyn Lam: Oh, thank you so much for that, Sana. That really, really makes for such a rich issue with such a lot of different papers. We're running out of time, so we don't even have the opportunity to really discuss, but I want to mention these so that the listeners will look out for them. Beyond the papers we've already discussed, we have state-of-the-art papers on cardiovascular care in women veterans and the management of cardiovascular disease in women with breast cancer. We even have two in-depth reviews. One on sex differences in advance heart failure therapies and a second on the role of breast arterial calcification in cardiovascular risk stratification in women. And finally, there's a research letter on the size of thoracic aortic aneurysms in women. So many papers, such a beautiful, beautiful issue. I just want to thank you both Sana and Biykem for leading this beautiful Go Red for Women issue.

                                Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                This program is copyright American Heart Association 2019.


Feb 11, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Dr Greg Hundley, director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Is income volatility a new cardiovascular risk factor? You have to stay tuned to hear all about that. But for now, join Greg and I over a nice little coffee chat, because we're picking up the journal right here and I'm going to tell you about our two top picks this week. Greg, you go.

Dr Greg Hundley:             Well my top picks, Carolyn, is really pertaining to senescence and senescent cardiomyocytes. Remember that? Senescence is a situation where there's a mismatch between energy demand and supply and so that facilitates the cells transitioning toward failure. They lose their ability to function. In other parts of the body, they lose their ability to divide.

                                                And these investigators assessed altered calcium transfer from sarcoplasmic reticulum to the mitochondria, because that's being casually linked to the pathophysiology of aging in heart failure. Because the advanced glycation end products or AGEs accumulate through life, the authors thought that maybe this intracellular glycation would be occurring in aged cardiomyocytes and their impact on the sarcoplasmic reticulum and mitochondria. So, their study, they investigated both mice and humans and the found that ryanodine receptor glycation was associated with more pronounced calcium leak in mice and also interfibrillar mitochondria directly exposed to sarcoplasmic calcium release from aging mice had increased calcium content, compared to those with younger ones.

                                                Now we're starting to implicate a mechanism by where senescence could be important in these mice. But of course, in Circulation in these wonderful basic science papers that we have, they also cover a translational human component. And what these group found is that there were higher levels of advanced glycation end products and reduced glyoxalase 1 activity present in left atrial appendages, from those patients that underwent surgery greater than 75-years-of-age, compared to individuals that were younger. And also, elderly patients exhibited hyper glycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity due to less respiring mitochondria.

Dr Carolyn Lam:                Wow Greg, that was a huge summary and how nice to link aging or senescence with AGE or advanced glycation end products. Seriously, that was new to me. Okay look, bring it home. What are the clinical implications?

Dr Greg Hundley:             What these investigators have done is now identified a previously unknown pathophysiological mechanism that may facilitate the transition from healthy, towards failing cardiomyocytes and the implication is that if you could disrupt that process, maybe you could halt the aging of cardiomyocytes. You got to be careful though I think with senescence, just as we know from the general literature. Senescence is a defense mechanism in cancer therapy, but it's a protagonist if you will, in aging. More to come in this field, but very exciting research.

                                                So Carolyn, tell me about your first paper.

Dr Carolyn Lam:                Happily, Greg. I'm going to take us to the cath lab and talk about functional assessment of epicardial coronary artery disease. This paper from Dr Koo and colleagues of Seoul National University Hospital, is the first to validate the physiological relevance and prognostic implication of all available novel resting pressure derived indices of coronary stenosis. This includes indices like resting full cycle ratio or RFR and diastolic pressure ratio or DPR, and they compared this to instantaneous wave free ratio or IFR and fractional flow ratio or FFR.

                                                What they looked at was more than a thousand vessels in 435 patients and showed that all the resting ... Just the resting. Not hyperemic but resting pressure divide indices, closely correlated with each other and showed excellent agreement and the same discriminatory ability for no FFR. All the indices also showed a similar pattern of changes to different anatomical and hemodynamic stenosis severity, regardless of the target vessels and importantly showed similar diagnostic performance for myocardial ischemia, defined by gold standard PET derived CFR and hyperemic myocardial blood flow.

                                                And finally, they showed that all these indices showed significant association with the two year vessel oriented composite clinical outcomes.

Dr Greg Hundley:             So, do we still need to do adenosine infusions in the cath lab?

Dr Carolyn Lam:                That's exactly what they're trying to drive at, because the major advantage of these resting indices, for example RFR over IFR, is that IFR doesn't require identification of a specific landmark or a specific time point during diastole. They may be simpler to perform and this first study showing their physiologic relevance and prognostic implication may enhance adoption of invasive physiologic assessment in daily clinical practice, which we know is important and a clinical benefit.

Dr Greg Hundley:             Excellent. I tell you, it would sure save time if we could use indices like that.

                                                Let me tell you about my next paper. This is from Renato Lopes, from Duke University Medical Center, in Durham. Also, one of your affiliates. In all of our cardiovascular/metabolic clinical trials today, cardiovascular death is a very important outcome. But what happens when, in doing a study like that and you have an undetermined cause of death, the US Food & Drug Administration Guidance indicates that deaths due to undetermined causes should be rare in well-run clinical trials.

                                                And so what this group did is they looked at 127,049 enrolled participants from nine trials and they looked at how deaths were adjudicated. And across nine clinical cardiovascular trials, in different therapeutic areas, the proportions of deaths adjudicated as related to undetermined cause ranged from 7-to-22% and overall, had an average of 16%. Interestingly, in multi-variable analysis, death due to undetermined cause, was associated with the therapeutic area and the year of publication of the study, and then also several patient factors including: gender, age, the region of enrollment, and time from enrollment to death.

Dr Carolyn Lam:                Gosh, this is so enlightening. Greg, having been on CECs and struggle with the adjudication, I really like this paper as well. But please, tell us all, why should we be concerned about this?

Dr Greg Hundley:             Great question, Carolyn. First we might think about, if you're reading a study, the proportion of deaths due to undetermined cause should really fall within this range. And have a mean of maybe 16%. Second, what if there are higher rates due to undetermined cause? Well, that may indicate there are issues with the trial quality. And then finally, researchers, whenever they're doing a study, should really report on the proportion of deaths where cause was unable to be determined.

                                                And there was a great editorialist, David Morrow, from Brigham and Women's Hospital, and really pointed out, you've got a couple factors here that lead to why there's undetermined cause of death. Maybe the documents are missing, or you're in a clinical situation where a subject lives alone, found dead, there's no autopsy. Uncertain duration. Sometimes there are limits on the study personnel; their ability to actually go out and acquire the data so that the team, like what you're on, can actually adjudicate the information. And a point that's made is really ... He used the word, doggedness, but with which he consistently worked toward and tried to get those medical records and pursue them, because that is very important.

                                                When we think, well what's the importance of a study like this? It's valuable to those that perform studies, because as we're working with our study coordinators, we need to make that information known to them. If we don't collect the exact cause of death in these important cardiovascular interventional studies, we may end up with an improper result. And also, for the investigative team. A really important study I think, providing guidance for the first time now about what we should expect in undetermined cause of death, when we're looking at cardiovascular trials.

Dr Carolyn Lam:                Indeed, and from talking about doing the trials to talking about a very important trial, I want to take you to The Partner 2 Trials and talk about the cost-effectiveness of Transcatheter Aortic Valve Replacement, or TAVR, compared to surgical aortic valve replacement, in patients at intermediate surgical risk.

                                                Now we already know that TAVR is cost-effective, although not cost-saving. But cost-effective compared to surgical aortic valve replacement in those at high surgical risk. But this paper refers to intermediate surgical risk. And the analysis is from Dr Cohen and colleagues from Saint Luke's Mid-America Heart Institute, and it's an analysis of the Partner 2A Randomized Trial and the SAPIEN 3 Intermediate Risk Registry.

                                                In summary, they found that TAVR was projected to lower total costs by $8,000.00 to $10,000.00. And to increase quality adjusted survival by 0.15 to 0.27 years, compared to surgical aortic valve replacement over a lifetime horizon.

Dr Greg Hundley:             Wow! Carolyn, I've got two questions for you. First of all, how does TAVR save those costs? And number two, was this true for everyone? Were there any caveats or special subgroups that this was really applied to?

Dr Carolyn Lam:                The cost savings in a TAVR cohort looked like they were driven by both a shorter length of stay during the index hospitalization, as well, as less resource utilization during follow-up. And that would be in the form of fewer hospital days, as well as fewer rehabilitation and skilled nursing facility days.

                                                As for the caveats, you see that the authors did acknowledge that the long-term durability of the valves involved like the SAPIEN XT and the SAPIEN 3 valves is still unknown, and so lifetime costs associated with TAVR, may be higher than we assumed, owing to the need of more frequent repeat valve procedures for example.

                                                Now if though, the long-term data demonstrate comparable late mortality with TAVR, and the surgical aortic valve replacement, these findings are really significant, because they suggest that TAVR may become the preferred treatment strategy for patient populations. Not only based on clinical outcomes, but even based on economic considerations.

Dr Greg Hundley:             It looks like that long-term information is going to be really critical here, so we'll look for more in this area.

Dr Carolyn Lam:                For sure. Wish we could keep chatting, but I think we need to move to the featured discussion.

Dr Greg Hundley:             And now to the very fun segment of our discussion this week at Circulation on the Run. This is Greg Hundley, from VCU Health. Director of The Pauley Heart Center. And today we have a fantastic paper from Adina Zeki Al Hazzouri from Miami, transitioning to Columbia University. And also, our Associate Editor, Dharam Kumbhani from the University of Texas, Southwestern.

                                                Today's paper, Adina is going to discuss is, Associations of Income Volatility with Incident Cardiovascular Disease and All-Cause Mortality in a US Cohort. And what she's done is worked with the Coronary Artery Risk Development in Young Adult Study, we also know that as, CARDIA. And it's really a prospective cohort conducted in urban centers, in Birmingham, Alabama, Chicago, Illinois, Minneapolis, Minnesota, and Oakland, California. The goal here was to asses a block of individuals, younger, aged 23-35 years, identified in the time window of 1990-to-2005 and then followed subsequently to look at income volatility.

                                                Adina, we're so excited to have you here. And can you tell us a little bit more about your study.

Dr Adina Zeki Al Hazzouri: Sure, the motivation for the study is the fact that we know that income volatility is on the rise. And what I mean by, income volatility, is the sudden and unpredictable change in income. And in the health researcher, we actually do not know as much, what is the effect or the influence of income volatility on health outcomes, and it is really common, most of us do experience these sudden or unpredictable changes in income. Whether they're little dips or little jumps in income. So they are really common, and I think it's really important to try to understand what would be their effect on health outcomes.

                                                We were really interested in specifically understanding their effect on all-cause mortality and incidents of cardiovascular disease events, so we took advantage of an ongoing perspective cohort study. The cardio study that you just mentioned. And what is really nice about this study is they were really relatively young back in 1990 when we first had the measure of income. They were between ages 23-and-35. And they were followed for over 20-years, so we had repeatedly over 10-years, or 15-years, repeated measures of income. And then we were able then to look in the subsequent 10-years for incident events, cardiovascular events and all-cause mortality, and what is also interesting in this study is that these individuals, given that their age range, so that they are in the peak of their working years, which makes it even more interesting in terms of applicability and inference of those findings that we're making in this study.

                                                We looked at, as I said, income volatility and we defined it basically as what is the standard deviation of these percent changes in income that you experience between the different visits in the study, which were on average, five years apart. And once we defined that, then we looked at it with outcome and what we really found was that those who experienced high volatility had around a two-fold increased risk of cardiovascular disease, as well as all-cause mortality.

                                                We also looked at another measure of income volatility which is the number of income drops, so how many times you've dropped significantly, which we defined as a drop of more than 25%. And that is lower than your average income throughout the study period. And we found similar results.

Dr Greg Hundley:             Adina, what could be the cause of this? What do you think as an investigative group, is the mechanism behind this finding?

Dr Adina Zeki Al Hazzouri: There could be various mechanisms playing roles here. Stress is obviously one of the important mechanisms. If you think about the instability of income, that instability in income could result in daily stresses, maybe inability to pay for bills. Also, that resulting in inflammation in all the stress pathway.

                                                Also, you could think potentially having this instability could also maybe hinder access to care, maybe coping mechanisms related to stress could alter adherence to treatment. Whether maybe someone has to take daily medications, having those dips or changes, sudden changes in income, could alter your adherence to those medications and then subsequently influence your risk for cardiovascular disease.

                                                Also, you could think access to health insurance. The social support, though it's not very well evidenced, but maybe if you've had always stable income, or low income, you're more likely to have more resilience. However, when you have these unpredictable changes, or sudden changes in income, you may not have that coping mechanism or support ready for you to deal with those sudden changes.

                                                These are some of the pathways that we think of that could potentially be playing a key role here.

Dr Greg Hundley:             Very good. Now let's turn to Dharam, our Associate Editor, from University Texas, Southwestern. Dharam, boy, surprising findings. A young cohort. I mean, they were 23-to-35 and in the next 10-years of their life they start to experience hard cardiovascular events. I mean, fatal and non-fatal myocardial infarction, and also, all-cause mortality. How do you put this in perspective, related to the workforce, and what do you think this means for this young population moving forward?

Dr Dharam Kumbhani:   At the outset we obviously want to congratulate Adina and her group, for this really, very interesting study in cardiovascular EPY and broadly intersects in health economics and health policy, as well for obvious reasons.

                                                Very interesting construct as you pointed out and what does this mean for younger subjects who experience these income volatility very early in their life. I think, just like any other EPY study, I think the perspective is helpful, because although the hazard ratio for these income volatility is two or higher, the absolute incidents rates are, again putting that in perspective is important, and so the absolute incident rates for example is somewhere between two-to-five, per 1,000 persons. So overall that impact, that's just helpful to understand what effects this would have.

                                                Hopefully, that helps. But obviously, very interesting analysis and brings up a lot of questions. I think one thing I may add to what was just mentioned is ... And this was highlighted very nicely by the editorialist, Dr Spatz, and her colleague from Yale. About how this is globally in the financial toxicity space, and there are a number of these indicators that are now being carefully studied like in this study, such as wealth shock and as I said, financial toxicity. And how they actually have an impact on cardiovascular outcomes.

                                                One of the feelings when you read a paper like this or when you read studies like this, and in fact this was one of our initial concerns as well, is to what extent you may have a component, or significant component of reverse causality. Your, "Patients who are sicker in some way," or have those culpabilities, be the ones that have these events is their relationship with other socio-economic indicators such as employment and how that would affect income volatility as well.

                                                I think the authors have done a really terrific job responding to that. And again, it shows an association obviously we know that, that doesn't imply that it's cause[owed], but it's a very interesting association. And that it's helpful to speculate both on the mechanisms, which were just outlined, and also what this means from a health policy standpoint. What that would mean for researchers in the cardiology community, or policy makers, things like that. So I think this is a very nice analysis and definitely brings up a lot of discussion points.

Dr Greg Hundley:             And a very important paper on multiple fronts. One, we've identified an issue in young, healthy individuals that could significantly contribute to adverse cardiovascular events. And then number two, I really liked your point on how this could impact public health policy, and maybe even how we need to think about reducing stress and how we design aspects of the workforce moving forward, so individuals don't suffer from these conditions.

                                                I want to thank, Adina Zeki Al Hazzouri, from Columbia. And our Associate Editor, Dharam Kumbhani, for these excellent comments. We look forward to seeing you next week.

Dr Carolyn Lam:                This program is copyright, American Heart Association, 2019.


Feb 4, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, from National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor for circulation from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam:                What does cardiac autoimmunity, glycemic control, and cardiovascular disease risk and Type I diabetes have in common? Well, you've got to wait for our feature discussion. This one's such a hot one, don't you agree, Greg? We could hardly finish talking.

Dr Greg Hundley:             Absolutely, and Myra, you're just going to love listening to her.

Dr Carolyn Lam:                Yep, but stay tuned. First, we're going to discuss a couple of papers each. Greg.

Dr Greg Hundley:             Thanks Carolyn. So, the first paper I've got is from Professor Van Rein at Leiden University Medical Center. And basically he's getting at the issue of bleeding in patients with atrial fibrillation. So this is a retrospective cohort that evaluates different anticoagulation strategies for atrial fibrillation. They examined 272,315 patients that had a median age of 75 years and followed them longitudinally over time. These individuals experience 31,459 major bleeding events, and what he did is he evaluated whether they were not taking anticoagulant therapy, whether they were on a vitamin K antagonist, a DOAC, antiplatelet therapies, and then all combinations of the above, including single, double and triple therapy.

                                                What he observed is relative to taking a vitamin K antagonist alone. The hazard ratios range from 1.13 to 3.73 in those that were receiving dual antiplatelet therapy of vitamin K antagonist plus antiplatelet therapy, a DOAC plus antiplatelet therapy, and then of course triple therapy, which had that highest hazard ratio.

Dr Carolyn Lam:                But were there particular combinations within these groups that had particularly high bleeding risk?

Dr Greg Hundley:             Well, yeah, Carolyn. As we might expect, triple therapy was the worst, but those that were receiving triple therapy, there were two subgroups that were particularly susceptible to having a bleeding episode. First, those that were greater than 90 years of age, and second, those that had CHADS-VASc 2 scores greater than six. Of course, these are very complicated patients, often particularly that latter group. So there are clinical implications. I mean, clearly, this isn't a randomized trial, but what we should take away from this is that if we have one of those two patient groups, age greater than 90, CHADS-VASc score greater than six, that we ought to minimize the time that those individuals are on that triple therapy.

Dr Carolyn Lam:                Talk about and bleeding, I've got a paper, and it's on the performance of the ABC scores for assessing the risk of stroke and systemic embolism or bleeding in patients with atrial fibrillation. This is a study that actually looked at the performance of these scores in an external cohort, which actually hasn't really been done. Now, as a reminder, the ABC score is actually the age biomarker clinical history stroke score, which helps to estimate the risk of stroke or systemic embolism. The ABC bleeding risk score incorporates biomarkers along with the clinical variables to estimate the risk of bleeding.

                                                All of these were tested in the ENGAGE AF-TIMI 48 trial, which was that multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS-VASc 2 score of two and above. Now, this was from Dr Morrow and the TIMI study group in the Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts. Basically what they found was that the ABC stroke and ABC bleeding risk scores performed well in stratifying the risk for stroke or systemic embolic events or major bleeding in this multinational trial.

                                                Compared to the CHADS-VASc score, the ABC stroke score provided both correct upward and downward reclassification of the stroke systemic embolism risk. Compared with the HAS-BLED score, the ABC bleeding score resulted in a predominantly correct downward reclassification of the bleeding risk.

Dr Greg Hundley:             So, this new ABC score, do we integrate it with HAS-BLED? Do we integrate it with CHADS-VASc 2? How do we use this clinically?

Dr Carolyn Lam:                So first of all, there are some important remaining unanswered questions, and this was really nicely discussed in an accompanying editorial by Dr Hylek from Boston University School of Medicine. Among this, first of all, the ABC scores need to be validated in patients outside of a clinical trial. Remember, this was a clinical trial cohort. Then there are questions about the timing of measurements of the score, the different settings, hospital and otherwise. Do these scores perform equally well across different vascular beds and in diverse patient populations at the same thresholds used?

                                                So, all these things still need to be addressed. And really, in Dr Hylek's words, the work has just begun.

Dr Greg Hundley:             This is an issue with the theme that might be bleeding, and I'm going to talk about a study from Professor Huisman from Leiden University again, and this is the RE-VERSE AD study. Again, patients that are receiving dabigatran and that may have a GI bleed or patients that are on this therapy and unexpectedly need an emergent surgical procedure, this investigative team evaluated the utility of idarucizumab on reversing that anticoagulant dabigatran. So what did they do? They administered 2.5 milligrams of idarucizumab twice separated by 15 minutes.

                                                And again, the study population was uncontrolled GI bleeding or those in need of an emergent procedure. The types of GI bleeds that were involved in this study, a third were upper GI bleeds, a third lower, and then a third, it was either unknown, or there was a mixture of both upper GI or lower GI bleeding. So how do we know that dabigatran is effective? We use a DTT time, and 98% of those with an elevated diluted thrombin time had that reduced after receiving these two twin 2.5 milligram doses at a time point of four hours after administration.

Dr Carolyn Lam:                Okay, but were there any complications?

Dr Greg Hundley:             Yeah, there were. So first of all, something to think about is that this is a high-risk group. In this study, 14.6% of the cohort actually later died either from the bleeding or what have you. Then another thing we need to be thinking about is when we reversed this anticoagulant, do patients experience thrombotic events? So what this group reported is 4.4% did within 30 days. What were those? Myocardial infarction, deep venous thrombosis, and subsequent PE. Then also at the 30-day time point, one patient experienced an ischemic event.

                                                Another question is once you've administered this, you've gone through the procedure. You stopped the GI bleeding, or you've had the surgery. In this particular study, 66% of those individuals had restarted their DOAC. Those events occurred on top of that. So, interesting information. Looking at administration of idarucizumab, and we'll be using this I think frequently as DOACs are used more frequently in the population, particularly dabigatran, so some important data in guiding us on what we might expect when we administer this therapy.

Dr Carolyn Lam:                I think going back to atrial fibrillation though, this is my other selected paper, and it's actually results from the GARFIELD-AF Registry. It's from Dr Bassand from University of Besançon in France, and colleagues, and basically, they looked at the early risks of death, stroke, systemic embolism and major bleeding in patients with newly diagnosed atrial fibrillation in the GARFIELD-AF Registry. They basically found that the rates of all three major clinical events was significantly higher during the first month than in the subsequent period set following up to 12 months.

                                                The leading causes of early death were heart failure, sudden death, acute coronary syndromes, infection or sepsis, and respiratory failure.

Dr Greg Hundley:             So, what's the take-home message here?

Dr Carolyn Lam:                This is observational, so the key thing to understand here, it's a registry. It's observational. We can't really tell chicken from egg with regards to its newly diagnosed AF verses events, which comes first, which causes what. But nonetheless, the increased hazards of an early event and especially cardiovascular mortality in these newly diagnosed AF patients really point to the importance of comprehensive care for such patients and really should alert physicians to detect warning signs of possible early mortality in these newly diagnosed patients.

Dr Greg Hundley:             Very good, Carolyn.

Dr Carolyn Lam:                I think that wraps it up. Let's hop to our feature discussion, shall we? I'm so super excited about today's feature paper because it may explain that strong link between hyperglycemia and cardiovascular disease in type one diabetes and all by revealing a potential novel pathway that may have been hiding in plain sight. And yes, I'm stealing the words of editorialists and our associate editor, Dr Naveed Sattar from University of Glasgow, and we're all so pleased to have with us the corresponding author of today's feature paper, Dr Myra Lipes from Joslin Diabetes Center in Boston, Massachusetts. Myra, start us off by telling us a little bit about your study please.

Dr Myra Lipes:                   Sure. So we were interested in examining the role of whether chronic hyperglycemia could trigger cardiac autoimmunity in type one diabetes, because chronic hyperglycemia is associated with subclinical myocardial damage, and we had actually previously observed just unexpectedly in a young adult cohort that ... Actually from Italy, where unexpectedly, we noticed that patients with the poorest glycemic control expressed cardiac antibodies. There's a lot of interesting people who are autoimmune-proned may overreact to injury of certain tissues.

                                                So, type one diabetes, it's a classical autoimmune disorder. So we examined, really tested this hypothesis, in stored samples from the DCCT/EDIC study, and this is a very landmark study where patients were randomized to tight glycemic control, intensive glycemic control. Then another group had just conventional control, and this was done over an average of six and a half years. So during this time, the samples were stored. Every year samples were stored from participants, and this was quite a rich data set that is publicly available. So we studied the development of autoimmunity in two groups that had very distinct separations of the A1C level.

                                                We specifically excluded people who developed kidney disease or cardiovascular disease events during the study. So this is a cohort that had relatively recent onset type one diabetes. They're relatively healthy, and again, groups were matched with cardiovascular risk factors at the beginning and the end of this DCCT period. And of course with our studies, we've also looked genetically because your HLA immune response genes can influence susceptibility to autoimmunity.

                                                These patients were actually matched in HLA genotypes. So what we found was that patients with poor glycemic control, there was expression over time. You could see a time course relationship between expression of antibodies over time on the levels of the antibodies that were different in the two A1C groups. The number of antibodies were different in that with the high group expressing more antibodies, more different types of antibodies. These are antibodies ... might say antibodies as like proteins in the blood, and they're actually directed against parts of the myocytes, the myofibrillar complex, and a major target is cardiac myosin heavy chain.

                                                We saw the different parts of the myosin heavy chain retarded, and the presence of two or more antibodies, different types of antibodies, different regions of the myosin to different isoforms. Also, we saw antibodies, the troponin, troponin I. So the number of antibodies with different ... with almost a complete absence of antibodies in a tightly controlled group. I might mention the A1C average was 6.5%, so this is a very tightly controlled group whereas the poorly controlled group is at the opposite extreme, the average A1C during DCCT. The mean updated A1C was about 10%.

                                                So, it was a very clean group, two different groups, and we could see that the number of the types, the number over time, very different in the two groups. In fact the profiles of these antibodies were almost very similar to patients with Chagas cardiomyopathy. That was our positive control group. Chagas cardiomyopathy is possibility to be a form of chronic myocarditis directed against cardiac myosin. So the profiles are almost indistinguishable. So on one hand, you have relatively healthy patients with type one before glycemic control, and that was very unexpected that this would look pretty similar.

                                                But very interestingly, and I might say unexpectedly, we saw ... It was very clear that the people with the highest titers of antibody and the most different types of antibodies, particularly two or more, were subsequently ... We noticed that those patients were at high risk for developing CVD events. And that's while the number of events was slow, we noticed that all the patients, some 60%, had two or more antibodies and developed cardiovascular events. Perhaps one more striking example is a single patient in the study could die of cardiovascular death, had a positivity for all five antibodies at highest titer.

                                                Then we looked at coronary calcification just to measure subclinical atherosclerosis. We noticed that the same numbers, two or more, and also the same antibody specificities that were the highest predictors of CVD events were also predictive of coronary ... had detectable coronary calcification. In addition, we looked at the levels trying to find mechanistically what could explain the link between cardiac autoimmunity and an increased risk for atherosclerosis. We looked at CRP, high sensitivity CRP levels.

                                                Again, these were measured about a decade after the antibody samples were obtained, and we saw that the positivity for multiple antibodies was also associated with markedly elevated ... subsequently elevated high sensitivity CRP levels with levels of six versus something like 1.4 in a group with one or less antibody. So these were very intriguing findings, suggesting a role for autoimmune pathways as a susceptibility to cardiovascular disease in type one diabetes.

Dr Greg Hundley:             Myra, that was absolutely incredible description of the study and all the particulars of the findings. I wonder if I could ask both you and Naveed, where do you see the next steps moving forward with this research in the future? Number one. And number two, is this in any way can be used to segregate patients that may need, for example, really aggressive glucose control with an insulin pump or something of that nature?

Naveed Sattar:                  I think we left this study as beautifully described as you see by Dr Lipes. I think the context ... We looked at this from editorial perspective ... is that most people don't realize if you have a middle-aged person with type one, their hazard ratio for cardiovascular risk is about somewhere between four to six fold for men and women respectively, which is much higher than type two. It's often thought that it's the area under the curve for hyperglycemia. But what this paper throws up is actually maybe there's another pathway, which we just didn't understand that this wasn't a permanent autoimmunity closing subclinical myocardial disease and inflammations.

                                                But potentially, for me though, there's a saying in British that one swallow does not make a summer. So, it would be nice for other groups to replicate this. I think the findings are, as they stand in isolation, fantastically well done. But it would be lovely if other groups had accessible samples, and I knew of several groups that have up towards tens of thousands of samples, maybe even not 10,000. Certainly 10,000 or so plus or minus samples for type and prospective outcomes to potentially validate the findings and extend them.

                                                And really, if the antibodies do help protect people at higher risk in a meaningful way and improve beyond what we can already do, then you're right. Absolutely. If we can pick up early people who are going to have substantially higher risk, you would want to potentially improve glycemic control, potentially pumps, CGM, closed-loop systems or more intensive statins or lower blood pressure targets or other types of antihyperglycemic agents, which seem to be being tested in type one as well. So that's really one example.

                                                And for me, the other thing would be really nice is to pull up any inflammation. Is this high systemic inflammation? Is it IL-6 level? Is it something else? What about troponin and BNP levels, et cetera. I'd be interested to hear what Dr Lipes thinks and how do you think to take it forward as well.

Dr Myra Lipes:                   So, this is something Dr Sattar said and I completely agree. Actually, right now, we're looking at the DCCT cohort as a whole for already. It's relatively small compared to the population-based studies. But there's 1,400 patients, and the subjects had CMR studies that were published in Circulation. So we're going to actually study next whether we see CMR evidence of systolic dysfunction and looking at the broader DCCT cohort. So, those studies are underway. But of course the ultimate test would be looking at if there were samples available from the Swedish NDRs, Scottish registry.

                                                I think it's something that's not often done prospectively. So that would be incredibly exciting, and that's the important thing. I'd say with type one diabetes, for screening for type one diabetes, the use of autoantibodies and particularly two or more different types of islet autoantibodies, and this is just putting things in a broader context, is the entry criteria for type one diabetes prevention trials and something cardiologists wouldn't be aware of but this particular thing. So in decades, people, researchers, in the field has spent decades optimizing islet antibody assays.

                                                So by analogy, it would be really important to standardize assays so that they can be done in Sweden and Scotland and so that other groups could confirm this, and I'm confident that this could be done, since the setting up of our assays was really built on the experience of people of developing standardized assays and rigorous cutoff points for antibody positivity. So it would be really important to work internationally to try to tap into this.

Dr Carolyn Lam:                Oh, my goodness. Myra, Naveed, these are such insightful comments. I think as Greg said earlier, I think we could go on forever discussing this paper, but I'm so sorry. Our time is up. Before we go though, I must point all readers to look at figure five of this marvelous paper. It puts together the whole schema of how autoantibodies can play a role both in myocardial and atherosclerotic cardiovascular disease and type one diabetes.

                                                Thank you so much. Greg and I loved having you. Listeners, don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Jan 28, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts of Circulation on the Run. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I am Greg Hundley, also associate editor from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam:                So, have you ever wondered in patients with atrial fibrillation and stable coronary artery disease beyond a year of coronary stenting, can you safely just continue on oral anticoagulation without antiplatelet therapy? Well, if you've ever wondered that ... I sure have. I'm sure you have too, Greg. Our feature paper this week does discuss this, so you have to stay tuned. But for now, Greg, what are your picks from this week's issue?

Dr Greg Hundley:             I've got a couple to discuss. The first is Patrick Hsieh from Taipei, Taiwan, and really is evaluating the gut microbiota and how that affects cardiac repair after myocardial infarction. I mean, who would've thought to chase an idea like this? But what this investigative team did is they had mice, so this was a basic science experiment, and they treated them seven days prior to ligation of their left anterior descending artery that would induce a myocardial infarction. They treated them seven days prior with ampicillin, metronidazole, neomycin, and vancomycin. What were they trying to do? Totally obliterate any bacterial load within their GI system. Then, they ligated that coronary artery, and at 21 days, they looked at histopathologically what was happening.

                                                And you know what they found? Those where they wiped out the bacterial load, they had increased cardiovascular events. And importantly, myocardial rupture was very high in this group of mice. Also those mice, they had reduced heart rate, and mechanistically what had occurred is there was a reduction in our immune monocytes that were trying to infiltrate the peri-infarct. They weren't there. They were not in those peri-infarct zones. And so, the thought here is that removal of the favorable microbiota in the gut can actually be harmful in the setting of myocardial infarction.

Dr Carolyn Lam:                Fascinating. So, microbiome as our pals. But wait a minute. I mean, how can you say it's from elimination of the microbiome versus some kind of effect of the antibiotics itself?

Dr Greg Hundley:             Yeah, that's a great question, Carolyn. The way they did this is they took another group of animals, and they supplemented them with lactobacillus probiotic, like the stuff we get in the grocery store. And those animals, they did not suffer any of the adverse cardiovascular effects. So, it really points to an important role of our gut microbiota. You know, and what do they do? They basically ferment these carbohydrates that we ingest, and produce short chain fatty acids that are a substrate for these mononuclear cells to help infiltrate those infarct zones. So, really exciting basic science question that this group examined.

Dr Carolyn Lam:                I love that you picked a basic science paper, and I love that you made even me understand it so well. Okay, but what I have is a clinical trial. So, it's the REDUCE-MVI trial, which is the first randomized trial comparing maintenance treatment with ticagrelor or prasugrel after a primary PCI. So, this is from Dr van Royen and colleagues. They're from Radboud University Medical Center in the Netherlands. Basically, they figured that despite successful restoration of epicardial vessel patency with primary PCI, coronary microvascular injury does occur in a large proportion of STEMI patients, and of course, adversely affects outcomes. Now, ticagrelor has been reported to increase plasma adenosine levels, which may have a protective effect on the microcirculation. So, the authors randomize 110 STEMI patients following revascularization to maintenance therapy with ticagrelor versus prasugrel, with the primary outcome being microvascular injury at one month as determined by the index of microcirculatory resistance in the infarct related artery.

                                                What they found was that there was no difference in the extent of microvascular injury and in the extent of infarct size by cardiac MRI at one month after the primary PCI. The attributed pleiotropic benefits of ticagrelor through the adenosine metabolism pathway actually could not be confirmed in the STEMI population, as plasma adenosine levels were actually not increased in the patients treated with ticagrelor.

Dr Greg Hundley:             So, what does this mean for the use of adenosine and its role?

Dr Carolyn Lam:                I suppose you're also asking, you know, is the adenosine hypothesis really out here? This is a study that really suggests we have to question it, but there are some limitations that we perhaps should keep in mind when we think about this. So first, before primary PCI, all patients were loaded with ticagrelor because this was standard of care in the participating centers. That, of course, could have modified microvascular injury already at the index event. Now, a second important thing is that the study may have been underpowered. There was a greater than anticipated variability in that primary outcome of index on microcirculatory resistance.

                                                The relatively low rates of risk factors, the small infarct size, the preserved ejection fraction could all have influenced this IMR values, as well as the potential effects of the pharmacological intervention. And furthermore, the natural recovery of microvascular dysfunction over time may have diluted the positive effects. And of course, selection bias is inevitable in a trial. And so, you know, although this really questions the adenosine hypothesis, there are still caveats to these results.

Dr Greg Hundley:             Very good. So, Carolyn, I've got another study to sort of go over, and this is from Dan Modin from the University of Copenhagen. And it's really addressing this issue. We all in the fall, do we all get our flu shots? And could that be helpful in patients with heart failure? You know, the ACC, the AHA, and the ESC all suggest flu shots, but there's actually no guideline to recommend. So, what did these investigators do? They looked in Denmark, and from the period of January of 2003 to June of 2015, they identified 134,048 subjects. And they looked at the vaccination status for those with a diagnosis of heart failure that were greater than 18 years in age. 55% percent of these were men. And then, they also looked at ICD-10 codes for cardiovascular events.

                                                Now, they examine the dates of when you had your vaccination, how frequently, what were your comorbidities cardiovascular-wise, medication use, etc. And what they observed is that those individuals that had more than one vaccination ... So, basically annual vaccinations for a three year period, they had an 18% reduction in all death, and a 19% reduction in cardiovascular death.

Dr Carolyn Lam:                So, is this all heart failure patients? Are there specific subgroups that we should be targeting?

Dr Greg Hundley:             At our institution, they really get on us. If we don't have our flu shots in September, I mean, they threaten to withhold everything, or maybe October. Well, interesting that you asked that question. Those individuals that had flu shots in the September to October window did much better than those individuals that had their vaccination November, December, or actually later in January. And the second group that benefited were the individuals that actually had annual vaccinations. So, if periodically you say, "Oh, I'm going to get it this year, but then I'm not going to get it two years from now." Not so good. It was those individuals that had those vaccinations annually.

Dr Carolyn Lam:                You know, Greg, it's making me question too, because here I am in a tropical island. We actually don't have seasons. So, what does that mean for us? That's one thing. And then, do we need even randomized trials now?

Dr Greg Hundley:             Yeah, I think you're right there, Carolyn, because first of all, you know the investigators targeted this because 50% of heart failure exacerbations are actually triggered by some sort of respiratory infection. So, that was kind of the thought behind this. But we do have to be careful about looking at this longitudinal data and making predictions or developing guidelines. A couple of reasons why. It could be that those that come in for annual vaccinations at the time points, well, maybe they also come in for more frequent heart failure visits with their doctor. So, it's not cause and effect.

                                                And in fact, there was another study, Get with the Guidelines heart failure study, and it actually showed no association. So, more work really needs to be done in this area. And just to point out quickly, there is a current randomized trial going on called Invested, and it's looking at different types of vaccinations, trivalent versus quadrivalent. They're underway in those with heart failure. And so, there's a lot more work in this area. But it was interesting getting it that old "get your flu shot," and it looks like at least longitudinally in cohort studies could be beneficial. And if you are going to do it, do it every year and get that September, October. So, Carolyn, what about your next paper?

Dr Carolyn Lam:                So, Greg, my second paper is another trial. It's the radio sound hypertension trial, this time focusing on renal denervation. In fact, it's the first trial to compare three different techniques and technologies for catheter-based renal denervation. It's from Dr Lurz from Heart Center Leipzig in Germany. And what they did is, they randomized 120 patients with resistant hypertension to three arms. Either one, radiofrequency, renal denervation of the main renal arteries. Two, radiofrequency renal denervation of the main renal arteries and the side branches and accessories. Or three, an endovascular ultrasound-based renal denervation of the main renal artery. The primary endpoint was change in systolic daytime ambulatory blood pressure at three months. In the end, endovascular ultrasound-based renal denervation was the winner over radiofrequency ablation of the main arteries, with or without ablation of the side branches.

Dr Greg Hundley:             Carolyn, does this mean that renal denervation is coming back? Are we going to actually start thinking about this as a viable option to treat those with longstanding hypertension?

Dr Carolyn Lam:                Greg, this was exactly addressed by an editorialist, Dr Ram from UT Southwestern and Apollo Hospitals and Apollo Medical College in India. Beautiful editorial. Basically, even with the publication of these new data, it is difficult to predict whether renal denervation is firmly back on track. You see, some caveats should be mentioned, including that in this trial, only patients with large renal arteries were chosen for this study. And patient enrollment was rather selective.

                                                For example, out of 1,884 patients screened, only 120 patients met the inclusion criteria. And then, importantly, in a few patients, the reduction in systolic blood pressure was really impressive, close to 40 millimeters mercury. But the majority of responders had a more modest effect, and in about 30%, there was no change in blood pressure.

                                                So, one of the ultimate things we need to learn to do is to identify the so-called hyper-responders from the non-responders. So, lots more work needs to be done in renal denervation.

                                                That brings us to a close of our little chat. Can't wait for our feature discussion coming right up.

                                                Our feature paper today deals with a very important topic in a very frequently encountered group of patients. And they're the ones with concomitant stable coronary artery disease and atrial fibrillation. You see, these are patients at high risk of both ischemic and bleeding events, and therefore, it's critical to identify the right antithrombotic regimen with the optimal benefit ratio, since this is going to be lifelong therapy. Now, interestingly, despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation with and without antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond one year of coronary stenting. I mean, Greg, I didn't even realize that we didn't have a randomized control trial. Did you?

Dr Greg Hundley:             Absolutely, Carolyn. And, you know, this is an important issue, because we have a lot of patients coming to the cath lab that have atrial fibrillation, and what is going to be the recommended anticoagulant and antiplatelet combination? And so, it's really time for a randomized trial.

Dr Carolyn Lam:                I know, and luckily for us, that's exactly what this issue's feature paper does. And I'm so pleased to welcome to the show Dr Satoshi Shizuta from Kyoto University Graduate School of Medicine, Japan, as well as associate editor Dr Shinya Goto from Tokai University in Japan. We're so proud to be publishing the OAC-ALONE trial, even though we understand it was a difficult trial. Tell us, what were the results?

Dr Satoshi Shizuta:           As you know, the results were somewhat inconclusive because of pretty much a combination of patient enrollment. Initially, we scheduled to enroll 2,000 patients during 12 months, but patient enrollment speed was extremely slow, much slower than expected. So, we extended the patient enrollment period from 12 months to 38 months. But finally, we could only enroll 696 patients, about one-third of the initially planned patients. The result was around 50% rate of primary end point during 2.5 years of follow up. And the hazard ratio of [inaudible 00:15:01] strategy, as compared with OAC plus APT was 1.16 with a 95 confidence interval of 0.79 to 1.72.

                                                So, in conclusion, our study failed to establish no inferiority of OAC-ALONE to combination therapy of OAC plus antiplatelet therapy in patients with AF and stable coronary artery disease beyond one year after stenting in terms of primary endpoint of death, MI, or stroke. So, this study was underpowered and inconclusive. So, future larger studies require to establish the optimal antithrombotic regimen in this same patient population.

Dr Carolyn Lam:                Thanks so much. Shinya, you've been thinking about this, too, and the performance of such a difficult trial. Did you have anything to add or to ask?

Dr Shinya Goto:                So, first of all, I would to congratulate Satoshi and the group. They have completed a very interesting randomizing trial. As Greg mentioned, there is two kind of patient who lead to coronary artery disease and atrial fibrillation, especially after, you know, one year after stenting. So, taking a look at coronary artery disease with atrial fibrillation, we don't have the established standard of care yet. So, Satoshi know, it is a long-time study. So, I understand the rich colored nature of the patient in this kind of trial. So, what is the most difficult point increased to encourage the patient in this long-term trial?

Dr Satoshi Shizuta:           We think that difficulty reflects substantial reluctance of most cardiologists to withdraw antiplatelet therapy, single antiplatelet therapy from stented patients, even the patients treated with oral anticoagulation for atrial fibrillation. So, that is the most important point.

Dr Shinya Goto:                You have already showed in this paper myocardial infarction recurrence of stents thrombosis. Not a huge problem in this kind of patient population, you know? Stroke is a bigger problem, mortality, not including cardiovascular is also the problem. So, you have suggested, you have a strong kind of mind, is it? And single antiplatelet therapy necessary after stenting. Your results are underpowered but still suggest how always you know would be enough in stable CAD patients with atrial fibrillation.

                                                I would congratulate you again.

Dr Satoshi Shizuta:           Thank you.

Dr Greg Hundley:             Satoshi, I have a quick question. So, in the randomization process, how can you achieve the physicians managing the patients to administer the anticoagulant therapy to guideline levels, particularly when they are also prescribed antiplatelet therapy? I noticed that in the editorial on this manuscript that was a concern, and suggesting that in future studies that the therapy really be defined, and not so much open label administration at the discretion of the prescribing physician. What are your thoughts on that?

Dr Satoshi Shizuta:           I agree with you, but in this kind of study, randomizing whether or not to withdraw a drug is very difficult to conduct. Financial support is limited, and in such situation, double blind placebo controlled trial is very difficult to conduct. As you know, several years ago, a loose trial was published in the Lancet. And also in the loose trial, the study design was open level, and also in the PCI and [inaudible 00:19:48], I think the study design was not blinded but open. In this paper figure two, our control level was set as a dependent based on the Japanese guidelines. In the Japanese guidelines, target IR was set as 1.6 to 2.6, a little bit lower than Western golden standard for elderly patients older than 50 years. And same 2.0 to 3.0 in patients younger than 70 years.

                                                And in that criteria, as you can see, if you get 2A of paper, the therapeutic range was extremely high. 76% in the OAC-ALONE group, and also 73% in the OAC plus APD group. We can clearly understand that the intensity of oral anticoagulation was different between the two groups. Most of the OAC-ALONE group, OAC was controlled with ionine level higher than 2.0. On the other hand, in the OAC plus APD group, the ionine level was mostly controlled between 1.6 to 2.2 or .5 or so. So, this is a great big limitation of the study. But even in this limitation, the bleeding events, there was numerical excess in the OAC plus APD group. And, regarding the TEMI major bleeding, there was a trend toward increased major bleeding in the OAC plus APD group. If the intensity of OAC was the same, of course, I am convinced that even in this underpowered sample five, the major bleeding will be statistically higher in the OAC plus APD group.

Dr Carolyn Lam:                Thank you so much Satoshi for really taking us under the hood, and showing us all the myriad of considerations that occurred to perform this trial.

                                                This is Greg and Carolyn. Thank you for joining us on Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Jan 21, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts of Circulation on the Run and if you don't know what this show is about, well, you have to listen to the previous episodes in January please.

                                I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley:   I'm Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: So Greg, before we pick up our coffees and begin discussing a couple of the paper, let's just tell everyone that this feature paper, they have to listen to because it is the results of the cardiac amyloidosis section, or sub-set of the APOLLO study. Have to listen to this one. But how about the other papers in today's issue Greg?

Greg Hundley:   Right Carolyn, the first one I'm going to start with is from Alexander Fanaroff at Duke University and the DCRI. And basically, this particular paper was looking at the procedural volume and how that might affect outcomes with those that are performing PCI. So they divided the cohort into those individuals that had less than 50 PCIs per year, 50 to 100 and then greater than 100 PCIs per year. So, this is looking at our national cardiovascular data registry within the United States, and of course, as you know, that's linked to Medicare claims data for those that are over 65 years in age. So they had 723,644 PCIs performed by 8,936 operators. And the surprise in this study was that those low volume operators, less than 50 PCIs per year had a one year rate of 15.9% of MACE as opposed to those that were high volume operators that had 16.9% MACE rates. That was significant at a P value of .004.

Dr Carolyn Lam: Wait a minute, this seems different from prior reports. Are you saying that those with low volume operators actually had lower mortality?

Greg Hundley:   Yeah, exactly. And you've pointed out something, cause previously what's been shown is that high volume operators have lower 30 day and in-hospital mortality rates. And that was actually confirmed in this study. But out of a year it was really the low volume operators in unadjusted results had lower rates of all MACE.

                                A very nice editorial by Dharam Kumbhani from UT Southwestern points out that high volume operators do tend to take on more serious cases, those with higher numbers of cardiovascular risk factors. And so, when they did adjustments and accounted for all those risk factors, actually the event rates were the same. Still though, they're the same. And so what could be going on? And the editorialist and also the authors of the paper point out, "Hey, maybe we shouldn't just be focusing on PCI volume per operator, but other quality metrics to look at outcomes. And so this really builds in to the whole quality discussion. Adherence to therapy with the patients in your health care system. What about operator longevity? An operator that may have been doing this for 10 years but has a lower volume, maybe that could come into play. So future studies I think, certainly all over the world in this field, this paper's going to direct us to focus more on other quality issues and not just procedural volume.

Dr Carolyn Lam: So, quality versus quantity. Interesting.

                                Well switching gears to a paper that I thought was nice, it is from Dr Lubitz from Massachusetts General Hospital in Boston and colleagues, and they sought to answer the question of whether refining a phenotypic classification of heart failure would facilitate genetic discovery. So, to do that, they defined all cause heart failure among almost 500,000 participants in the UK bio-bank and performed a GWAS study and then later refined the heart failure phenotype by classifying individuals with left ventricular dysfunction but without coronary artery disease as having nonischemic cardiomyopathy and then repeated the GWAS. And basically they found that the GWAS in the all cause heart failure yielded multiple genetic signals for known heart failure risk factors, such as coronary artery disease and atrial fibrillation.

                                However, after refining the heart failure phenotype to a nonischemic cardiomyopathy sub-set, this enhanced the detection of genetic loci associated with dilated cardiomyopathy, which appeared to operate independent of the traditional heart failure risk factors. So that was pretty interesting.

Greg Hundley:   So where do we go from here with that Carolyn? I mean, what is this telling us and how are we going to move forward with this information?

Dr Carolyn Lam: I think the clinical implications are first that common genetic variants associated with both clinical and sub-clinical heart failure, because they looked at left ventricular dysfunction, these genetic variants may be leveraged to improve heart failure risk prediction and prevention. But obviously future studies are warranted to investigate the prognostic and therapeutic implications of these findings.

Greg Hundley:   Very good. Well I'm going to take us back into the cath lab again and we're going to address fractional flow reserve. And remember, typically, we get fractional flow reserve measures using guide wires, and that's kind of a tough thing to do sometimes in terms of adding links to the procedure, etc. So what these investigators did, they had 10 centers in the United States, Europe and Israel. And this was William Fearon from Stanford University who did this study. And they looked at 301 subjects and they had 319 evaluable vessels. Now what did they compare? They looked at guide wire derived fractional flow reserve versus angiographic derived. Simply, just when you're doing the injections, looking at how quickly that contrast flows down the coronary arteries.

                                And so, in this study the mean fractional flow reserve value was 0.81 and 43% of the vessels they studied had an FFR less than or equal to that magic number of 0.8. Interestingly, the angiographic obtained FFR measures were 94% sensitive and 91% specific for identifying the guide wire derived FFR. That's really incredible. And importantly, the accuracy of this contrast measure was 87% for FFR values between 0.75 and 0.85, that magical threshold.

Dr Carolyn Lam: Well that is impressive, suggesting that we don't need guide wires. I mean, is that true for all patients? All vessels?

Greg Hundley:   Right, so that's sort of the kick here, this is really interesting new data but let's look at the patients that they studied. First of all, they were relatively stable I would say. They had either angina or maybe even unstable angina and non-ST elevation MIs. But no ST elevation MIs. The average stenosis by angiography that they looked at was about 63% and then, very importantly, you have to look at the exclusion criteria. So things that, other conditions within the heart that are going to impact FFR were excluded. So, all their patients had an EF greater than 45%. Nobody had a CABG. Nobody had a chronic total occlusion. Nobody had a heart transplant, aortic stenosis, no heart valve surgery, no left main. It couldn't have had a recent stent within 12 months. It couldn't have had severe diffused disease, no collaterals, no in-stent thrombosis or stenosis. So this technique I think could be useful when you've got that patient perhaps with stable angina, single vessel disease, stenosis severity of 50 to 60% and none of these other conditions, preserved EF etc. But for many of the patients that we send to the cath lab, this technique, we still need a little bit more development. We don't know its utility. You've got another paper?

Dr Carolyn Lam: I've got another few papers because I'm going to drag you out of the cath lab right now and into the ICU. And we're talking about cardiogenic shock and it's really nice that we have these three papers in today's issue. One's an original paper and two are On my Mind articles. Now the original paper talks about the randomized shock cool trial. This is from Dr Thiele from the heart center Leipzig in University Hospital in Germany. And it is an un-blinded, randomized trial of 40 patients with cardiogenic shock undergoing primary percutaneous coronary intervention. And without a classical indication from mild therapeutic hypothermia, but randomized one-to-one to mild therapeutic hypothermia for 24 hours versus control. And basically the mild therapeutic hypothermia did not show a substantial beneficial effect on the primary outcome of cardiac power index at 24 hours or on any other of the hemodynamic parameters. And there was also no difference in the short and long term outcomes. So a neutral trial.

                                But taking a step back and just talking about these patients with cardiogenic shock and all the different ways that we have now to keep them alive, I really want to highlight these two On My Mind papers. One is by Drs Gill, Grunau and MacRedmond from University of British Columbia. And they really talk about the need to define limits for extracorporeal cardiopulmonary resuscitation. In a very similar vein, Drs Mulaikal, Nakagawa and Prager from Columbia University also wrote a beautiful piece on ECMO, ECMO as a bridge to no recovery. And when is enough enough? So really, really interesting conversations and discussions regarding what is death, when do we have to put a time limit perhaps to these therapies? And yet not limit the potential life-saving effects of these. I really strongly encourage our listeners to read these papers and also to stay tuned because coming right up, a very important paper on the APOLLO study in our feature discussion.

                                For today's feature paper we're discussing the results of a sub-study of the APOLLO study. Now this deals with cardiac amyloidosis, a super, super hot subject. And we have super, super hot guests today on the show. The first our corresponding author, doctor Scott Solomon from Brigham and Women's Hospital as well as our associate editor doctor Justin Ezekowitz. Welcome both, and let's just plunge straight into it. So Scott, tell us, tell us about this APOLLO sub-study.

Scott Solomon: APOLLO is a study of patients with hereditary transthyretin amyloidosis and, as you know, that hereditary transthyretin amyloidosis is an inherited disease caused by mutations of the transthyretin gene and these mutations cause the transthyretin protein to misfold and then accumulate as amyloid fibrils which go to the nerves and go to the heart. And we know that this can cause severe polyneuropathy and cardiomyopathy, partly depending on which mutation the patients have. And we, as cardiologists, are aware that when amyloid infiltrates the heart it can increase cardiac wall thickness, it can cause increase in chamber stiffness, it can result in severe diastolic dysfunction and these patients, often with cardiac involvement of amyloid, have a really markedly reduced life-span and really poor quality of life.

                                The APOLLO study was a study of a new agent that is designed to reduce transthyretin, it's a transthyretin knock-down agent. It's basically an RNAi therapeutic, it basically is a small, interfering RNA that basically blocks the production of transthyretin and this is one of several approaches that are currently being considered for amyloid disease. And APOLLO is primarily designed as a study to look at neuropathy. The primary end-point was a neurologic scale to look at neuropathy, but it was also designed to secondarily look at some cardiac end-points, especially in the patients who were felt to have cardiac involvement.

Dr Carolyn Lam: Cool. And so your current paper deals with that cardiac amyloidosis sub-set, but it was pre-specified, it was planned, right?

Scott Solomon: Yeah, it was a pre-specified sub-group. In fact, what we did is we actually did echocardiograms on everybody in the study and then defined a pre-specified cardiac sub-population that was comprised of patients who had a very high likelihood of having cardiac amyloid involvement, and so this was patients who had a baseline left ventricular wall thickness of 13mm or greater and no history of either aortic valve disease or hypertension. And so this was a group that we thought most likely had evidence of cardiac involvement. And just so it's clear, we did echocardiography on everybody in the study and in this paper we reported in both everybody and in the pre-specified cardiac sub-population. So we looked a number of things in these patients including various measures of cardiac structure function including wall thickness, left ventricular mass, ejection fraction, cardiac output, atrial size, volumes and myocardial strain which, as you know, has been particularly useful in assessment of patients with amyloidosis. And we also looked at reduction or improvement in Anti-proBNP which, as you know, is a very good measure of the severity of heart failure in patients.

                                And so, of the 225 patients who enrolled overall in the APOLLO study, 126 were part of this pre-specified cardiac sub-population. And in this group of patients, we've observed a reduction in left ventricular wall thickness of about a millimeter. And this was statistically significant in the patients who were treated with patisiran compared with placebo. We also saw an improvement in global longitudinal strain and improvement of cardiac output and an increase of left ventricular end-diastolic volume. In this case an increase in end-diastolic volume is actually a good thing because these patients often start out with smaller end-diastolic volumes because of the increased wall thickness. Those improvements in echocardiography were really paralleled by dramatic improvements in Anti-proBNP and we started out with patients with abnormal Anti-proBNPs in the range of about 800. These were significantly reduced, highly significantly reduced with a P value of about seven times 10 to minus eighth at both nine and 18 months, so pretty dramatic relative reduction in Anti-proBNP in the patisiran group compared to placebo.

Dr Carolyn Lam: Super exciting, and it really adds to mounting evidence isn't it? That we're sort of reaching a really effective treatment for these patients and who knows how common they are. But Justin, you've been thinking a lot about this, what are your thoughts?

Justin Ezekowitz: This is a terrific paper, and this is a groundbreaking therapy. Scott, this really has something for everybody, for example functional Anti-proBNP and echocardiographic measures of improvement and also less deterioration which I think is also holding it in its tracks. The question is, if you have 126 patients in the cardiac sub-group, whether or not this is really prime for clinical integration, as to start using this therapy broadly or do we need to really broaden the scope and do larger outcome studies with this therapy for these patients, recognizing some of the gaps in any clinical trial design and implementation. So what are your thoughts on that?

Scott Solomon: First of all, it's important to remember that the APOLLO study was designed primarily to look at the neurologic outcomes, not the cardiac outcomes. The cardiac outcomes were technically considered exploratory and, in fact, although really pretty impressive in this group, this wasn't really how the study was designed. And so the current indication for this particular therapy. Patisiran is for the improvement in the neurologic outcomes, not for the cardiac. So I think that there will need to be additional studies that will look more specifically at the cardiac effects, although I think these are among the most impressive findings we've seen with any agent that is interfering with transthyretin. And just to put this in context, there are a variety of ways in which amyloid can be affected and one of the other approaches to this disease has been not to reduce the production of transthyretin but to stabilize transthyretin.

                                And you may be aware of the ATTRACT trial which was presented at ESC and published in the New England Journal, which was actually an outcomes trial in patients with cardiomyopathy secondary amyloid and they used a drug which is a TTR stabilizer and showed a significant reduction in cardiac events and mortality. And I think that in the context of that study, this is extremely exciting as well because it says that there are multiple potential approaches to affecting transthyretin and potentially improving outcomes in patients with cardiac amyloidosis. There are other approaches that also are being tested. In fact, another therapy that works in a similar way to patisiran is atersin which is an agulo nucleotide anti-sense molecule. And so, I think that it's such an exciting time now in this field because there almost certainly will be several different approaches to transthyretin amyloidosis.

                                So, I think, Justin, to succinctly answer your question I don't think we're quite ready yet with patisiran but stay tuned because there will be more trials for sure. The other thing that we have to realize is that this study was done in mutant or hereditary amyloidosis but there's a very broad group of patients out there with wild type amyloidosis and there's no reason to think that a therapy like this won't work there as well. So that has to be tested too.

Justin Ezekowitz: I think, Scott, that's a true way to put it. I think one of the other questions is the substantial difference between the trials and sub-groups of the trial between the three major therapies you just described about wild type versus hereditary. It does make you wonder if either one individual therapy or a combination of the therapies might give the right way to precisely manage these individuals according to their phenotype, neurologic status or cardiac status.

So, I maybe just want to draw you on one other point which is that you used global longitudinal strain as one of your outcomes and it sounds like, and from all the data we've seen, it looks like GLS will be the way to go for earlier phase two and other types of studies. What are your thoughts based on experience?

Scott Solomon: Well in general I'm a big fan of global longitudinal strain because I think it is, in many respects, more robust than our standard measures of cardiac function like ejection fraction, it's not volume dependent the way ejection fraction is. In particular in amyloid heart disease, as you know, global longitudinal strain can be quite abnormal and, interestingly, it can be quite abnormal in a very specific pattern. And patients with amyloid is typically sparing at the apex, so the apical strain is relatively normal compared to the strain at the base of the heart. And this is kind of interesting and we've certainly been looking at this as well in amyloid heart disease but I agree that this global longitudinal strain as a measure of potential benefit for a therapy has a lot of potential.

Dr Carolyn Lam: You know, that's just so amazing. I just have one last question for both of you. Where do you think the field is going? Do you think it's going to be a race to treatment or a race to diagnosis? I shudder to think of the number of cases we're missing, what do you think Justin?

Justin Ezekowitz: Carolyn you just brought up a great point which is, one is our diagnostics need to improve and be broadly applicable and implementable in any health care system, so I think that race has to speed up and become more cost-effective and efficient to know who indeed we need to screen closer. That's point number one but number two is the therapies ... the race has to be focused around what will be the best way to treat patients rather than the cost-effectiveness initially, but then once we identify the three or four different agents that work with different groups and how you can combine them, then the consideration has to be how we can apply these more broadly to the groups that really haven't had a therapy that has had a meaningful impact trajectory.

Dr Carolyn Lam: Scott, what do you think?

Scott Solomon: Well I would add that one of the most exciting things I think in this area, Carolyn, and this is going to interest you I think because of your own interests, is that there's probably a lot of amyloid out there that we don't know about. Especially in these patients that we're currently calling heart failure with preserved ejection fraction. There's some data from Mayo clinic and from groups in Europe suggesting that 15 to 20% of patients with HFpEF, might actually have wild type transthyretin amyloid. And that means that we've got to get better at making this diagnosis, especially where our suspicions are high. Because we might all of sudden have a targeted therapy for some of these patients, so I think that's one area where things are really exciting. And then with respect to which of these therapies is going to be beneficial, I mean I think that we're still in the early stages, it's very possible as Justin said that even a combination of TTR stabilizers and knock-down agents are going to provide the best benefit. But I think we're going to see a lot of very interesting studies in the next several years in this field. It's really great to have a potential molecular target, and targeted therapy for a type of cardiomyopathy and I think this is one of the really few areas where we have that as this point. So I'm extremely excited.

Dr Carolyn Lam: Thank you so much for publishing your paper with us in Circulation.

                                Well audience you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

                                This program is copyright American Heart Association 2019.


Jan 14, 2019

Dr Carolyn Lam:                Hello. We're here at the American Heart Association meeting in Chicago where circulation has 19 simultaneous publications this year. And that is a huge increase from six in the past to 19, all thanks to the man next to me.

                                                But first, let me introduce myself. I'm Dr Carolyn Lam. I'm associate editor from the National Heart Center and Duke National University of Singapore. I'm the voice you hear on 'Circulation On the Run'.

                                                I'm so pleased to be here in person today with Dr Dharam Kumbhani. He's associate editor from UT Southwestern and he also leads the simultaneous publications for this journal. So big applause for this amazing bonanza this year.

Dr Dharam Kumbhani:   Thank you.

Dr Carolyn Lam:                Next to him, we have Dr Sana Al-Khatib and she's from the Duke University. And finally, Dr Gabriel Steg from University of Paris. Wow! Okay, we've got 19 papers to chat about. No, I'm just kidding. We're going to talk and focus on the seven simultaneous publications that were late-breaking science.

                                                Why don't you start us off, Dharam. We will first start with the interventional trials, and there were three of them. I'd love you to chat about the first of them, but even before that, maybe, tell us what it's like to get a simultaneous publication. Because I think people underestimate the amount of work it takes to do that.

Dr Dharam Kumbhani:   Thanks a lot, Carolyn. I think under Joe's leadership the whole space of simultaneous publications in late paying clinical science has really been a big endeavor for him and for the journal. We just have an amazing team that's able to work on this in very quick order. So, for the viewers, I think it's a very involved process, but it's a very gratifying process.

                                                We work very closely among the associate editors, the senior editors, and then the circ staff, and we have very rapid turnaround time. So we owe a lot of gratitude to our reviewers who frequently will turn these reviews in within 48 hours. Our goal has been that we respond back with a decision usually within five to seven days. So it's been very gratifying.

                                                Then it moves onto the next set of revisions, et cetera. But even among the papers that we are unable to accept for circulation, it's just a quick turnaround time for the authors so they haven't lost as much time and can potentially look elsewhere.

                                                It's been a really gratifying process. It's been a great, great team effort. I appreciate everything you said, but really I don't deserve all that credit. It's been a great team effort.

Dr Carolyn Lam:                No, it's been rumored there's a lot of lost sleep on your end, so thank you, thank you Dharam for this. And maybe you could open with the ISAR-TEST 4, that's been [crosstalk 00:02:47].

Dr Dharam Kumbhani:   Yeah, well thank you. I think we had some really interesting interventional trials and Dr Steg will discuss a couple of them as well.

                                                ISAR-TEST 4 was a very interesting trial. It is one of the first 10 trials that gets to the 10-year mark, so this is just the 10-year follow-up results of that. It was about a 2500 patient trial. It was done in Germany, multiple centers. Really they were trying to assess the space that they were trying to ... Or the knowledge gap that they were trying to fill was the durability of the bioabsorbable polymer stents.

                                                Specifically, they were looking at a bioabsorbable polymer sirolimus-eluting stent, the Yukon stent, and then they compared that with durable polymer stents including Xience or the everolimus-eluting stent and then Cypher, which is no longer available in the U.S., but that's a permanent polymer sirolimus-eluting stent.

                                                The primary results were published and presented a long time ago. There was really MACE events at one year and it showed non-inferiority for this bioabsorbable polymer stent back then. So, then they had, incredibly, 83% of the cohort that they were able to follow-up out of 10 years. And what they showed is that ... I don't want to necessarily get into the numbers and the details as much, but what they showed is that this bioabsorbable polymer sirolimus-eluting stent tended to have similar outcomes to Xience, which we accept as state of the art current generation stent, permanent polymer. And it did better than the Cypher stent, both in terms of MACE events and stent thrombosis.

                                                So suggesting that, the big advance in the field for this is ... This is a long-term follow-up of the stent. It suggests that outcomes may be similar in this patient population. Although only 12% were really enrolled with an MI in this patient population. Most of them were stable or less sick ACS patients. And they show fairly good outcomes out of 10 years, comparable to Xience and better than Cypher.

                                                I think it was interesting. Gabriel, what is your take [crosstalk 00:04:57].

Dr Gabriel Steg:                I think it's important. There's been a tremendous interest in international community on trying to tease out which are the best types of stents and beyond brands, try to understand the type of stent, the coating, the drug that you put on it, whether the polymer is durable or not durable. I think these types of fairly well done, large randomized trials with long term flow are critical.

                                                A lot of the focus in the interventional community originally was on lumen size, late loss, angiographic parameters short term. And now the field has matured, and we've moved to clinical outcomes, patient-oriented outcomes, long term follow-up. And it's important because we've learned from long term trials such as PROTECT that the result at one year may not predict what happens at five years, and sometimes you have surprises.

                                                So, it's really important. We owe it to our patients because these are irretrievable devices. Once you've implanted them, they are there. We talked about Cypher being out of the market, but there are more than a million patients who walk every day on this plant with a Cypher in their coronary artery, so we better know what the long-term follow-up is.

Dr Dharam Kumbhani:   Yeah, that's a great point.

Dr Carolyn Lam:                Wow. And then thanks also for the discussion that allows me, as a noninterventionist, to realize ... It's hard to keep track of what's happening with all the different types of stents and polymers and so on. But could you then summarize for the field, does that mean that these biodegradable ones are now ... Do I sound ignorant when I say that? That they are now really in the game. Is that what it does?

Dr Dharam Kumbhani:   This whole bioabsorbable field, there are nuances. So this really is testing a bioabsorbable polymer where -

Dr Carolyn Lam:                Oh!

Dr Dharam Kumbhani:   So, with every stent you have a stent, you have the polymer, and then you have the drug.

Dr Carolyn Lam:                Thank you.

Dr Dharam Kumbhani:   And so, the polymer and the drug go away, and then you're left behind with a bare metal stent. And that's this Yukon stent.

Dr Carolyn Lam:                Got it.

Dr Dharam Kumbhani:   The one that has been in the press a lot more is the bioabsorbable scaffold where the stent and the polymer and the drug, everything in theory should be gone at a certain period of time. So this is ... It's an important distinction though. Because I know that it's very confusion when you just say bioabsorbable and it's unclear if you're talking about the polymer or you're talking about the stent, itself. But this really was a bioabsorbable polymer issue, so you're left behind with a bare metal stent at the end of it.

Dr Carolyn Lam:                Got it, crystal clear, and thank you. That's cool. That's super.

Dr Sana Al-Khatib:            I agree, for an electrophysiologist too.

Dr Carolyn Lam:                But now, let's go into the AMI field. There were two trials that really spoke to acute management patients coming in with an AMI and with cardiogenic shock, for example. Gabriel, could you tell us a little bit about the IABP-SHOCK II trial, as well as the really talked about a door-to-unload IMPELLA Trial.

Dr Gabriel Steg:                The IABP II trial is a randomized trial looking at the benefit, or lack thereof, of intraaortic balloon pump in patients with cardiogenic shock and acute MI. It's been standard practice since the '60s to offer IABP pumping to patients with cardiogenic shocks and AMI.

                                                So, literally more than a million patients have been implanted with IABP, but the reality is when we look at the randomized trial evidence of benefit there was none. They were very small trials, inconclusive, underpowered. Professor Thiele from Germany and his colleagues deserve enormous credit for having had the courage to really do what needed to be done. A proper randomized controlled trial, of course open label.

                                                And what they found in IABP II, which they already reported a few years ago, was that there was no acute benefit of IABP on survival short term, or for that matter on many of the secondary clinical outcomes looked at in this trial. They subsequently reported one year mortality.

                                                What they did here is they gathered follow-up on almost all of the cohort at more than six years. And they found that the long term survival is identical for patients who received an IABP and those who did not. So I think this nails the issue. But there's another thing we learn. The mortality at six years is staggering, it's close to 60%. And although a large fraction of the patients die in the first 30 days, you still have an additional 10% of patients who die between the first year and six years.

                                                So there still remains a very sick patient population for whom we need to investigate new strategies. I don't think it's going to be necessarily mechanical. We have to think of all of the strategies we do to prevent and mitigate cardiogenic shock to build up. And that's gets us to the second trial that I'll talk to you about in a minute.

Dr Sana Al-Khatib:            I have a quick question about this. Did they provide any information about modes of death in these patients?

Dr Gabriel Steg:                Yes. They did capture information about that. Off the top of my head, I'm unable to provide information, but yes they did capture that. The German system allowed them to retrieve information about causes of death and it's a closed system. It's a national trial, so they were able to get enormous follow-up.

Dr Sana Al-Khatib:            Because this information can help us inform what interventions are needed next.

Dr Gabriel Steg:                Yes. That's really important.

Dr Dharam Kumbhani:   To your point about ... You use a very interesting word, the last nail. That's actually how Dr Hochman addressed her editorial. She wrote a really nice editorial-

Dr Gabriel Steg:                The leading expert in the field.

Dr Dharam Kumbhani:   And so, I'm interested in your thoughts. The use of balloon pumps for shock, there's a discrepancy between the American guidelines and the European guidelines. Last year the European guidelines were updated. It is really such a practice changing guideline in that it now lists routine use of balloon pumps in cardiogenic shock-

Dr Gabriel Steg:                Class III.

Dr Dharam Kumbhani:   -as a class III indication. Going through training, that was all you had when someone came in with shock, you would throw in a balloon pump. So that's really quite a practice changing event.

Dr Gabriel Steg:                Yeah. These investigators are embarking on new studies with ECMO and I think it's going to be fascinating to see whether ECMO, which also gets increasingly used worldwide, whether there is evidence to acutely support or not whether this is useful. I think they are doing the proper thing. They are doing the right thing, randomized trials. And we could commend them because these are really difficult trials.

Dr Carolyn Lam:                Absolutely.

Dr Gabriel Steg:                In the acute MI setting, shock patients, ECMO, IABP, that's really difficult. They are brave investigators, they are good investigators, and I think they provided the community with a clear answer.

Dr Carolyn Lam:                And exactly the kind of papers that we like publishing at circulation, isn't it? Now what about the door-to-unload?

Dr Gabriel Steg:                That is actually a good segue with door-to-unload because if we can't properly treat shock once it's there, can we do something to prevent shock? Can we do something to preserve myocardium? One of the experimental findings that is very clear is that if you unload experimental myocardial infarction, if you unload the left ventricle you reduce infarct size.

Dr Gabriel Steg:                So, investigators have been trying to translate this experimental finding into the clinical arena using the Impella device. There's enormous interest, particularly in North America for Impella use in acute MI patients with larger infarcts with the idea that if you can unload the left ventricle, you might be able to mitigate the extent of the myocardial infarction, and therefore avoid cardiogenic shock and probably improve prognosis.

                                                Although this is a very attractive theoretical concept, it still deserves to be tested. And so, if you want to test it you have to unload the ventricle as soon as possible, ideally before reperfusion, which means that you're going to have to delay reperfusion for the time of implanting the device and unloading the ventricle. And so what the investigators did in this trial is to study whether delaying proposedly by 30 minutes reperfusion, to unload the ventricle for 30 minutes prior to reperfusion, was feasible and reasonably safe.

                                                It's a small trial. It's really a pilot trial. By no means does it test the proof of concept of the device or the theoretical issue, but it shows that it's feasible. There doesn't seem to be a massive increase in total time to reperfusion because just by change the group that was not delayed had a longer time to PCI, so eventually things are sort of evening out.

                                                They looked at MRI size of infarcts at follow-up. There was no obvious difference, but of course it could still be tied to errors. We're not totally sure about this, but it certainly paves the way for doing a proper proof of concept randomized trial, testing unloading versus no unloading with a true control group. And I think that's what investigators are looking forward, but I understand there's immense interest for this concept in international community, particularly in the United States and I'm quite curious to see what this future trial will look like and what the results will be.

Dr Carolyn Lam:                Yeah, indeed. Gabriel, I noticed you were very careful to frame it, to say what the trial was trying to address and what it wasn't. And there's been quite a bit of buzz after that.

                                                Do you agree with everything Gabriel has said and what have you heard?

Dr Dharam Kumbhani:   I think he was incredibly eloquent in outlining the premise of the trial and what it really showed. I think the one thing that ... And this was brought up in the very nice editorial by Dr Patel from Duke as well, is it would've been really nice to have a control arm which didn't have any unloading. Because these are not patients with shock, that just directly had primary PCI. And then comparing infarct size.

                                                So, I think that was one of the pieces of information that would've been helpful to then put this in perspective. When you have an infarct size of 8% or 10%, how does that compare in the same patient population in their testing? You're absolutely right about the need to do difficult trials like this, where a lot of times it's just assumed to be true and is embraced in clinical practice.

                                                As I gave the example about the balloon pump earlier, where as a Fellow you saw someone in shock and your reflex was to put in a balloon pump. And so, I think testing these very difficult patient scenarios, as well as just in terms of trial execution, it's amazing to have two trials on that.

Dr Gabriel Steg:                If I may come back to this?

Dr Carolyn Lam:                Yes.

Dr Gabriel Steg:                It's funny because we've been using the IABP for years, thinking this is what we should do in shock. Now our German colleagues have proven that IABP doesn't work. So a lot of investigators have reverted, saying "Well, we should use Impella." But where is the evidence showing that Impella is beneficial?

Dr Dharam Kumbhani:   That's right.

Dr Carolyn Lam:                That's right.

Dr Gabriel Steg:                We have none, so I think that's a trial that deserves to be done.

Dr Dharam Kumbhani:   And ECMO. Yeah, exactly.

Dr Carolyn Lam:                Yeah, ECMO. Exactly. And, you know, going back to door-to-unload, it's important to prove safety in order to go to the next step, which is exactly how you frame-

Dr Gabriel Steg:                I think it shouldn't be over interpreted.

Dr Carolyn Lam:                That's how it should be, exactly, received by the community. So that's great. Now let's switch gears a bit.

                                                Sana, in EP world, the EP guided noninvasive radio ablation of VT. Fascinating stuff. What are your thoughts?

Dr Sana Al-Khatib:            I absolutely agree, definitely. This was a phase two study that the authors did. They enrolled 19 patients, so it was a small study, but it was really helpful. Remember, there's a major clinical need there. These are patients who have an ICD, who have recurring ventricular tachycardia, that have been treated with at least one antiarrhythmic medication, at least one catheter ablation procedure, and then what do you do with those patients? This is actually a clinical scenario that comes up frequently and we absolutely need to be looking for more therapies for those patients.

                                                So that's what that study was about, trying to explore new ways to treat these patients. To be able to do it noninvasively, I think is fascinating. That's what ... They enrolled these patients. Patients had to have failed these treatments, antiarrhythmic medications, prior catheter ablation, and they underwent noninvasive imaging to really localize the source of the ventricular tachycardia, where it's coming from, and then they subjected them to stereotactic body radiotherapy to ablate those sources of ventricular tachycardia.

                                                And, of course, the results were fascinating because they showed on the effectiveness side that this seemed to be very effective because if you look at the reduction in the burden of ventricular tachycardia, and a couple of their patients actually had significant PVCs and PVC induced cardiomyopathy, there was a significant reduction in the rates of these arrhythmias in these patients with this intervention, which was great to see.

                                                In fact, to be specific, about 94% of these patients, so 18 out of the 19, had significant benefit. And in about 89% of the patients there was more than 75% reduction in the arrhythmia. So these are actually really interesting findings, especially in a patient population where we really don't have other options. Now of course you're going to ask me about the safety. What are the safety concerns?

                                                Of course, this was a primary endpoint for the authors. They did look at safety up to 90 days and they found that there were two significant adverse events that occurred in those 90 days. One was heart failure and one was pericarditis. The concern, of course, with radiation is what else can we expect especially if you follow the patients longer? So certainly we need more data. The authors acknowledged that beautifully and I think their intent is to launch a multi-center randomized clinical trial. I don't know if it will be randomized, but at least a multi-center clinical trial to see if they can replicate those findings. So that was very interesting to see.

Dr Carolyn Lam:                Yeah it was. Thanks, that was really exciting.

                                                So, some exciting trials in my world of cardiometabolic disease too, and I want to highlight two. The CARMELINA trial and the CAMELLIA-TIMI 61.

                                                First the CARMELINA trial. This was a secondary analysis of CARMELINA and this was ... CARMELINA, if I can remind everyone, is a cardiovascular outcomes trial, randomizing about 7000 patients with type 2 diabetes and atherosclerotic cardiovascular disease, and/or chronic kidney disease. Randomizing them to the DPP-4 inhibitor linagliptin 5 mg a day versus placebo, following up for a median of about two years.

                                                We know that type 2 diabetic patients are at risk of heart failure and there's always been a bit of a question mark when it comes to DPP-4 inhibitors and their risk for heart failure. And so this secondary analysis looks specifically at the hospitalization for heart failure and related events in CARMELINA. The important thing is that all these were prospectively centrally adjudicated events, and this was a pre-specified post hoc analysis.

                                                And the summary of it all is that linagliptin was not associated with an increased risk of hospitalization for heart failure or the composite of cardiovascular death in hospitalization or the related outcomes. Importantly, the authors did also sensitivity analyses and interaction analyses to show that the results were consistent whether or not patients had a history of heart failure, which was in 27% of patients, regardless of the baseline ejection fraction that was measured within a year of starting the drug, and also regardless of renal function. So EGFR or urinary albumin to creatinine ratio.

                                                This is really important because this trial adds to the growing perhaps understanding of DPP-4 inhibitor heart failure risk. The whole question mark actually came with SAVOR TIMI and that was saxagliptin. But since then there's been three other trials that have showed no heart failure risk. EXAMINE, TECOS, and now CARMELINA. So, an important addition and I think it should reassure us.

                                                And then from diabetes and heart failure risk, which is always very hot, but now obesity. The CAMELLIA-TIMI 61 trial looked at renal outcomes in this trial. Now what was this trial? It was actually testing lorcaserin, and that is a selective serotonin 2C receptor agonist, in about 12,000 obese or overweight patients.

                                                Basically, the primary results showed that it did not increase any ... It met it's CV safety outcomes with weight loss and so on. But this time they looked at renal outcomes. Because obesity has been known to be associated with hyperfiltration of the kidneys, you get albuminuria and it's apparently worsening of kidney disease. So what we need to know is pharmacological weight loss going to be associated with improved renal outcomes?

                                                And basically, that is what CAMELLIA-TIMIA 61 showed. Their renal outcomes were new or persistent albuminuria and then the standard doubling of EGFR or end-stage renal failure, renal transplant or renal death. And that was improved by lorcaserin. Along with that, there was the anticipated reduction in weight, HbA1c, and BP. It does look like, from these late breaking results that we have another tool in our toolbox.

Dr Sana Al-Khatib:            And for the clinicians out there, which patients should they be thinking to use this medication in? What kind of obesity are we talking about? At what point do you introduce that?

Dr Carolyn Lam:                This is common garden, just defined by BMI that was above 27. And I don't think they're saying to use it in patients with renal dysfunction, but to sort of say to look and see whether weight loss also associates with renal function improvement, and it does. It's reassuring.

Dr Sana Al-Khatib:            Yeah, okay.

Dr Carolyn Lam:                And then ... Okay, let's round up with that last trial. A very interesting one because it's pragmatic mobile health and wellness. Tell us.

Dr Dharam Kumbhani:   It's really a monumental effort. This is ... I'll be brief, but it's really a phenomenal trial from an epi standpoint and implementation standpoint. This is from India. It was coordinated by the Center for Chronic Disease Control and the Public Health Foundation of India where, as everyone knows, India is now the diabetes capital of the world and chronic diseases have very quickly overtaken other infectious causes as the number one cause of mortality and morbidity.

                                                This was a big undertaking, really collaboration from three continents, but it was a community based plus a randomized trial. They had 40 community health centers and what they were trying to see is primarily for hypertension and diabetes. That if you implemented a structure and typically using this mWELLCARE tool, which is basically an electronic medical records storage facility and then it also has inbuilt clinical decision support.

                                                And really for hypertension and diabetes management, but also, they had tobacco and alcohol screening, abuse screening, and also for depression. So what they really wanted to do ... A very ingenious endeavor and they try to see if doing this systematically on a clustered randomized fashion if that would actually influence patient outcome. They had a little over 3000 patients and they followed them for 12 months.

                                                Unfortunately, the trial, itself, as far as the primary endpoint, which was change in systolic blood pressure and hemoglobin A1c, they had pretty significant reductions in both arms, about 12 to 13 millimeters, which is amazing from a population health standpoint, in both arms not statistically significant, and in hemoglobin A1c also by 0.5% in both arms.

                                                Just suggesting that having this more frequent interactions with the medical health system, itself, was driving a lot of this benefit. So although the trial, itself, was negative for the primary endpoint, I think it's a huge step forward for the management of chronic disease epidemiology and burden in developing countries.

Dr Gabriel Steg:                Neutral.

Dr Carolyn Lam:                Ah, true.

Dr Dharam Kumbhani:   Fair point.

Dr Carolyn Lam:                We've discussed this whole array of seven trials and they are difficult trials. I mean, talk about another difficult type of trial to do, cluster randomized pragmatic trial. It's amazing the breadth of simultaneous publications we've had this year. Thanks again to everyone for introducing this and thank you for joining us today.


Jan 7, 2019

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Caroline Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley:                   And I'm Greg Hundley, Professor at the Pauley Heart Center of Virginia Commonwealth University Health Sciences in Richmond, Virginia.

Dr Carolyn Lam:                In case you guys missed us last week, this is how our new podcast is gonna work. Greg and I are going to invite you for coffee with us, almost with a journal in hand, and we're gonna chat about the week's issue, highlighting two original papers each, that we thought were awesome. And don't you worry, the feature discussion is still there, authors will join us for a feature discussion right after our coffee.

                                                And for this week, the feature paper speaks about the MOMENTUM 3 trial, and talks about the important analysis of stroke outcomes in this trial. But before that, I think Greg, you've got a couple of papers don't you?

Greg Hundley:                   Absolutely Carolyn. So the whole issue, I think we're gonna pick out several stroke papers, really a stroke theme. The first paper is Ankit Maheshwari. He looked at the utility of P-wave morphology on the 12-lead electrocardiogram, to help predict ischemic stroke in patients with atrial fibrillation.

                                                Now, how did he do this? Basically, they looked at a large cohort of individuals from the ARIC study, and these were patients that developed atrial fibrillation. And electrocardiograms had been recorded prior to their Afib episode.

                                                So, what were they looking for in P-wave morphology? Well, they were looking for changes in Lead three. They were looking for changes in V1. They were also looking for extension of that P-wave. So a prolonged duration. And what they observed, is that that abnormal P-wave, could forecast abnormal atrial remodeling, that might be an indicator of future stroke.

Dr Carolyn Lam:                Huh, interesting. But is it really reproducible? Did they validate it somehow?

Greg Hundley:                   Yeah, so that's great Carolyn. You know, in papers like this, you like to take a finding in one large cohort, but then you've got to reproduce it. So they went to the MESA Study. Remember now, Mesa are individuals without cardiovascular disease. ARIC are patients with cardiovascular disease. And the finding was reproducible in MESA. Also, what the authors did, is they looked at the relevance of this EKG finding to our existing CHADS-VASc2 scoring system.

                                                And what was really smart by these investigators, is that if you added the information from the abnormal P-wave morphology to the CHADS-VASc2 score, you could forecast stroke. Now you say, well CHADS-VASc2 is already pretty reliable, but what about those patients that have a CHADS-VASc score of one right? We're always kind of wondering, do we anticoagulate them? Do we give them aspirin, et cetera. Well if the P-wave morphology was abnormal and they were at higher risk for stroke, that could sway you as a clinician, to go ahead and prescribe anticoagulation for that group of patients.

                                                And something very simple, just from the 12-lead EKG before the patients went into atrial fibrillation. You've got a paper that also is sort of focusing on stroke. You want to tell us about that?

Dr Carolyn Lam:                Yeah, one big data to another big data series. This time, it's Get With The Guidelines Stroke series, and this paper is from Dr Menon from University of Calgary in Canada. Where they described the door to treatment times for endovascular therapy in acute stroke. What is that? Well that's a time interval from when the patient arrives in the emergency department or the door, to the first pass of the treatment initiation and endovascular therapy. And basically they found that the median door to first pass time was 130 minutes. Only 3% of patients achieved a door to first pass time of less than 60 minutes.

                                                In multivariable analyses, older age arrival during nonregular hours and a history of diabetes, were all associated with the longer door to first pass time. And finally, among hospitals with an annual endovascular therapy case volume of 40 or less, every five unit increase in that volume was associated with a 3% reduction in this door to first pass time.

Greg Hundley:                   It sounds like that could be really useful information for stroke centers, you know, that are managing these patients acutely. How do you think these results are going to impact that Carolyn?

Dr Carolyn Lam:                Great question. So first thing is, I think it provides some benchmark times for this in hospital workflow, and it obviously shows areas of improvement. For example, improving workflow during nonregular hours, or increasing the experience of a center, and basically emphasizes the point that efforts on streamlining workflow and saving time, need to continue so that the full potential of endovascular therapy is realized.

Greg Hundley:                   Oh wow, that's outstanding. I'm gonna transition sort of to a basic science paper, also trying to help manage patients with stroke. This one is looking at the safety of all of the dehydrogenased right stem cells. Well, what the world is that. In animals, what has been shown previously, is this particular cells type, that's harvested from your bone marrow, can be infused into the carotid artery, and those animals experience smaller neurologic deficits after stroke. And so with that encouraging result in animals, these investigators sought to test the efficacy of this type of therapy, well not really the efficacy, but the safety of this type of approach in those patients that have sustained actually quite a large stroke.

                                                You had to have a relatively large neurologic deficit to qualify for this study. And just quickly, the way this works is these cells enter up through the bloodstream and they modulate inflammation. By modulating inflammation, that facilitates healing in the stroke patient.

Dr Carolyn Lam:                Yeah, but wow. I mean bone marrow, biopsy and isolating the cells and so on. How is the study done?

Greg Hundley:                   So, the key here is you've had your stroke, you're still in the hospital with a large neurologic deficit. And so day 11 to 17, you undergo a bone marrow biopsy. Then the cells are purified, and they're reinfused into your carotid artery by the way.

                                                And so, what was the study trying to do? Well, it was actually looking at the safety off all this. And what would the concern be? You're infusing these cells into the carotid artery. They go into the cerebral microcirculation, and those that are working in this field, are concerned is that going to promote more emboli? Is that going to promote thrombus? Extend the size of the infarct in the brain, et cetera?

                                                So, the investigators performed MRI's and neurologic exams. And what they found is the neurologic findings in the patients really didn't change, so there was no benefit. But the study wasn't set up to look for a benefit. And there were four patients that had a little bit of an enlargement of the stroke observed on MRI. So, a lot more to come in this basic science realm, but it's interesting to see investigators thinking about this in a whole different way, where we're harvesting one cell type from your body, and then infusing it up into the brain to sort of help rescue the situation.

Dr Carolyn Lam:                Well, another paper dealing with stroke. This time, a Mendelian randomization study to explore whether genetically determined circulating levels of cytokines and growth factors, may be associated with stroke. And this was done in the mega stroke GWA data set and validated in the UK biobank, and it’s by Dr Dichgans and colleagues from the university hospital, Ludwig Maximilian University of Munich. They basically found, that a genetic predisposition to higher circulating levels of monocyte chemoattractant protein one, was associated with a higher risk of stroke. The associations also found for the etiology of the stroke subtypes, and especially for large artery stroke and cardioembolic stroke. In fact the genetically determined levels of this monocyte chemoattractant protein one, was also associated with higher risk of the related phenotypes of coronary artery disease and myocardial infarction.

Greg Hundley:                   So, how do you bring this to practice in the clinic Carolyn?

Dr Carolyn Lam:                So, this is still some steps away, but I do think that it very nicely supports the idea that inflammation as part of the pathogenesis of stroke, and of course additional work is needed to determine whether targeting the specific monocyte chemoattractant protein one, or it's downstream effectors, may be a meaningful strategy to lower stroke risk. So, terribly interesting.

Greg Hundley:                   Yeah, you know it sounds like hitting inflammation or targeting that, is a real theme here from the basic science group. Well this is great Carolyn.

                                                And now, I guess we'll transition over to our feature article.

Dr Carolyn Lam:                Absolutely. So, we're here to discuss the long-term results of the MOMENTUM 3 Trial, and that was a randomized controlled trial of the HeartMate 3 versus the Heartmate II left ventricular assist device. And this time, with a focus on stroke. The outcomes that's just so important to our patients. Greg and I are incredibly pleased to have with us, the authors, Dr Mandeep Mehra from Brigham and Women's Hospital, as well as our senior associate editor, Dr Biykem Bozkurt, to discuss this paper.

                                                Mandeep, perhaps just set the scene by telling us what this secondary analysis found?

Dr Mandeep Mehra:       This analysis is really focused on the issue of stroke, as you pointed out. I'd like to just lace into context what this is important. Ever since the advent of left ventricular assist device therapy from the 80s and early 90s, to now, one of the major Achilles' heels, whether we have used pulsatile flow devices or non-pulsatile flow devices, has been the very constant occurrence of a high incidence of stroke, beyond the stroke rates were predominantly as compared to ischemic strokes. Then with the newer devices, we actually saw a reversal, where we began to see more ischemic strokes as opposed to hemorrhagic strokes, almost an equal parts at this time point.

                                                And this has been one of the critical reasons why we have not been able to expand the therapy beyond the very, very sick patient.

Greg Hundley:                   Very nice. And another particular in the results here is, you didn't really see a difference in stroke rates, either hemorrhagic or ischemic strokes early, but you did start to see a difference after 180 days. Why do you think that's the case?

Dr Mandeep Mehra:       That's a great point Greg. We really saw no difference in the first 30 days. When we analyzed this data, we divided it into a perioperative, a first 30-day time point. Then, we looked at the short-term time point up to 180 days or six months, and then beyond that to the two year end point. What became very clear is that most of the gains that we saw in the stroke rate, began to appear after the first 30 days, did not quite reach statistical significance at six months, but really the differences became heavily pronounced after six months, all the way out to two years.

                                                So, first point that I would make Greg, is that we did see differences beyond 30 days, it's just that they didn't reach conventional statistical significance. The second thing is, the more important point that you make, asking why that was the case. We actually think that the reason behind that, is that the first three months or so after that implant, really is a period of chaos in these patients, where the hemocompatibility, which is essentially the interface between the device as well as the patient, is attempting to be established. And it's very similar in a way as we see in heart transplantation Greg, where the real challenge in heart transplantation is between rejection and infection.

                                                And in the case of left ventricular assist device is the challenges between bleeding and thrombosis. It turns out that three months, whether it be transplantation or whether it be left ventricular assist devices, seems to be this period of chaos and adjustment, during which the patient and the device are starting to get to know each other.

                                                And this is why we think that most of the gains occurred after this period of chaos was overcome.

Greg Hundley:                   No, it's really interesting that after accounting or adjusting for all the anticoagulant drugs, antiplatelet drugs, even the other medical therapies that were applied, you found these results. I mean, maybe also bring in Biykem here to answer the question, what is this machine doing that's providing such a benefit?

Dr Biykem Bozkurt:         The two-year results being quite impressive for the HeartMate 3 are truly encouraging. Because I think we truly see a concordance benefit beyond 180 days, especially the nondisabling strokes, giving the hope to the providers that we can further perhaps enhance the field by focusing on optimization of anticoagulation strategies, prevention of atrial fibrillation, and maybe even consider our algorithms or pathways for stroke. Because, in this protocol, even though the stroke management was not standardized, and I'm sure that the data will not yield that information as to which centers were able to approach the stroke management in a perhaps evidence based approach, the sobering facts are regardless of the device, at two years, approximately half of the patients died. Even the non-disabling stroke patients had increased mortality compared to no-stroke patients.

                                                And if you examine evidence-based approaches, only one-third of the hemorrhagic stroke patients had reversal of anticoagulation, and a very small percentage ... actually, none of the patients had device intervention for the ischemic stroke. That raises the question of yes at two years the HeartMate 3 results are very promising. But, can we further even advance the field by doing evidence based standardized pathway driven stroke treatment approaches.

                                                The other very interesting finding from this trial is, in ENDURANCE trial, which was another trial with centrifugal device, HVAD device, there was an association of the stroke rates with inadequate control of blood pressure and anticoagulation, which was not noted in this trial. Maybe Mandeep can comment on do we truly have the adequate power to be able to infer whether blood pressure control and/or appropriate anticoagulation management strategies will matter?

Dr Mandeep Mehra:       Biykem you've said it really well, and I'd like to just make some additional points with respect to the question. So, first of all Greg you're absolutely correct, that we tried to search for anything that would predict this reduction in stroke with the HeartMate 3, and it turned out that all we were left with is the device itself. So, it really begs the question, what is it about the device or it's interface that may have resulted in this.

                                                And of course, some of what I'm about to tell you will be speculation, but it may actually carry some water. So, for example, the HeartMate 3 is very unique in one other aspect, and that is that, even though it's a small profile device, it's engineering principles are such that it allows for very wide blood flow pathways. And in fact, despite its small profile, the blood flow pathways allow for 20 times more red blood cells to travel through the primary and secondary pathway, than other devices.

                                                What it means is that as blood is going through this device, it is exposed to very low sheer stress. And in return, the benefit that we see very clearly with this device in a very, very important way, is the fact that we see almost no denovo pump thrombosis developing with this device. Certainly, if the device doesn't carry some small quad risks in it, that cause problems with the device, it's probably also not causing the production of smaller non-device malfunction producing thrombi, which may with other devices, actually develop and cause strokes.

                                                So, we think that particular engineering enhancement, may play a very important role in reducing this stroke rate that we have observed.

                                                The second very important point that Biykem brought up, is this notion about the management of ... whether it be with anticoagulants or with blood pressure management. And for a moment let's dwell on the blood pressure issue. One of the striking things with the other centrifugal device, the HVAD device, is that the ENDURANCE Trial showed a significantly higher stroke rate with that device. And in fact, in a subsequent study, the ENDURANCE Supplemental Trial, when blood pressure was tightly, tightly controlled in the device, there appeared to be a small signal in reduction in strokes, although it still did not meet the non-inferiority endpoint, compared to the HeartMate II in the second supplementary trial that was done with that device.

                                                So, what's unique about this? Well, we can very clearly say maybe we just didn't have enough ability to show a difference in this particular trial, we didn't analyze it the right way, because we didn't have a blood pressure intervention or low or higher permissive blood pressures in this trial. But I would say that there's one other issue that I think may have played a very important role in this, and that is the HeartMate 3 is intrinsically developed with a fixed pulse algorithm. And in fact, the HeartMate 3 has a capacity where the magnetically levitated rotor upregulates itself and then downregulates itself every two seconds, and creates an internal pulsatility.

                                                Now, engineers developed that pulsatility to really decrease stasis, so that the pump wouldn't thrombose. But we often see that it provides sufficient peripheral pulsatility, not to the pulse pressures that we would normally like to see, but certainly to some degree, where the vasculature can perceive or transduce some degree of pulsatility. Why that may be important is, that it may actually allow for preservation of baroreceptor function in these patients, which tends to be lost in continuous flow pumps.

                                                And how important that is for blood pressure regulation and its vascular effect, may be something that needs to be looked at into the future. But it's certainly a very, very intriguing issue for us to examine.

Dr Biykem Bozkurt:         Mandeep, one final question or comment. Do want to comment on the stroke rates of HeartMate II compared to former trials. Because that comes as a common query as to why in MOMENTUM 3 the stroke rate in HeartMate II, appear to be higher than the former trials.

Dr Mandeep Mehra:       So very quickly, I'll tell you they're not. So, if you look at the 2009 randomized trials, randomized patients with a HeartMate II versus the HeartMate XVE trial, the two-year stroke rates with the HeartMate II in that trial were 19%, exactly what we observed at two years in this trial.

                                                Other trials have shown exactly that same number. The only trial in which there appeared to be a difference in those numbers, was in the ENDURANCE Trial, where the two-year rate of any stroke was 12%, and was a little lower in the HeartMate II than what we observed. However, I will caution you that if someone dies before having a stroke, then they die without a stroke. And so, stroke can sometimes we underestimated if the population that is enrolled, such as a transplant ineligible population at very high risk, is dying more often than having the chance of a stroke.

                                                So, I actually do not think at all that there was any difference whatsoever compared to prior trials. And even when you look at the ENDURANCE Supplement Trial, which is probably the most contemporary comparison of HeartMate II stroke rates, with MOMENTUM 3, the ENDURANCE Supplement Trial was only a one year trial, and the stroke rates even at one year were right on target with what we observed at the HeartMate II group in MOMENTUM 3. So, frankly that criticism is probably an unfounded criticism.

Dr Biykem Bozkurt:         Thank you.

Dr Carolyn Lam:                Wow, thank you Mandeep and Biykem, for really helping us go under the hood with this paper. I'm heart failure trained as well, but I learned so much, I'm sure our listeners did as well, and I'm sure you agree too Greg.

                                                Thank you so much for joining us today. Don't forget to tune in again next week.

                                                This program is Copyright American Heart Association 2019.


Dec 31, 2018

Dr Carolyn Lam:                                Welcome to Circulation on the run, your weekly podcast summary and back stage pass to the journal and its editors, and welcome to a whole new podcast format in 2019. Ha-ha, I bet that surprised you. Well guess what? This new format promises more interaction, more discussion and a whole lot more fun, and that's because to begin with, you don't have to listen to me talk to myself half the time anymore. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore, and I am simply delighted that Santa gave me a partner on this podcast, and co-hosted with me, and my gift is none other than Dr Greg Hundley, associate editor from the Pauley Heart Center, at Virginia Commonwealth University Health Sciences. Welcome Greg.

Dr Gregory Hundley:                       Thank you so much Carolyn. How exciting is it to start this new year with this exciting format, where we'll take several of the key manuscripts from Circulation and discuss them? Picking five each time, and as you've alluded to, we're not going to get rid of that favorite format, where we take a select paper and interview and work with the authors.

Dr Carolyn Lam:                                Exactly. In fact, maybe I could liken it to welcoming everyone to join us over a cup of coffee, each week, with the journal in the hand and we're just going to discuss it, and never forgetting that feature paper with the authors, and this week's paper is huge. I love it. We're actually going to be talking about blood pressure control in the barber shop. But before then, here's the articles that we've chosen to discuss. So Greg, you got your coffee ready? Shall we start?

Dr Gregory Hundley:                       Absolutely Carolyn, and let's get going first with Gorav Ailwadi, from University of Virginia, his paper evaluating the utility of MitraClips in those with secondary mitral regurgitation. This is really a follow-up from the EVEREST study. It's not a randomized trial, but it's a longitudinal look over time, at 616 patients. Interestingly, those individuals that had class three or four heart failure, that had the MitraClip, the left ventricular volumes got smaller in a year, the hazard ratio for events became less. The magnitude of mitral regurgitation went from 4+ down to 2+. Exciting findings.

Dr Carolyn Lam:                                Interesting, but you know Greg, these all sound so positive. Why is it so different in the Mitra FR study?


Dr Gregory Hundley:                       Absolutely Carolyn. So, as you know, Mitra FR, that was a randomized trial. So, this study doesn't compare, the EVEREST study in this issue, doesn't compare with conventional medical therapy, that's number one, and Mitra FR did. Also, the Mitra FR patients were a little bit sicker. The ejection fraction really was 15 to 40 percent, and in the EVEREST study, much higher, average 45 percent. In fact, many had a normal EF. So it really raises a lot of questions as to whether or not this finding will hold up in future randomized trials, which we'll be looking to see the results.

Dr Carolyn Lam:                                Indeed, and it was really nicely discussing the accompanying editorial wasn't it, which I really enjoyed. Well, the paper I picked out Greg is from Dr Gatzoulis from The Royal Brompton Hospital, and it's actually the MAESTRO trial. Now, MAESTRO is a randomized control trial of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. Short and long of it, macitentan did not show superiority over placebo on the primary endpoint of change in baseline to week 16 in exercise capacity. And there was also no relevant trends observed for the secondary endpoints.

                                                                However, among the exploratory endpoints, macitentan did reduce Nt-proBNP in the main cohort, and improved pulmonary vascular resistant index, and exercise capacity, in a hemodynamic sub-study. Importantly also, there were no specific safety concerns with macitentan.

Dr Gregory Hundley:                       Sounds really interesting, Carolyn. But how did this compare with prior studies that have really focused on endothelin?

Dr Carolyn Lam:                                Great question. So, MAESTRO's only the second randomized control trial of an endothelin receptor antagonist in Eisenmenger Syndrome. BREATHE-5 was the first, and this used a different endothelin receptor antagonist that was bosentan, also in Eisenmenger Syndrome, and actually found that bosentan reduced pulmonary vascular resistance as its primary efficacy endpoint, without worsening systemic pulse of symmetry.

                                                                So, very different trials in terms of endpoints, as you can hear, but also importantly, different populations that were enrolled. MAESTRO enrolled a more heterogeneous population with more complex forms of Eisenmenger, including patients with Down syndrome, had a broader WHO functional class inclusion, and allowed the use of pre-existing therapies such as PDE5 inhibitors.


Dr Gregory Hundley:                       That's really spectacular, Carolyn. Very interesting findings for something that these vasoconstrictors, vasodilators, often very harmful. Switching over, I've got sort of another paper that is also working on vasodilation, but comes really from the world of basic science. And it's from Ingrid Fleming from Goethe University in Frankfurt, Germany, examining how does hydrogen sulfide, a common gas that we have in the environment, it smells terrible, we worry about sulfuric acid and acid rain, but how does this promote vasodilation in the system?

                                                                And so, in this basic science study, they unlocked sort of a key that this hydrogen sulfide is produced by cystathionine gamma-lyase, CSE. And why is that important, and what does it do? Well, production of H2S by CSE goes and inhibits human antigen R, or HuR, that regulates cellular proliferation and growth. And so, basically these authors have unlocked a mechanism by which hydrogen sulfide can be protective.

                                                                So, what's interesting Carolyn is that patients can have elevated levels of L-cysteine, increased expression of CSE, so you've got the components and the manufacturer of H2S, but they still have low arterial levels.

Dr Carolyn Lam:                                 Hm. So, how can this be addressed then? How can we raise that H2S?

Dr Gregory Hundley:                       That's what's so clever that the investigators found out, Carolyn. They found a slow-release oral active drug, a sulfide donor called sodium polysulthionate, H2R, or sulfhydration, and can inhibit atherosclerosis development or progression when these levels are low.

Dr Carolyn Lam:                                Indeed. sodium polysulthionate. Awesome, Greg! That is so cool. Honestly I just loved your explanation of that. Okay. Well, I've got another paper to share. And this is from Dr Bress and colleagues from University of Utah School of Medicine. And this one is really interesting because these authors estimated the number of cardiovascular disease events that could be prevented, and the treatment-related serious adverse events that could occur over ten years, if U.S. adults with hypertension were achieving the 2017 ACC/AHA guideline recommended BP goals, compared to their current blood pressure levels, as well as compared to achieving the older 2003 JNC7 goals, or the older 2014 JNC8 goals.

                                                                Now, basically they found that achieving and maintaining the 2017 guideline blood pressure goals over ten years could prevent three million cardiovascular disease events, a greater number of events prevented compared to prior guidelines, but this could also lead to 3.3 million more treatment-related serious adverse events.

Dr Gregory Hundley:                       So, Carolyn, hasn't a main concern of this type of work been that these new guidelines over-extend the reach of our treatment?

Dr Carolyn Lam:                                That's a real concern that I've also heard. The lower blood pressure thresholds used to define hypertension in the 2017 guidelines could indeed lead to more diagnoses. However, this paper helped because remember that the recommendation for anti-hypertensive drug treatment in patients with the pre-treatment blood pressure of 130-139 systolic, or 80-89 diastolic, was limited to those at high cardiovascular disease risk. So not everyone, but only those at high cardiovascular disease risk.

                                                                And so, treatment under the 2017 guidelines, by these data, would lead to more health gains, while only extending treatment to 5.4% more adults with hypertension compared to JNC7. So, this paper really modeled these things out with important contemporary U.S. adult populations using a national representative, a sample of U.S. adults, and NHANES, as well as REGARDS, and they also used estimates of benefit from the recent large meta-analysis of 42 blood pressure-lowering trials.

                                                                So, important data that I think are going to be reassuring to a lot of people managing these patients. Well Greg, that really brings us to the end of our little chat. Now, let's move to our future discussion, shall we?

                                                                Could cutting blood pressure in a barber shop be the long-term solution to hypertension in African-American men? Well, the future paper of this first issue in 2019 really talks about it. Greg and I are so delighted to have with us the authors of the paper, Dr Ciantel Blyler, and Dr Florian Rader from Cedars-Sinai Medical Center, as well as our associate editor, Dr Wanpen Vongpatanasin.

                                                                So, Ciantel, can you just perhaps start by telling us what you found.

Dr Ciantel Blyler:                               So, what we're talking about today are the 12-month results as a follow-up to our 6-month results that we published earlier this year. So, we took 319 African-American men in Los Angeles County, and randomized them to two groups. One group saw a clinical pharmacist who worked with them to reduce their blood pressure, and the other group just worked with their barber to talk about blood pressure, and encourage usual follow-up.

                                                                And, as we saw at the 6-month mark, blood pressure really improved in the group that was able to work with the clinical pharmacist. So, we saw an almost 29 mm Hg drop in the intervention group, as compared to only 7 mm Hg in the control group.

Dr Gregory Hundley:                       Ciantel, Florian, that is really exciting results. What is a collaborative practice arrangement, and how did you affect that in Los Angeles?

Dr Ciantel Blyler:                               So, collaborative practice is actually widespread in the United States. California is one particular state that is kind of ahead of the curve with respect to collaborative practice between pharmacists and physicians. But what it essentially allows a pharmacist to do is to prescribe, monitor, and adjust medications underneath a physician's supervision. So, a document is drawn up, medications are selected, and an algorithm so to speak is put together so that a pharmacist can treat a patient independently of a physician needing to be there.

Dr Greg Hundley:                             Very nice. And did you find in the pharmacist-led group that these patients were taking a different anti-hypertensive regimen, or were they more compliant? What do you think was the reason for the discrepancy in this magnificent blood pressure drop in this group of hypertensive men?

Dr Florian Rader:                              So clearly, there were a lot of differences between the two groups. First of all, we had a protocol with our favorite blood pressure medications that we use clinically here in the hypertension center at Cedars-Sinai. Essentially it is long-acting calcium channel blocker, specifically Amlodipine, longer-acting angiotensin receptor blockers, or ACE inhibitors, and a third line, usually a thiazide diuretic, and also a longer-acting one, not the usual Hydrochlorothiazide, but specifically Indapamide that we used for this research study.

Dr Greg Hundley:                             And do you think that there was more compliance in this pharmacist-led group?

Dr Florian Rader:                              One would expect that. First of all, I think that seeing the clinical pharmacist, more frequently being reminded of taking the medications, having feedback by actually seeing the blood pressure numbers in the barber shop, I think would help. But then, in addition, we choose these medications not only because they affect it, but also because they're easy to take. They're once-a-day medications with very high continuation rates in larger studies, so they're just easier to take than other medications that are oftentimes prescribed.

Dr Greg Hundley:                             It sounds like also, there might have been a trust factor. Because you're seeing the same person over and over in a very nice environment. Was that a factor?


Dr Ciantel Blyler:                               Absolutely. I think there's a different level of trust that's established when you meet somebody on their own turf. So I think the fact that we met men in barber shops where they felt comfortable, where many of them had been going to the same barber for over a decade, it made all the difference in terms of establishing a rapport, and gaining their trust with respect to having them take medications. So, I think that was a huge part of why we saw increased adherence, and really sort of a commitment to the program.

Dr Greg Hundley:                             And we certainly recognize how harmful hypertension is in individuals of Black race. How does this group in Los Angeles translate to perhaps other Black men in the United States? Particularly, for example, in the South.

Dr Ciantel Blyler:                               I think the program could translate really anywhere. I think what makes it so tailored to African-American men is this notion of going into a barber shop, which is a very important place in the Black community. So, again, sort of going back to what I said earlier, most of these men had been seeing the same barber as frequently as almost every two weeks for over a decade. So, it really helps increase the frequency with which we could interact with the men, and it helped with continued follow-up and adherence to the program.

                                                                With respect to the area of the country again, I think it translates.

Dr Carolyn Lam:                                I've got a follow-up question to that, if you don't mind. So, I'm here listening all the way from Singapore, and I'm just so impressed, and frankly just enamored by this study. And wondering what is the barber shop to my local Chinese guy? I'm actually wondering if it's the kafei dian and that stands for coffee shop, and I'm also wondering what about the women? Wanpen, do you have any insights that you want to share?

Dr Wanpen Vongpatanasin:         I believe that even Dr Victor had thought about the beauty shops, that is a barber shop study in parallel, and this could very well work very well. Who knows, we could be going to massage parlor, anywhere, that when we feel relaxed and be ourselves, we go out our way, out of our regular activity, and it could really be a neat idea. And for a study, I'm not sure I could do something out of the box. I would say it must have been successful as this approach, and partly it could be because of the additional pharmacists engage likely. So, I think this is a perfect combination.

Dr Greg Hundley:                             Wanpen, you had mentioned Ron Victor. Maybe Ciantel, Florian, and Wanpen, you used to work with him. What did Ron mean to this study? Ron Victor unfortunately passed away this past Fall.

Dr Florian Rader:                              Ron hired me almost seven years ago now straight out of fellowship. He was personally my mentor. He taught me all the tricks when it comes to the work of the management of hypertension, so personally I owe him a lot. Regarding the study, he's been thinking about this for a long time, this approach to hypertension management. He's tried it in Dallas. It worked partially, but not very well because he didn't have a pharmacist, and he didn't have somebody that made it their goal to lower blood pressure no matter what.

                                                                And in this study, we had somebody like that, the clinical pharmacist. So, Ron Victor has thought about this for a long time, has done a lot of analysis of the Dallas hypertension study, and figured out why it didn't work out in Dallas, and really cooked up a recipe for this trial, and the results speak for themselves.

Dr Greg Hundley:                             Wanpen, do you have anything to add about Ron? I think he was your mentor as well.

Dr Wanpen Vongpatanasin:         Absolutely. I trained with him actually from the internship until fellowship, and I owe my career to him. And actually, I see this idea stemming from the Dallas heart study when he did the survey, and realized that if you just wait for patients to show up in the clinic, that you're not going to get anywhere, because African Americans have higher blood pressure at a younger age, and are more susceptible for target organ damage. And as we all know, by the time many presented with, they already have end-stage kidney disease or cardiovascular disease by the time first presentation. So, to avoid it, we have to go into much earlier, not wait until they come to the healthcare facility, and I'm glad to see that this idea is really becoming widely successful more than anyone can imagine.

Dr Carolyn Lam:                                What a beautiful tribute. What a poignant note. Thank you, all of you, for your great input, and for publishing this amazing paper with us at Circulation!

                                                                Thank you, listeners, for joining us today on Circulation on the Run with Greg Huntley and me. Thank you, and don't forget to tune in again next week.

                                                                This program is copyright American Heart Association 2019.


Dec 24, 2018

Dr Amit Khera:                  Welcome to Circulation on the Run, your weekly summary and backstage pass to the journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas. And I have the privilege of standing in for Dr Carolyn Lam, your usual weekly podcast host. Today we have a special treat. It is our semiannual fellows and training FIT podcast. And the additional part of this treat is we have three very special FITs today. These are our assistant editors for social media for Circulation. And really I want to introduce you just a moment, but I want to thank these three for their hard work and efforts. It really is them that helped bring our social media to life. And importantly for us, we really have a commitment to enhancing fellow education involving fellows in our editorial process and really making sure that the journal is appealing to fellows in training. So we really rely on these three to help us understand what best resonates and what is most helpful for fellows in training. So without further ado, Jainy Savla from UT Southwestern. Welcome Jainy.

Jainy Savla:                         Thanks for having me on the podcast today.

Dr Amit Khera:                  And we have Daniel Ambinder from Johns Hopkins University. Hi Dan.

Daniel Ambinder:             Hey Amit. Thanks for having me on the podcast today.

Dr Amit Khera:                  Absolutely. And finally we have Jeff Hsu from UCLA. Hi Jeff.

Jeff Hsu:                               Hi Amit and hi everyone. Very glad to be here.

Dr Amit Khera:                  Well, Jainy, I'm going to start with you. You've been with us on the social media side the longest. I think it's maybe almost a year or a bit more that you've been working on these efforts. And again, very much appreciate all of your hard work and insight. Tell us a bit about yourself.

Jainy Savla:                         So I'm currently a research fellow at UT Southwestern. So I completed my general cardiology training and I've been doing some extra research training in one of our basic science labs there.

Dr Amit Khera:                  So not surprisingly with your background, do you select an article? So we've asked them each to select one article as they've been working through the social media side and see all of our articles come through. Each to select one that they found was interesting and perhaps summarize for us what it included and what appealed to them. So Jainy, tell us a little bit about the article you chose and why you chose it.

Jainy Savla:                         So, I chose one of the articles that was published in April of 2018 from the Molkentin team lab. And this is a basic science article that focused on which types of cells contribute to heart regeneration. They hadn't thought that there was cardiac progenitor cell that could contribute to the development of new cardiomyocytes. And more recent data has shown that maybe that's not quite the case. So what this study did was used a lot of fancy lineage tracing models to try to figure out which types of cells we're actually contributing to the development of new cardiomyocytes. So importantly, what came from this was that one of their models, they were able to delete two transcription factors that are necessary for cardiomyocytes to develop from these progenitor cells. But they found that when they did that, they even got a higher number of cardiomyocytes that formed. And then what they were able to show in this paper was that actually comes from fusion of leukocytes to cardiomyocytes. And then interestingly, they found a role for one of these transcription factors and the development of endothelial cells. So that was kind of a new, not known function of one of these genes that was previously thought to be just contributory to cardiac development.

Dr Amit Khera:                  It's really a fascinating article when you think about it. Most of the science we publish are people bringing to light new discoveries and certainly there was a component of that here. But in many ways, it was kind of a different article where there had been this a prevailing thought about these c kit positive cells and here they're actually had gone through, refuted what people had thought was happening with these in this de novo cardiomyocyte formation. So you'll see that very often where people's articles or work is headed out to sort of maybe refute or set right what's happening in the literature in the field. Can you comment on that as to that type of article and how that appealed to you in this study?

Jainy Savla:                         That is interesting because previously it has meant that these cells can be used as a therapeutic option in human patients. But some of them were recent data showed that perhaps the new cardiomyocytes weren't actually coming from these cells, but it was hard to say. So the nice part about this paper was really they used a lot of important lineage tracing models to really show where these cells are coming from. And it helped clarify some of the, I guess, more confusing science that had been in the field since there were a few papers that showed these cells were contributary and then a few papers that have shown that maybe they weren't. So I think that's really helpful, particularly when you're talking about things that could be potentially used as therapeutic agents in human. And also the interesting thing is that while these cells themselves may not be useful to perhaps harvest and give to someone, you could potentially alter these cells and then they produce cells that fuse with cardiomyocytes. Or could you use this a different way? So I thought that was also interesting about this article.

Dr Amit Khera:                  Great points in it. It does remind us again that in our enthusiasm for rushing things to clinical practices in some things in this field, the importance of rigorous basic science to really understand the molecular underpinnings. And as you mentioned, there's some new insights here that could be used for clinical therapeutic purposes in the future. So definitely an interesting article and glad you enjoyed it and brought it to our attention. I'm going to ask you a bit of a different question. You again have been working with this in the social media side for longer. You've seen this now for some time about the different articles that come through. I know you and I've had several conversations about our different platforms, Twitter or Facebook, and how they're different and how we engage with them and how we engage with the audience. Can you tell us a little bit just reflecting now on your time and working with social media from a journal perspective, kind of what you've learned? What are some interesting observations over this year?

Jainy Savla:                         Definitely one interesting observation is just that their general usage of these social media platforms has increased significantly since I've started doing this. And you can see this with when we get articles that are accepted, how many authors have Twitter handles that they'd like to be tagged in some of these posts. And that's just gone up significantly since I've started doing this. And that also changes sort of what the comments we get on some of the posts and the back and forth discussions that we're seeing on these platforms. And then the second thing I found really interesting over time is that the way people use Facebook is really different from the way people use Twitter. And you can follow the discussions that people have linked to our posts a little bit better on Facebook. And then on Twitter, there's also a lot of similar discussions about these posts. But they kind of manifest in different ways and it's really interesting to see how that plays out.

Dr Amit Khera:                  I think those are fantastic points. And from a fellow's perspective, how do you think fellows are engaging with social media now compared to maybe, I don't know, when you started your training a few years back. What have you seen in a positive light?

Jainy Savla:                         I mean in general, there are more fellows on Twitter now than when I was a first-year fellow. Even myself, I've got my Twitter account when I was in fellowship. I didn't have one prior to that. I mean it's interesting because people are able to showcase their work a little bit better I think with these types of handles whereas before maybe you wouldn't know that even one of your own co fellows had published something. So it's kind of nice to see people use that kind of as a networking tool in some ways or to showcase some of their own work, which is something that when I was a first year and I didn't have a Twitter handle and there weren't as many fellows on Twitter, I didn't really notice some of the work that's being done by some of my colleagues at my level.

Dr Amit Khera:                  Those are great points and I'll stoplight some of the things you just said talking about it being a way for fellows to really showcase their work, to help with networking and in some ways, it's sort of the great equalizer. So I think it's really a valuable platform specifically for fellows. Well thank you Jainy. I'm going to move on to Daniel and hear a little bit from Daniel. Tell us a bit about yourself.

Daniel Ambinder:             I'm currently a second year cardiology fellow at John's Hopkins Hospital and I plan on doing interventional and structural cardiology in the future.

Dr Amit Khera:                  Great and certainly a lively and growing field and so many exciting things happening. Well, it's interesting you chose an article today that is more of a clinical article and obviously quite different than the last one we heard, but equally as interesting. Tell us a little about the article you've chose and why you chose it.

Daniel Ambinder:             I was very excited about this article that was published in Circulation back in July 2018. So, it's by Dr Borlaug and Reddy on how to diagnose HFpEF and what they did was they took patients with clinical dyspnea and they used invasive human dynamics to kind of assess whether or not they had HFpEF. And by doing so they were able to generate a list of clinical and eco based guidance to help us kind of identify patients with heart failure with preserved ejection fraction. So they came up with this amazing little table which was featured in Circulation and on Circulation twitter, where they have a chart that basically goes through several clinical variables including weight and hypertensiveness, atrial fibrillation, pulmonary hypertension, being elderly. And filling pressure is based on echo cardiographic information. And by that they were able to generate a score and give you a probability of if your patient has HFpEF or not.

                                                And the reason why I really enjoyed reading this article and also posting this article was because going through internal medicine and not being so fundamentally aware of echo and kind of what goes into understanding left ventricular filling pressures, it was challenging to make a diagnosis of heart failure with preserved ejection fraction. Do you just basically say, "My patient has lower extremity swelling but normal EF? They have heart failure with preserved ejection fraction and [inaudible 00:09:32] on the [inaudible 00:09:33]. And so I thought that this would be really helpful to the medical community at large. And in fact, shortly after we posted it, I saw that our cardiology console fellow is actually utilizing this exact table to help one of the medicine teams manage a patient with lower extremity swelling and come to the diagnosis of heart failure with preserved ejection fraction. So that is why I chose this article for today.

Dr Amit Khera:                  That's a great article and I thought you summarized it very well. And it is a field. HFpEF you'd see a lot of articles in Circulation on this topic. We have many people that are interested from an editor’s level but also from a society level. This is a huge problem, but we know very, very little. And I'm sure you know that as well and this was a wonderful tool. Just shows you're sort of the beauty and simplicity. Although if you read it, the message were pretty rigorous and they had a lot of great work that they did to develop it. But I love that the H2 HFpEF, how they basically came up with it h for heavy and the f from fibrillation. So I thought that was incredibly creative and a very simplistic but useful score. So, you said your, tell us about yourself. Have you used the H2 of the HFpEF score yet?

Daniel Ambinder:             Absolutely. I use it in clinic on a daily basis. And I actually pull up the Tweet in my office and show the patients why I think that they have heart failure preserved ejection fraction, especially since many of my patients start to get really nervous when you start talking about heart failure. But then they don't understand that they have a normal functioning heart. They can't really put those two together. And so going through this chart and going through the etiology, or at least what we know about heart failure with preserved ejection fraction, turns out to be quite helpful.

Dr Amit Khera:                  And the basis of this study goes back to hemodynamics. This obviously is a cohort where they had done invasive hemodynamics to essentially diagnosed HFpEF based on pressure. So as you, as someone who's going interventional and structural where we are really seeing kind of the rebirth or refocus on hemodynamics again, tell me a little bit like what you're learning in terms of hemodynamics and how you think that importance in today's practice of cardiovascular medicine.

Daniel Ambinder:             One of my passions is spending as much time as I possibly can in the cardiac ICU. And we're fortunate to meet many different patients that come in with very different kinds of cardiogenic shock for other hemodynamic compromise from other types of shock. And I have found it extremely helpful to think about either using a virtual Swan or by actually getting the measurements with a PA catheter to kind of identify where the break in the system is to hopefully provide our patients with the ability to turn them around in a fast manner before they develop metabolic compromise from prolonged hypoperfusion.

Dr Amit Khera:                  Great summary of how you're using hemodynamics and the training. And I'm going to pivot. The last question for you is when we first met I think several months back and we're communicating about your interest in social media, one thing that was really interesting and fascinating was the great work you're doing on Twitter on your own account where you essentially, if I think you told me this right, you sit on your iPhone and basically in this matter of a very few minutes would construct cases and teaching points on Twitter. So tell me a little bit about that, about using Twitter for medical education and learning cardiology and cases. And I know you're passionate about that. So tell us a little bit more about that.

Daniel Ambinder:             Back in May, last year, I had been in my first year of cardiology fellowship. And I was really kind of obsessed with grabbing as much imaging and cases as I could to construct them into teaching stories to share these important stories that I encounter with other people. And so also share the aha moments that I have when I'm learning from my mentors about a new clinical condition or even a clinical condition that I've encountered many times. We never thought about any unique way. And so I was putting these all together and developing somewhat of a library of cases. But I would share them with the residents that I was working with at the time. And then Dr Erin Michos was one of my mentors at Hopkins. She's an echocardiographer and she kind of exposed me to the Twitter community where you're really able to just start reaching out to different people and share the same insights that I had saved on my drive on my computer. And so I started constructing these cases, putting that together and developing them and then associating them with like a few bullet pointed tidbits of pearls that I can put on Twitter. And I quickly realized what an amazing community Twitter have to offer in terms of cardiology and in terms of the medical education community at large.

                                                At first, I realized you can't put out content and not expect to participate in a conversation. It has to be two ways. You have to really engage with others and others will engage with you. And then just a couple months later, it's really grown that you can post a case, post the teaching pearl and in about 24 hours it can be viewed thousands and thousands of times, really internationally. And generates just so much great conversation. So it's been really a tremendous way to communicate with the world, especially within the cardiovascular world.

Dr Amit Khera:                  Well thanks. I think there's so much learning that can happen and I think the work you're doing with cases and with others. And I know when I've gone on Twitter, even in just two minutes you can see really fascinating things and learn a lot. So keep up the good work and appreciate your efforts there. I'm going to switch gears and finally finished with Jeff Hsu from UCLA. Jeff, tell us a bit about yourself.

Jeff Hsu:                               I'm a fellow at UCLA. So I actually finished my general cardiology fellowship pretty recently and now I'm a research fellow in the STAR program here. I'm also enrolled in the PhD program at UCLA in the Department of Physiology and planning to defend in the next few months. So right now, very stressed out about that. Starting in July, I'll be starting advanced fellowship in advanced heart failure and transplant here at UCLA.

                                                Well excellent and best of luck to you in your PhD defense. Now you also chose a very interesting article that again, all of yours are a bit different. So tell us a little about the article you chose and why you chose it.

                                                When I chose this article, I was really excited by a few weeks ago. It was published in the December 4th issue of Circulation called Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells. So this came out of the lab of Joe Wu at Stanford and the co first authors is Ning Ma, Joe Zhang and Ilanit Itzhaki. But I think the beauty of this article is that it really addressed this frustrating clinical scenario in question that we often encounter nowadays in this era of genome sequencing. And now that we're sequencing a lot more people, since the cost of sequencing has come down a lot, we were finding a lot of these mutations that we don't know what to do with, so I think Dr Wu's lab really try to address this question using the disease model with the cardiomyopathy. So, leveraging Dr Wu's expertise in using human induced pluripotent stem cells or iPSCs, they found a patient who is actually healthy but apparently had this mutation in this gene called MYL3 or myosin light chain 3. And so this patient had a variance of uncertain significance in this gene.

                                                Now, notably, this patient, again had no clinical phenotype, was very healthy and the patient's family members over three generations were all healthy too. But had this mutation that based on in silico analyses was thought to be likely pathogenic. So using cells from this patient that they reprogrammed into cardiomyocyte, they tested various properties of these cells from the same patient to see whether or not they thought this mutation is actually a pathogenic mutation. So again, using these reprogrammed cardiomyocytes, they tested a variety of things including gene expression, sarcomere structure, and cell contractility, action potentials, and the handling of calcium. And they saw that even with this mutation, there were no abnormal findings in vitro in their system.

                                                Now just to prove that their cell culture system and this in vitro model of testing the pathogenicity of certain mutations actually works, they actually took cells from a patient who did have the clinical phenotype as a result of a known mutation that causes hypertrophic cardiomyopathy. And found that when testing those cells in vitro, they did demonstrate abnormal phenotypes in all the parameters I mentioned before. So I thought this is really exciting. I thought this is a great way to address, potentially answer whether or not we think these variants of uncertain significance that we often encounter are indeed pathogenic because we are often just left in this situation where we don't know what to do with this information. But this potentially at least is a proof of concept for this protocol where we can finally take advantage of the ability to take cells from our patient and actually test them in the lab to see whether or not either various treatments work or whether or not these mutations that actually will results in pathology down the line. So I thought overall this was a great paper that was a great summary of how we can take the bedside to the bench actually. And I'm just really looking forward to the future where we can maybe then bring it back to the bedside.

Dr Amit Khera:                  Well thanks. I think that's an excellent choice and a great summary. And this article really hit all of the kind of timely and cutting-edge topics in the era genomic medicine and precision medicine have really kind of individualized treatments. And when we get stuck, these VUSes, these are a nightmare. And also this is sort of proof of concept for extending this to other treatments and other ways to test drugs and therapies. I've heard Joe, we talk about this before and use the word disease in the dishes. He did I think in the article itself and it's exactly that. I mean the potential here is profound. I'll pivot this into the next question for you. For our roles, one thing we do is we interact a lot with media and I interact a lot with them to help translate, I guess, the articles that we have to things that would be able to be digestible for media and for lay individuals. It was interesting because it's hard for us to do that with basic science and most of the time we have some difficulty in translating that. But this one translated pretty well and I think we had done some various press releases and things because it really showed the potential of modern medicine and kind of the excitement of it.

                                                But that gets to the question I have for you, something we have discussed as well, your interest in basic science and some of the challenges of taking basic science articles and digesting them down to a couple hundred-word tweet. Even as beautiful as all the pictures are, and in this article I think there's six figures, but each panel is 10 pictures or 10 figures by themselves. And how do we digest basic science articles down to make them really appeal to people on social media and help people understand that may not be in the fields or in basic science that are clinicians, if you will. I know you've thought about that a little bit. Tell me a little bit about your thoughts on that.

Jeff Hsu:                               Jainy, Dan and I have this challenge on a weekly basis, figuring out how to summarize great articles such as this one into a short tweet. And I think that is a big challenge particularly for basic science articles on social media to make it appeal to a broader audience because the audience you're seeing on Twitter and Facebook, again, they're not just basic scientists. If you want to catch people's attention, you need to find a way to really understand the big picture of the question you're answering in your basic science research. So I think that is a challenge. You're challenged to make your science appealing to a broader audience. But I think again, that's one of the advantages of social media is that you can appeal to a larger audience and have a wide range of people engage with your research and understand your research. So it is something that we work on is to try to pick out the figure that best represents the science that was done in these basic science articles.

                                                It can be quite challenging because a lot of times one picture won't do it justice. So it's tough to distill a full article in one picture. It is helpful when some articles do have a summary, a graphic or figure where they typically reserve their last figure for either a cartoon or some type of schematic that really explains either the mechanism or pathway that they explored in their article. So what we've found is that these articles that do have some of these illustrations or summary figures, they seem to engage a larger audience on Twitter and social media. So personally I find it more appealing when I do see these summary figures. So if there is one recommendation, I would have the basic science researchers, especially trainees is in this age of social media, try to come up with an illustration or summary figure for your research. I think it helps you figure out what is truly important with the research that you've done and helps you communicate this research to a broader audience. And I've seen a lot of people take advantage of a graphic designers to really help them illustrate their research. And I found that to be very effective in articles I've read on social media.

Dr Amit Khera:                  Thanks Jeff. That's a great point and great suggestion. And certainly these days the most effective communicators are those they can translate their complex science into easily digestible bites and can think of ways to portray them in ways that sort of summarize, like you said, be it summary figures or otherwise. And it's a challenge and also talent. And you all are certainly perfecting that. Well, I think we've had an excellent conversation. I have to tell you, I'm so excited to get the chance to spotlight you all. You do excellent work each day. Every week you're working hard and coming up with great ideas and suggestions and we really value having your input as fellows and training and as a colleague.

                                                Thank you for joining us today on our FIT podcast. Amit Khera standing in for Carolyn Lam. We look forward to seeing you for our next edition of Circulation on the Run. This program is copyright American Heart Association 2018.


Dec 17, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                In today's feature discussion, we will be doing a deep dive into the LEADER trial results, looking at new results of liraglutide and its effects in patients with type two diabetes, with or without a history of myocardial infarction or stroke. All of that coming right up after these summaries.

                                                In today's issue, five groups of investigators in two original basic research articles and three research letters tackled the same biological question, and all reached the same conclusion that cells in the heart expressing the SCA-1 cell surface antigen do not become cardiomyocytes to any meaningful degree, and instead become endothelial cells. Among the original basic papers, first author Dr Vagnozzi, corresponding author Dr Molkentin from Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, and their colleagues use the inducible recombinase method and generated a constitutive recombinase at the SCA-1 locus. They found that cardiac resident SCA-1 positive cells were not significant contributors to cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells generated cardiac vasculature throughout development, during aging, and following injury with trivial contribution to the cardiomyocyte population.

                                                In the second paper from co-first authors, Drs Zhang and Sultana, with corresponding author Dr Cai from Indiana University School of Medicine and colleagues, these authors engineered a series of genetically altered mice to identify and track SCA-1 positive cells in the heart, and found that SCA-1 positive cells were purely of the endothelial lineage. Together with three research letters, these five papers add to the growing body of evidence that in adult mammals, our new cardiomyocytes arise from preexisting cardiomyocytes and rarely, if at all, from adult cardiac stem cells.

                                                Could metformin be cardioprotective in patients with type one diabetes? Co-first authors Drs Bjornstad and Schafer, corresponding author Dr Nadeau from University of Colorado School of Medicine, and their colleagues hypothesized that adolescents with type one diabetes have impaired vascular function, and that metformin may improve insulin resistance and vascular dysfunction.

                                                To test this hypothesis, they studied 48 adolescents with type one diabetes and 24 non-diabetic controls using MRI of the ascending and descending aorta, as well as assessment of carotid intima-medial thickness by ultrasound, brachial distance ability by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic euglycemic clamp. The adolescents with type one diabetes were randomized one as to one to three months of 2000 milligrams metformin or placebo daily, after which the baseline measures were repeated.

                                                The authors detected early signs of cardiovascular disease with MRI in these adolescents with type one diabetes compared to controls. They further found that three months of metformin therapy improved insulin sensitivity as assessed by gold standard hyperinsulinemic euglycemic clamp, both in normal weight and obese adolescents with type one diabetes. Moreover, metformin improved carotid intima-medial thickness and aortic wall shear stress and stiffness. Thus, metformin may hold promise as a cardioprotective intervention in type one diabetes.

                                                What are the clinical genetic and environmental determinants of varicose vein formation? Co-first authors Drs Fukaya and Flores, corresponding author Dr Leeper from Stanford University, and colleagues applied machine learning to agnostically search for risk factors of varicose veins in nearly half a million individuals in the UK bio bank. They found that greater height appeared as a novel predictor of varicose vein disease in machine learning analyses, and was independently associated in multi-variable adjusted Cox regression. Using Mendelian randomization, they demonstrated that greater height had a causal role in varicose vein development. A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development, and skeletal/limb biology, and discovering a strong genetic correlation between varicose veins and deep vein thrombosis. The knowledge greatly expands our understanding of disease pathophysiology, and may help future improvements in the management of varicose veins and their associated complications.

                                                The final original paper describes the effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events, and all-cause mortality in patients with type two diabetes and chronic kidney disease. First and corresponding author Dr Mann from Friedrich Alexander University of Erlangen in Germany and their colleagues performed a post hoc analysis of the LEADER trial comparing the liraglutide's treatment effects in patients with and without kidney disease.

                                                As a reminder, LEADER was designed to recruit a subgroup of at least 660 patients with an estimated glomerular filtration rate, or eGFR, less than 60, approximately 220 patients with severe renal impairment, eGFR less than 30, and at least 440 patients with moderate renal impairment with an eGFR of 30 to 60. The authors found that the liraglutide reduced the risk of major adverse cardiovascular events, and all-cause mortality compared with placebo in patients with chronic kidney disease defined as an eGFR less than 60, and also in patients with albuminuria defined as a urinary albumin to creatinine ratio above 30.

                                                The overall risk of adverse events did not differ between the liraglutide and placebo treated patients either with or without chronic kidney disease in the LEADER trial. In summary, these results show that liraglutide added to standard of care reduced the risk of major cardiovascular events and all-cause mortality in patients with type two diabetes and chronic kidney disease. Furthermore, these results appear to apply across the chronic kidney disease spectrum that was enrolled.

                                                And that brings us to the end of our summaries. Now for this week's feature discussion.

                                                Cardiovascular outcome trials have transformed the world of treating patients with diabetes. And for our feature discussion today, we're going to be talking about a new analysis from a very important trial, the LEADER trial of GLP-1 receptor agonists, and that's the liraglutide. I'm very proud to have the corresponding author of this paper with us, Dr Subodh Verma, and he's from St Michael's Hospital and University of Toronto, and our senior associate editor, Dr Gabriel Steg, from University of Paris. Actually, Gabriel, I'm actually going to start with you for once because I recall perhaps something you may have written about cardiovascular outcome trials.

Dr Gabriel Steg:                Yeah, it's really funny. I'll try to take it graciously. You know, I wrote a frame of reference in Circulation a few years ago, wondering whether we were doing good by doing all these large outcome trials for safety with new anti-diabetic drugs, because there had been not one but two, three, four, five, six trials that were essentially neutral, enrolling more than 107 patients and participants at the expense of millions of dollars, and not much came out of it. And this was published in circulation. I was very happy until the next trial comes up, and this is EMPA-REG. And the next one is LEADER. And we have two trials that literally transform our vision of anti-diabetic agents as major agents for cardiovascular prevention. The trial we're going to discuss today, which you wrote about, is one of these trials. And I think I have to revisit my own writings and probably eat my hat.

Dr Carolyn Lam:                So indeed, that's a great segue. Thank you, Gabriel. And Subodh, tell us then, what did you look at this time in LEADER? And maybe start by saying a little bit about LEADER, and the rationale for doing this particular sub analysis.

Dr Subodh Verma:           Right. So, as Dr Steg mentioned, these were FDA-mandated studies to look at safety and potential efficacy of newer antihyperglycemic agents. The entire premise was that cardiologists and cardiovascular specialists were not really getting that excited about antihyperglycemic therapies in people with diabetes, because there was no data that they did much. And as Dr Steg mentioned, even the data leading up to some of these trials were disappointing, suggesting that they're safe, but they neither reduce nor increase events.

                                                So, I think EMPA-REG and LEADER really changed the calculus in many ways of how we look at cardiovascular risk reduction with antihyperglycemic agents. LEADER was a trial that was 9,340 patients. These are patients that were at high cardiovascular risk, but unlike EMPA-REG that only enrolled people with prior to ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a position of enriching the population with this spectrum of patients with cardiovascular disease and risk factors.

                                                So, some were in so-called high risk primary prevention who had not had established ASCVD, but had multiple risk factors such as uncontrolled hypertension or chronic kidney disease. Some had evidence of ASCVD, but had not had a prior myocardial infarction. And some, in fact, had had a prior MI stroke or PAD. So, it was a broad population of patients that was enrolled. And the primary result, again, for the primary outcome of MACE, demonstrated a significant reduction in favor of liraglutide versus placebo. And then for the individual components of that primary outcome, they were all statistically significant, or at least went in the right direction. Importantly, CV death was reduced by 22% with liraglutide versus placebo.

                                                I would like to emphasize that in this day and age, and Dr Steg has nicely set the stage, we have started thinking about how do we think about cardiovascular phenotypes of patients. You know, is a drug more likely to reduce heart failure? More likely to reduce ischemic events? And with LEADER, we found that in fact the trial actually reduced mostly ischemic events, and was really not that beneficial on heart failure related outcomes.

                                                So, that was the broad positive outcome from LEADER. They've led to guideline changes worldwide that patients with diabetes should be prioritized to receive an agent that has shown benefit, particularly if they have cardiovascular disease. And one of those agents was empagliflozin. The other was liraglutide. But, secondary prevention is a pretty crowded space, and not everybody can get everything, and not everybody should get everything, and not everybody can afford everything. So, I think leaders like the two of you here are often thinking about, how do you risk-stratify these populations, and how do we start thinking about people who are at greater risk, people who can actually derive benefit? And I think that's the smart and thoughtful way of doing this. And is there a certain threshold at which point the therapy loses its ability to reduce cardiovascular events, at least in the short term?

                                                So, in that theme, in that vein, what we looked at here was an analysis of people in LEADER who truly had a prior ischemic event. And the work that Dr Steg and others have done in REACH registries, etc. clearly establish that that's a population of patients, type two diabetes and a prior ischemic event. You don't really need many more calculators beyond that. That's the highest risk population. And then, the next level is really type two diabetes with a ASCVD. And we know that from REACH as well, that that's the next level of risk. And then, what about people who have type two diabetes just by itself? Which certainly are much higher risk than people who don't have diabetes, but we didn't have a non-diabetic group to compare to.

                                                And what we find is that the higher the baseline risk defined by this, the greater is the absolute risk reduction. The P value is consistent for ... You know, this is non-significant for heterogeneity. but specifically, people with a prior ischemic event derive benefit. People without a prior ischemic event who've had ASCVD derive significant benefit. But, in fact, we found that the curves were almost superimposable for people who did not have prior ASCVD. And that's not to say the GLP-1 receptor agonists should not be used in diabetes in the absence of cardiovascular disease, because they're great glucose lowering agents. They cause hypoglycemia, they cause weight loss. And potentially, within longer exposure times, cardiovascular benefit may actually emerge. And we've heard data from Dr Gerstein's study called Rewind that is positive, that will be presented next year. Harmony Outcomes was a study that was presented recently that also showed a benefit. So, whether in the primary prevention group we see a benefit in the future remains to be seen.

Dr Carolyn Lam:                Oh, that's a great, great summary. But Subodh, you know, it's become a bit of what do we define as a primary and secondary prevention anymore, you know? And the patient that already got type two diabetes. Now, in this paper, it's very nice. As you said, has a history of myocardial infarction and stroke. And maybe I could just clarify to the audience, you couldn't just pick up the primary paper and see that because the way the inclusion exclusion criteria were designed in LEADER, you can't just pick up the sub-groups. So, this specific analysis, so carefully and wonderfully done, was absolutely needed. But then you know, what do you think? What's primary and what's secondary prevention anymore?

Dr Gabriel Steg:                Well, I want to commend the authors for doing the careful stratification of diabetic patients they've done in the paper, and particularly for pointing out that it's one thing to have had an event where you actually ruptured a plaque and had a traumatic event. And it's very different from merely having plaque in one of your carotids or your arteries, and which is, of course, in turn very different from the majority of diabetic patients who have neither an event, nor diagnosed plaque or established plaque. And when we think about preventing cardiovascular and diabetes, we have to remember that the outer circle, the broader circle of diabetic patients who haven't had disease is the largest component.

Dr Subodh Verma:           True.

Dr Gabriel Steg:                And these are the patients whom we treat every day with the hope of eventually keeping them from harm, safe from harm, or with therapies that are new and potentially beneficial. And I think your research very clearly shows that there's a gradient of benefit. The sicker the patient, the greater the benefit in preventing MACE. And as long as you get to more healthier phenotypes of diabetes, then there is less of a benefit. Which doesn't mean that we shouldn't use these agents. As you point out, they're very convenient and effective agents for glucose control. But then, their cardiovascular benefits are more uncertain. And I think this is the key message from this analysis, and it's a great analysis.

Dr Subodh Verma:           Thank you. I appreciate that. I totally agree that for the doctor in the trenches, particularly the cardiologist who's just trying to get their feet wet with antihyperglycemic therapy, you know? Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at low dose, and maybe a new way of doing surgery or putting an LVAD. But it's very hard to get their attention when it comes to antihyperglycemic therapy. So, defining for them the population that matters the most, where the greatest risk and risk reduction can be achieved, I think is quite important from a clinical standpoint. And I think most cardiologists will agree that type two diabetes and a prior ischemic event is a high-risk population. Type two diabetes in a prior ASCVD is a high-risk population, and the magnitude of CV death reduction here is something meaningful for them to pay attention to.

Dr Carolyn Lam:                Yeah, indeed. That's what I love best about this paper. It's actually asking the question the way a cardiologist would, exactly like you had both put. So, what do you think is the next step now? Do you think we need to look at this primary prevention type two diabetics with no established cardiovascular disease? Do we really need to? Is it that we need a method analysis, which you can talk about? Or, is it that we need longer follow up? Or, what next?

Dr Subodh Verma:           I think that first of all, we have to get rid of the terminology, and maybe as a heart surgeon, I can be a little bit provocative and just say it. I wrote an editorial to the Declare Study that was just published yesterday in The Lancet called "Pumps, Pipes, and Filter: Do SGLT2 inhibitors cover it all?" Then I made a strong statement there that this nomenclature of primary and secondary really is artificial because it only captures ischemic risk, and does not capture risk of heart failure or renal disease. So, in a patient, as you've asked, Carolyn, who has type two diabetes, whose renal function is 54 or GFR is 55, who's not had a prior MI ... Is that patient primary prevention? Maybe from an ischemic standpoint, but he's clearly secondary prevention from a renal standpoint.

Dr Subodh Verma:           So, I think we need to just think about all disease as a spectrum, and not as an artificial cutoff that, if you've had an ischemic event, suddenly the world changes for you there. Because, that gradient I think is probably what we need to somehow appreciate as to where that risk lies. The patient who's 40 who's had no risk factors, you know? The Rashami paper from the New England Journal that looks at risk factor control and diabetes make a very compelling story that if you control your five risk factors, you actually don't have an excess risk of cardiovascular events in diabetes, at least from MACE. The story is whether anybody can have those five risk factors controlled. But, early on in diabetes, with diabetes duration not being that significant, with risk factors not being that significant, I think maybe that's not the population to go after. But certainly, waiting for ASCVD to develop and then start therapy is also not the right way of doing it, so ...

Dr Carolyn Lam:                Interesting. I really wonder what new guidelines are gonna show. Gabriel, any other perspective?

Dr Gabriel Steg:                Well, first of all, I love the editorial. I thought the title was fantastic, and you summarize here what we need to think about when we think about diabetes; not solely the pipes. As an interventional cardiologist, I'm very interested in the pipes.

Dr Subodh Verma:           Me, too.

Dr Gabriel Steg:                Not solely the pump, but also the filter. And there's more than the heart and vessels in the complications of diabetes. So I thought it was a great, great title. My view is that we still need to remember that if we take the lifetime perspective, a healthy youngster with type one diabetes, a relatively healthy patient in his fifties with type two diabetes, their probability of dying from cardiovascular disease is enormous. Even though risk calculators will give them a relatively low probability over the 5 year or 10 year term, eventually that's what's gonna get them. And therefore, we still have progress to make. We are fortunate to have lived an incredible period in the past few years where we've had emergence of new risk preventive therapies in diabetes. That's incredible. It's an epiphany. But, it's not over. We need more information, more trials in other populations. We need to look at renal function and heart failure. So, it's a great time to be doing clinical trials in diabetes.

Dr Subodh Verma:           Right.

Dr Carolyn Lam:                And indeed, a great time to be publishing in circulation. We've been really doing a lot of publications in the cardiovascular outcome trials in diabetes here.

Dr Subodh Verma:           And it's being noticed. There's no doubt about it.

Dr Carolyn Lam:                I hope so. And, maybe a time for a new frame of reference, because what you just said was diametrically sort of in contrast.

Dr Subodh Verma:           I would emphasize one more point, and that is, you know in atherosclerosis, the dominant mechanism has been LDL, right? And Dr Steg here is changing the landscape of that with Odyssey Outcomes and many other strategies. But again, in Circulation, Dr Bhatt, and I, along with the LEADER investigators, recently presented and published a paper showing that liraglutide's benefit is seen independent of LDL cholesterol, and all the way down to people with LDLs of below .5. So, the point is that this mechanism of benefit of GLP-1 seems to be complimentary to LDL lowering. And therefore, I think it offers great hope that you can actually reduce the ischemic burden in diabetes, not just by ultra-low LDL, but by potentially additional mechanisms as well.

Dr Carolyn Lam:                Absolutely. And then now, because I have to have the last word here on this show, let's not forget heart failure outcomes in diabetes. I think it's underestimated. I think it's really important. Okay, and with that, thank you gentlemen for joining me today.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2018.


Dec 10, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. What are the long-term effects of oxygen therapy in patients with suspected acute myocardial infarction? Well, to find out, stay tuned for our discussion of our feature paper this week, coming right up after these summaries.

                                                The first two original papers demonstrate that, similar to neonatal mice, one day old and two-day old neonatal pigs are capable of mounting a cardiac regenerative response following myocardial infarction, which is characterized by restoration of contractile function, cardiomyocyte replenishment, and minimal fibrosis. Now, interestingly, this regenerative capacity is lost after the first two days of life.

                                                The first paper is from co-corresponding authors, Drs Yeh and Cook from National Heart Research Institute of Singapore and National Heart Center, Singapore, and the second from co-corresponding, authors Drs Zhang and Zhu from the University of Alabama at Birmingham.

                                                These authors report collectively that proliferation of preexisting cardiomyocytes appear to be the primary source of cardiomyocyte replenishment in neonatal pigs with markers of cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis elevated following injury in the one day and two-day old hearts, but not at later time points.

                                                Furthermore, cardiomyocyte DNA synthesis was increased following neonatal pig myocardial infarction. Cardiomyocyte proliferation significantly decreased after this two-day window, which was associated with a marked reduction in telomerase activity.

                                                Heart failure with preserved ejection fraction may look different in the young compared to that in the elderly. First author, Dr Jasper Tromp, corresponding author, myself, Carolyn Lam from the National Heart Center, Singapore and Duke National University of Singapore, and our colleagues from the Asian Heart Failure Registry studied more than 1,200 patients with HEF PEF from 11 Asian regions and found that 37% of our Asian HEF PEF population was under 65 years of age. Younger age was associated with male preponderance, a higher prevalence of obesity, and less renal impairment, atrial fibrillation, and hypertension. Left ventricular filling pressures and the prevalence of left ventricular hypertrophy was similar in the very young of less than 55 years and elderly HEF PEF of more than 75 years of age.

                                                Compared to age matched controls from the community without heart failure, the very young HEF PEF patients had a three-fold higher death rate and twice the prevalence of left ventricular hypertrophy. Thus, young and very young patients with HEF PEF display similar adverse cardiac remodeling as their older counterparts, but very poor outcomes compared to controls without heart failure.

                                                Obesity may be a major driver of HEF PEF in a high proportion of HEF PEF in the young and very young.

                                                How important is hospitalization for heart failure as a complication of diabetes? In the next paper from first and corresponding author, Dr McAllister from University of Glasgow, the authors examined the incidents and case fatality of heart failure hospitalizations in the entire population age 30 years and older resident in Scotland during 2004 to 2013.

                                                Over the 10-year period of study, among 3.25 million people, the coot incidence rates of heart failure hospitalization were 2.4 per thousand-person years for those without diabetes, 12.4 for those with type two diabetes, and 5.6 for those with type one diabetes. Heart failure incidents had fallen over time for people with and without diabetes, but remained around two times higher in people with diabetes than those without diabetes. Heart failure case fatality was higher in people with type one diabetes. Duration of diabetes and glycated hemoglobin was associated with increased risk of heart failure in type one and type two diabetes. Thus, clinicians should be aware of the importance of heart failure and diabetes, especially in type one diabetes where this is under appreciated.

                                                What are epigenetic mechanisms contributing to ischemia reperfusion injury? Co-first authors Dr Yu, Yang, and Zhang, co-corresponding authors, Dr Xu from Nanjing Medical University, Dr Sun from Fudan University, and Dr Ge from Fudan University, and their colleagues evaluated the potential role of megakaryocytic leukemia one, or MKL 1, as a bridge linking epigenetic activation of NAD pH oxidases, or NOX, to reactive oxygen species production and cardiac ischemia reperfusion injury in mice. They found that genetic deletion of pharmaceutical inhibition of MKL 1 attenuated cardiac ischemia reperfusion injury in mice. MKL 1 levels were elevated in macrophages, but not in cardiomyocytes in vivo, following cardiac ischemia reperfusion injury.

                                                MKL 1 recruited the histone acetyltransferase, MOF, to activate NOX transcription in macrophages. Pharmaceutical inhibition of MOF attenuated cardiac ischemia reperfusion injury in mice, and pharmaceutical inhibition of NOX one or four attenuated cardiac ischemia reperfusion injury as well.

                                                These findings provide a novel link between MKL 1-mediated epigenetic regulation of gene expression in macrophages and ischemic heart disease. This opens the door to small molecule compounds targeting the MKL 1 MOF NOX access as a novel therapeutic strategy against ischemic heart disease.

                                                Is the time from last hospitalization for heart failure to placement of a primary prevention ICD associated with patient outcomes? First and corresponding author Dr Ambrosy from the Permanente Medical Group in San Francisco performed a post hoc analysis of Medicare beneficiaries enrolled in the national Cardiovascular Data Registries implantable cardioverter defibrillator, or ICD registry, all with a known diagnosis of heart failure and an ejection fraction of less than 35%, undergoing a new ICD placement for primary prevention.

                                                They found that older patients, currently or recently hospitalized for heart failure, undergoing initial ICD placement for primary prevention, experienced a higher rate of periprocedural complications and were at increased risk of death compared to those receiving an ICD without recent heart failure hospitalization. Additional prospective real world pragmatic comparative effectiveness studies should be conducted to define the optimal timing of ICD placement.

                                                The final original paper presents result of the VERDICT trial, a large scale randomized controlled trial evaluating the value of very early invasive strategy conducted within 12 hours of diagnosis on long term clinical outcomes in patients with non-SD elevation acute coronary syndrome. First and corresponding author Dr Kofoed from University of Copenhagen and colleagues studied 2,147 patients who were randomized and found that an invasive strategy performed within 4.7 hours after diagnosis was not associated with improved outcomes, compared to an invasive strategy conducted within two to three days.

                                                However, in the pre-specified subgroup of patients with a GRACE risk score of more than 140, a very early invasive treatment strategy did appear to improve outcomes, compared to a standard invasive treatment strategy. And that wraps it up for our summaries. Now, for our feature discussion.

                                                For our feature discussion today, we are talking about oxygen therapy for patients with suspected acute myocardial infarction. Something that seems so benign, something we've taken for granted, and yet now we now question since the Detox AMI trial. Well, for today's feature paper, we have a follow-up of this trial, and I'm so pleased to have actually our associate editor, but also author of this paper, Dr Stefan James from Uppsala Clinical Research Center, and the guest editor for this paper, Dr David Morrow, who's from Brigham Women's Hospital and Harvard Medical School. So, thank you both for being here.

                                                Stefan, could I just ask you to start by taking us back. How was Detox AMI first conceived? What made you even question oxygen therapy? And then, perhaps then, tell us about what this new paper adds.

Dr Stefan James:              I think that's so interesting because I think we all learned in medical school that for myocardial infarction, you should always deliver oxygen. That's sort of the first choice. And the other sort of first choice that we learned was morphine. Some of the other important things that we learned was to give not only oxygen but morphine, and nitroglycerin, and perhaps aspirin. And by those four, only aspirin is really the agent that has been proven beneficial to patients.

                                                But we thought for many years actually about this oxygen hypothesis, or we were interested in trying to understand, is it really helpful to give patients oxygen? Or are we in fact harming patients? Because there is, as you may know, there is a metanalysis performed long ago with small trials on the fibrinolysis era that showed actually a threefold increased risk of dying in those patients who had received oxygen in randomized various small trials, and their animal experience actually suggesting that oxygen is also hazardous. You don't think about that so often, but it's really an agent that constricts arteries, and so as the arteries close by a clot in myocardial infarction, there is no way the oxygen that you breathe in your nose can reach the suffering myocardium. It actually contracts the arteries, and may make the infarct larger than it would be otherwise.

Dr Carolyn Lam:                I love that explanation. Alright, so what did you find in the current analysis of longer term results?

Dr Stefan James:              So, we performed this, the main oxygen trial that we call Detox. We built it upon our national registries, and so we decided to include not only MI patients, but patients who were suspected of MI, in order to be able to enroll patients before the diagnosis was clear. We didn't want to wait for troponins, so we enrolled patients in the ambulances, in the emergency departments, in the cath labs, or in the wards, patients who had suspected myocardial infarction.

                                                Most of them, eventually, did have myocardial infarction, but a proportion did not have myocardial infarction. They had other diseases that resembles MI and have breathing problems. And we selected the cut point of 90%. We said if they are below 90%, they're hypoxic, and it would be unethical to withdraw oxygen, if you were hypoxic. So, we sort of arbitrarily selected the cut point of 90%. And then, we randomized patients to receive oxygen or do not receive oxygen.

                                                We considered to do double blind, but in order to do a double blind, you need to provide air on a mask. And air is not available in ambulances or in the emergency department. We cannot put a mask without anything in it because then it will feel more difficult to breathe. So, we had actually oxygen versus nothing, and we enrolled all patients coming to the cath labs, and emergency departments, and ambulances in Sweden. And thanks to the infrastructure that we have built on the national registries, we were able to enroll these to conduct this large trial, larger than any other trial, 6,600 patients.

                                                In the main study, we found no benefit, and fortunately, no harm of providing oxygen for our primary end point, which was all caused death. But we realized that we were little bit underpowered actually to really clearly rule out that there was any benefit on the primary endpoints. And so, we said, we probably need a longer follow-up, and we probably also need other important measures such as heart failure. Because we thought that oxygen may, if it works, it may reduce the infarct size and may result in a lower risk of heart failure in the long-term. We don't believe that we will reduce the risk of re-MI because we're not interfering with atherosclerosis or plaque ruptures, but we may interfere with the development of heart failure.

                                                So, in this particular paper, we said, longer follow up in order for patients to possibly develop heart failure and increase their risk of heart failure hospitalizations. So, in this paper, we used as a primary endpoint of this analysis, death or hospitalization for heart failure, post MI. And with this way of calculating events, we are more sure that we are not underpowered for this evaluation.

Dr Carolyn Lam:                Right. And the results?

Dr Stefan James:              The results were completely neutral. There was no benefit at all in any sub group. It doesn't matter if you were ST elevation MI, or no ST elevation MI, or no MI, or high risk prior MI, prior heart failure, respiratory disease, there is no benefits and no harm, which is good. And those results are supported by our findings on troponin levels. So, we checked troponins repeatedly. I shouldn't say top troponin, but the highest measured, we did not find any difference between the two groups in Troponin elevations. And we did not find any difference in LVEF and in Echo performed during the initial hospitalization.

                                                So, I think both of those results support the primary endpoint of death and repeat hospitalization for heart failure.

Dr Carolyn Lam:                So David, you've thought a lot about this, and also framed it so nicely when we were just talking a little bit earlier. What do you think is the real significance of this paper on so many levels?

Dr David Morrow:            Yeah, I think there are many levels. I think it's such important work because it takes something that we are still doing in many hospitals every day for patients and is difficult to study because it's become part of standard of care, as Dr James pointed out, and so the authors are to be congratulated for being able to study this intervention. And I think in additionally because it is a therapy that's not associated with high cost, has been part of our care for so long, it's not one where there is the support for a large type of randomized trials. So, the ability to perform this with relatively low costs by nesting it in a registry is important, not only for this particular test, but also as a model for future research of so many interventions that we make right now where they started in a time where our threshold for a need for data was much less.

Dr Carolyn Lam:                Yeah. Indeed. That's wonderfully put. I am also really struck. It's the importance of the message, but also especially about how you do a pragmatic registry-based randomized trial. The ability of Sweden to do this, it's just rock the world, right? Because we really need solutions like that for our clinical trial world, which has to be sustainable somehow. Could you maybe take us behind the scenes a little bit? I mean you did already in your description. I didn't realize there were so many considerations when you're planning this, but how easy or difficult is it to do a trial like this?

Dr Stefan James:              We call the entity RRCT. We call it registry based randomized trial, but being aware that there is no strict definition of what is a registry based randomized trial. So, sometimes for some simple interventions like strategies, we can use only the registry for collection of baseline variables, procedure variables, and also outcomes. The registry can really do everything. The only thing we need to add is a randomization, so then we just program into the registry, which is used live in front of the patients.

                                                So, when I enter a patient in the registry, the personal identification number collects me to the population registry that supports directly back to me name and gender of the patient, and then I enter all the baseline characteristics anyway in the registry. And then, there is a question that comes up that screens my patients. So, the system proposes to me to randomize patients who are eligible because I programmed the inclusion/exclusion criteria. So, it proposes to every doctor in the country, this is a patient that is eligible potentially for this trial and just click randomize, and that's the trial. Everything is completed by that. No extra tests, no visits, no follow up, no telephone calls.

                                                That's the basic, very simple format that can only be used for a strategy, like a device or a strategy. But many of the questions we have in medicine are really regarding strategies. How long should you treat? How often do you need to come back? Sort of strategies. Then, when we've tried to expand this to pharmaceutical agents, and oxygen was the first pharmaceutical agent that we wanted to try. You may not consider oxygen as a pharmaceutical agent, but it is in fact. But it's not manufactured by any companies, and we are still, in this trial, wanted to keep all-cause mortality as the primary end point because that's very reliable. That's indisputable, and in our country it's absolutely 100% correct. If they registered dead, they are dead. There's no question.

                                                The next level we did in the validate was a true pharmaceutical agent manufactured by a company, [byobatterin seprin 00:18:31]. A little bit more complex because you need to be careful about making sure that the patients are receiving the pharmaceutical agent in the right manner, in the right time point. We need to be a little bit careful about collection of side effects, and complications, and so on, but it also worked very well in that trial. If they validated, we did actually adjudicate events because in the primary end point we had it where it was more complex primary endpoint, including myocardial infarction. If you include myocardial infarction or bleeding events, that needs to be defined in a certain way according to protocol. You need to adjudicate. If you really need to rely on the outcome assessment.

                                                We're not trying to take this type of study to the next level, to use it for typical oral pharmaceutical agents. Our largest trial now running is the spirit HFPF lactone versus no treatment in patients with HFPF. And again, this is a pharmaceutical agent that is a very inexpensive. There's no company that would sponsor such a trial, but we think it's a really important question. There's so many patients that suffer from HFPF, and in order to do that trial, it has to be simple and inexpensive.

                                                So, that's running. We hope to be successful. There are, of course, many challenges. Like any other trial, it's difficult to write a protocol. You have to be very dedicated and detailed for any trial. So backstage, this is not easier than any other trial, but for the investigator, it is much easier. That's the reason we have succeeded to reach out to every hospital in the country, and every physician seeing these patients are investigators. And many of them have never done any trials before. They have no experience with research, but still they should be able to randomize and do the trials because it seems to be so easy for them and for the patients. That's the whole idea.

Dr Carolyn Lam:                Yeah. I'm just enamored by the whole concept, and of course, a lot of people I think are wishing that we could institute that in all countries as well. Trust me, a lot of conversation has occurred about that in Singapore, for example, where population based capture is possible. But, as you said, it's not that easy. It's got to be well thought out. Protocols still have to well thought out. Investigators still need to be trained, and so on.

Dr Stefan James:              We want the investigators to feel that it's easy, that it's attractive to participate. Not for money, just because it's so easy and so interesting to be part of such an experiment.

Dr David Morrow:            I think testing some of those therapies that are commonplace that they're used to, and our nature of practice is this is the perfect type of setting than more complicated interventions where you may need to train the investigators more in order how to implement to them, and apply the therapy correctly. That's the new trend, is ... I think the key issue is that in order to reliably test things where mortality is not the acceptable outcome that you could power adequately for, it's really the endpoint collection in the safety collection, and because of the robust medical record systems you have, you're able to do that. And we're so far from being able to do that reliably in the United States right now that it's not possible to do that. Unless we have specific well-constructed registries, which we do in some areas. I think we're learning, and hopefully we'll get there, but we're far behind [crosstalk 00:21:55].

Dr Stefan James:              [crosstalk 00:21:55] Yeah, but even-

Dr David Morrow:            [crosstalk 00:21:57] Nationals-

Dr Stefan James:              Even if you're not able to do a registry based, I think we all should consider in all trials to do it as easy as possible and really try to ask ourselves, what is the most important reason we're doing this trial? Sometimes we need to collect a lot of extra information because we need to understand the mechanisms or the side effects. If that's the case, I don't think at this trial methodology is not suitable. You shouldn't perform it that way. It needs to be the more traditional, more conservative, more expensive and burdensome way, but for many therapies, a more simple approach, more pragmatic approach is preferable.

Dr Carolyn Lam:                Well, thanks again for diving into that because it gives us a real, to me at least, even greater appreciation for this paper when you understand the amount of work that's gone into it. But may I just end by saying, what do you think is the take home message for clinicians now? David, for example, you started by saying everyone's still doing it? I fully agree.

Dr David Morrow:            Yeah. I think it's a very simple message, and that we know that oxygen is not effective in patients who have an oxygen saturation above 90%. And there's really no rationale to use it.

Dr Carolyn Lam:                Perfect. Has this been put in practice in Sweden already?

Dr Stefan James:              It has been. One of the virtues of running these registries is that we can also check the adherence to the results, so we can check that this is not used anymore.

Dr David Morrow:            And since the investigators are your entire country, they all learned actually from participation in these trials.

Dr Stefan James:              Exactly. Exactly.

Dr David Morrow:            There's more of an investment in it already.

Dr Carolyn Lam:                That's amazing. So, thank you again for sharing. Thank you for publishing this in circulation and for helping us to do that.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright the American Heart Association in 2018.


Dec 3, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Our featured paper this week reports the five-year clinical outcomes and valve durability in the largest available cohort to date of consecutive high-risk patients undergoing transcatheter aortic valve replacement. You must listen up for this discussion, coming right up after these summaries.

                                                The first original paper describes a personalized risk assessment platform that promotes the implementation of precision medicine by helping us with the evaluation of a genomic variant of uncertain significance. A genomic variant of uncertain significance is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded and thus cannot be definitively annotated. These variants therefore pose critical challenges to the clinical interpretation and risk assessment. New methods are therefore urgently needed to better characterize their pathogenicity.

                                                Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author Dr Wu from Stanford University School of Medicine and colleagues recruited a healthy, asymptomatic individual lacking cardiac disease clinical history and carrying hypertrophic cardiomyopathy associated genetic variant in the sarcomeric gene, MYL3, which has been reported by ClinVar database to be likely pathogenic.

                                                Human-induced pluripotent stem cells or IPSCs were derived from the heterozygous carrier, and their genome was edited using CRISPR/Cas9 genome editing to generate karyo-specific IPSCs. Extensive essays, including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic IPSC-derived cardiomyocytes, and together, the platform was shown to elucidate both benign and pathogenic hypertrophic cardiomyopathy-functional phenotypes.

                                                Thus, this paper demonstrates for the first time the unique potential of combining IPSC-based disease modeling and CRISPR/Cas9 genome editing technology as a personalized risk assessment platform for determining the pathogenicity of a variant of unknown significance for hypertrophic cardiomyopathy in a patient-specific manner.

                                                Transcatheter aortic valve replacement is increasingly being used for the treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement. The next paper provides real world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated transcatheter vs. surgical aortic valve replacement.

                                                Co-first and corresponding others, Dr Werner and Zahn from Clinical Ludwigshafen in Germany compared clinical characteristics and outcomes of more than 7,600 patients with intermediate surgical risk who underwent isolated transcatheter or conventional surgical aortic valve replacement within the prospective all-comers, German aortic valve registry between 2012 and 2014.

                                                Multi-variable analyses reveal that factors that were associated with performing transcatheter instead of surgical aortic valve replacement included advanced age, coronary artery disease, New York Heart Association class three or four, pulmonary hypertension, prior cardiac decompensation, and elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area.

                                                Unadjusted in-hospital mortality rates were equal for transcatheter and surgical aortic valve replacement, whereas unadjusted one-year mortality was significantly higher in patients with transcatheter aortic valve replacement. After propensity score matching, the difference in one-year mortality was no longer significant. Thus, this large registry analysis suggests that both transcatheter and surgical aortic valve replacement are reasonable treatment options in a real world population with aortic stenosis and intermediate surgical risk.

                                                The next paper demonstrates a key role of vascular endothelial growth factor receptor 1 in hemorrhagic telangiectasia type 2. Now, this is an inherited genetic disorder where haplo-insufficiency of the activin receptor-like kinase 1 gene, ACVRL1, results in blood vessels that are prone to respond to angiogenic stimuli, leading to the development of telangiectatic lesions that can bleed.

                                                First author, Dr Thalgott, corresponding author, Dr Lebrin from Leiden University Medical Center and colleagues used ACVRL mutant mice and found that vascular endothelial growth factor, or VEGF receptor 1 levels were reduced, causing increased VEGF receptor 2 signaling that promoted sprouting angiogenesis, correcting the abnormal VEGF gradient, by expressing membranal-soluble VEGF receptor 1 in embryonic stem cells or blocking VEGF receptor 2 with antibodies in mutant mice, normalized the phenotype both in vitro and in vivo.

                                                Importantly, VEGF receptor 1 was reduced in the blood and skin blood vessels of patients with hemorrhagic telangiectasia type 2 compared with H match controls, demonstrating an important role of VEGF receptor 1 in these patients and explaining why their blood vessels might respond abnormally to angiogenic signals. These findings support the use of anti-VEGF therapy in hemorrhagic telangiectasia type 2.

                                                The next study suggests that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease following acute rheumatic fever. First author, Dr Kim, corresponding author, Dr Wicks from Walter and Eliza Hall Institute of Medical Research and University of Melbourne and their colleagues analyzed the immune response to group A streptococcus in peripheral blood mononuclear cells from an Australian Aboriginal acute rheumatic fever cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing.

                                                They then tested the widely used immunomodulatory drug, hydroxychloroquine for its effects on this response. They found that group A streptococcus activated persistent IL-1 beta production and selective expansion of a specific group of T helper 1 cells that produce GMCSF. Furthermore, hydroxychloroquine limited the expansion of these group A streptococcus-activated, GMCSF-producing T helper cells in vitro.

                                                Gene transcriptional profiling of peripheral blood mononuclear cells from patients with acute rheumatic fever showed dynamic changes at different stages of disease. Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis where GMCSF plays a pivotal role, the authors therefore proposed that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart fever following acute rheumatic fever.

                                                The next paper identifies a new anchoring B genetic variant in unrelated Han Chinese probands with ventricular tachycardia. In this paper from co-first authors, Dr Zhu, Wang and Hu, co-corresponding authors, Dr Hong from Second Affiliated Hospital of Nanjing University, Dr Mohler from Ohio State University Wexner Medical Center and colleagues, the authors identified the first anchoring B variant, Q1283H, localized to the ZU5C region in a proband with recurrent ventricular tachycardia.

                                                Knocking mice with this variant showed an increased susceptibility to arrhythmias associated with abnormal calcium dynamics. The variant was associated with loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed after depolarization-mediated trigger activity, and arrhythmogenesis. Furthermore, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias, representing potential therapies for anchoring B variant-associated arrhythmias.

                                                Does variability in metabolic parameters affect health outcomes? First author, Dr Kim, corresponding author, Dr Lee from Seoul Saint Mary's Hospital College of Medicine and Catholic University of Korea and their colleagues used nationally representative data from the Korean National Health Insurance system, consisting of more than 6.7 million people who are free of diabetes, hypertension, or dyslipidemia and who underwent three or more health examinations from 2005 to 2012 and were followed to the end of 2015.

                                                Variability and fasting blood glucose and total cholesterol, systolic blood pressure and body mass index was measured using the coefficient of variation, standard of deviation, variability independent of the mean, and average real variability. They found that a high variability in fasting glucose and cholesterol, systolic blood pressure and body mass index was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Variabilities in several metabolic parameters had additive associations with the risk of mortality and cardiovascular outcomes in the general population.

                                                These findings suggest that treatment strategies to reduce fluctuations in metabolic parameters may be considered another goal to prevent adverse health outcomes.

                                                How much exercise over a lifetime is necessary to preserve efficient ventricular arterial coupling? First author Dr Hieda, corresponding author Dr Levine from Texas Health Presbyterian Hospital Dallas and University of Texas Southwestern Medical Center and colleagues studied 102 seniors and grouped them based on their 25 years of exercise training history. The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure and stroke volume index.

                                                They found that there was a graded dose-dependent improvement in ventricular arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Their data suggested that the optimal does of lifelong endurance exercise to preserve ventricular arterial coupling with age appeared to be at least four to five sessions per week. The sufficient lifelong endurance exercise was effective for maintaining the normal dynamic Starling mechanism, left ventricular compliance, and arterial compliance with aging, all of which may lead to favorable effect on cardiovascular stiffness or function.

                                                And that brings us to the end of our summaries this week. Now, for our feature discussion.

                                                Transcatheter aortic valve replacement is taking over the interventional world. It's really rapidly growing, and we're increasingly using it for the treatment of aortic stenosis. It was initially used for inoperable and high-risk patients but now is indicated even in the treatment of intermediate-risk patient, and even low-risk patients are being enrolled into current trials.

                                                So, with TAVR being used for low- and intermediate-risk patients, the longer-term results of this treatment involved your abilities becoming more and more important. Well, gratefully, we have today's feature paper, and it describes the five-year clinical outcomes and valve durability of the FRANCE-2 Registry.

                                                I'm so pleased to have with us the corresponding author, Dr Martine Gilard from University Hospital of Brest in France, we have our editorialist, Dr Anita Asgar from Montreal Heart Institute, and we have our associate editor, Dr Dharam Kumbhani from UT Southwestern.

                                                Martine, congratulations on this largest cohort of high-risk patients and long-term outcomes. Could you please tell us what you found?

Dr Martine Gilard:            Yes, and I'll just quote, actually, to have a follow-up of five years. We have 1,200 patients arrive at five years after rotation of TAVI. Each patient was a high-risk patient because it was at the beginning of each treatment, and in this time, it's only the high-risk patient was implanted with TAVI, and actually, we can follow this 1,200 patients, 50% of these patients of these patients have an echography because when we analyze these patients, we have an echography at five years, and the patients who have not echography at five years, the only difference is the age.

                                                It's very old patient. It's very difficult to make this echography on this patient to come back in our center, so it's why there is not all the patient who have an echography at five years.

                                                But our patients who have an echography, we can see that it's a very, very good result at five years. There is always the same area, just after before, of the valve. There is the same gradient. There is not a sign of deterioration.

                                                As you know, we have some guidelines published last year about how we asked to define deterioration of the valve, surgical or TAVI, and if we apply this new recommendation, we saw that in this largest cohort, at five years, there is only 13% of patient who have some sign of deterioration, and of these patients, we never need to make another valve in valve because the deterioration was not so important, and patient leave with this valve like that. There is no necessity to make a new valve in valve, so at five years of this very high-risk patient treated by TAVI, there is no necessity to implant a second valve because the valve deterioration. It's a very, very important message.

Dr Carolyn Lam:                Thank you, Martine. Indeed, an important message. And Anita, you wrote a beautiful editorial about it. First, could I ask you to frame the issue? I mean, is there any reason we would expect the durability to be any different from a surgical replacement?

Dr Anita Asgar:                  I think that's a great question, Carolyn, and I congratulate again Martine and her team for doing a fantastic job to add some very important results to the clinical literature on TAVI. Five years is relatively early to see structural valve deterioration, so in a sense, it's not surprising, and we would consider this sort of medium-term follow-up rather than really long-term durability, but very reassuring that in a high-risk population of patients, that TAVR performs very well in this population of patients and as mentioned, is very low to the dynamic structural valve deterioration.

                                                One question I have for Martine is, as you mentioned, there was only about 12% that had some evidence of structural valve deterioration hemodynamically, but this didn't result in another procedure, and I wonder if you could explain a little bit about that, whether it's the hemodynamic dynamic value, and yet there's a clinical indication for re-intervention. How do you incorporate the two?

Dr Martine Gilard:            It's actually hemodynamic deterioration, there is some form of regurgitation. However, there is no need or clinical indication to make another intervention. So, if you compare this research to the bioprostheses surgical paths, the only one who have, at five years, no need to make a re-intervention appearing rotated, which is a valve, a surgical valve we have a longer bioprostheses surgical path.

                                                So, if we compare this best bioprostheses surgical valve, we have sustained results at five years. At five years, we have no need to make a re-intervention because the deterioration was not so important or as needed for clinical evidence as a need to make a new intervention.

Dr Anita Asgar:                  So, there were some increased rates of heart failure in those patients with structural valve deterioration in your paper, and I know that in the paper you did mention that this is not an adjudicated outcome, and there wasn't a VARC definition for heart failure, but what's your interpretation of increasing heart failure events in these patients with structural valve deterioration?

Dr Martine Gilard:            We have no real definition about that. We know that there is another registry. We say that there is an increasing of heart failure, and during the follow-up, and the result of this heart failure increase in mortality. There is an increasing of heart failure, but the number of these patients, there is more. So I don't know if this due to because patient is a high-risk patient, or it's because of the TAVI, but it's very difficult actually to have a real explanation about that.

Dr Carolyn Lam:                Thanks, Anita and Martin. Dharam, could you share some of the thoughts and the discussions that were going on behind the scenes with the editors when we saw this paper?

Dr Dharam Kumbhani:   Professor Gilard, this was a really excellent paper. We really appreciated you sending it to us, and I think for us, the fact that this was a very large cohort, the largest published cohort that has gotten to five years in a TAVR population, in a multicenter study, and having very good follow-up up to five years, with these patients is always this competing hazard that you want to know what the valve is doing at five years from an echocardiographic and hemodynamic perspective, but there's such a high competing hazard of death, just given the population that you're enrolling, and still, you had one of the largest echo follow-ups on these patients, so we want to congratulate you on the study and really a monumental endeavor, and so really great, great work there.

                                                And I think this is, exactly some of the questions that I think we had and I'm sure that the audience would have as well, I guess the one other question I have, and it's not really a question about your paper. So the median Euro score is 21 in this study, approximately 21, so that's obviously gonna, consistent with the patients that are being enrolled at that time between 2007 and 2012, which were predominantly high-risk and inoperable patients. Can you talk to us a little bit about the landscape of, how is TAVR practice in France as a society or from the regulatory standpoint, what are the benchmarks that you have achieve as you move towards low-risk now? Because intermediate-risk, I'm assuming is a [inaudible 00:20:16], so could you talk to us a little bit about the landscape there?

Dr Martine Gilard:            Yes. In France, it's difficult because we have the authority to follow, not immediately, the ESC recommendations, so actually in France, we are allowed to implant only patients with high risk, patients with complication of surgery, and actually just since one year, patients with automatic risk, but we have no authorization to implant patient with low risk.

                                                However, the most important fact is the heart team, and if they write. Because we need to have something written, and if they write, if they explain that it's necessary to implant a patient at low risk because of some point while not including the risk score or it's very difficult to explain, for example, frailty or something, we can implant a patient with low risk.

                                                But normally actually, it is only for complication or high risk and for intermediate risk like the recommendation of the ESC.

                                                So the rate of implantation in France increased because we implant only 2,000 people per year, but actually, in 2017, we have implanted 10,200 patient, and this year, we think that we implant 12,800 patients, so as the number of patients increase, the number of patients who have a very high risk decrease because there is a futile indication, and we have a lot of futile indication, so we doesn't implant patient while too high-risk, and we select the most majority of patient implanted in France was high-risk but also intermediate-risk.

Dr Dharam Kumbhani:   So, you think you're implanting more intermediate, like that is a bigger population that is getting TAVIs right now in France?

Dr Martine Gilard:            Yes, exactly.

Dr Carolyn Lam:                How about perspectives from Montreal? What do you think the implications of this findings from today's paper in relation to the types of patients that you might perform this in now?

Dr Anita Asgar:                  For us, this is exceptionally reassuring, and as Martine has said, I mean, we have transitioned as well away from that very inoperable cohort C type of patient to more your higher-risk patient or intermediate, and to be honest, everyone over the age of 80 in Canada essentially is getting a TAVR.

Dr Carolyn Lam:                Oh, wow.

Dr Anita Asgar:                  Because regardless of their risk, and we've been very aggressive with that because trying to get patients back to an appropriate quality of life is very important, and to seeing this very reassuring data is telling us that, as she has already mentioned, we have reached the standard, at least in midterm follow-up as the gold standard of surgical valve replacement, and so structural valve deterioration is not as big a concern.

                                                I think we still however need longer-term data when we're looking at lower-risk patients, and lower-risk patients, let's remember, are not 60-year-olds. They're the 75-year-old, perhaps. But we're still gonna need some more data, but it's very reassuring, and patients are asking for it and are really advocating on their behalf to have a less invasive approach, and I think we can say now with more certainty that we know after five years, your chance of structural valve deterioration is actually quite low, and so I think that's very helpful from our point of view.

Dr Carolyn Lam:                I love that, Anita, and it's so consistent with the title of your editorial, "Closing in on the Finish Line". Love it, love it, and recommend all listeners pick it up and have a good read. Dharam, I want to leave the last words to you. What do you think are the implications of this paper?

Dr Dharam Kumbhani:   Well, I think that, as Anita said, this is very encouraging results that, in this kind of extreme and high-risk patient cohort, that there appear to be no medium- to long-term signals of structural valve degeneration, that the biggest hazard from this procedure is all upfront, and after that, it's pretty much, it's as we have seen with surgery, that after that, the actuarial rates come back to what you would expect.

                                                If they didn't have aortic stenosis and then they would die from whatever causes they had. Now obviously, that wasn't tested, but it seems like looking at the curves, that that seems like what's going on, so I think they've done a great service to our TAVR community in terms of showing us these results in very large, multicenter cohorts from France.

Dr Carolyn Lam:                Thank you so much for joining us today. Thank you, listeners. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2018.


Nov 26, 2018

Dr Carolyn Lam:                Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. We will be discussing accelerated diagnostic protocols for chest pain, a very, very important issue in Cardiology with very important new safety and effectiveness data on one such protocol provided in our feature paper this week. Coming right up after these summaries.

                                                Our first original paper this week identifies a new link between specific gut bacteria and atherosclerosis. Co-First authors, Dr Yoshida and Emoto, corresponding author, Dr Yamashita, from Kobe University Graduate School of Medicine, and colleagues recruited patients with coronary artery disease and controls without coronary artery disease but with coronary risk factors. They then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples. Subsequently, they used atherosclerosis prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Their analysis of gut microbial profile in patients with coronary artery disease showed a relative depletion of bacteroides vulgatus and bacteroides dorei compared to controls with coronary risk factors. Gavage with live bacteroides vulgatus and bacteroides dorei decreased fecal and plasma lipopolysaccharide levels and protected against atherosclerosis in apoE deficient mice. Fecal lipopolysaccharide levels in patients with coronary artery disease were significantly higher compared to controls. These findings suggest that bacteroides treatment may serve as a novel and effective therapeutic strategy for suppressing lipopolysaccharide-induced inflammatory response in coronary artery disease.

                                                The next paper identified a potential novel molecular target in the treatment of myocarditis. Co-First authors, Dr Chen and Zeng, Co-Corresponding authors, Dr Song from Fuwai Hospital in Beijing, and Dr Yang from Shenzhen University School of Medicine, and their colleagues aim to elucidate the role of BCL2 Like protein 12 in the pathogenesis of biased T Helper-2 response in myocarditis. Using a combination of mouse models of myocardial inflammation and human hearts from patients undergoing heart transplantation, the authors found that CD4 positive T-cells isolated from hearts in myocarditis at the end stage of heart failure expressed high levels of BCL2 Like protein 12, which was required for the development of aberrant T Helper 2 polarization in the heart. Thus, BCL2 Like protein 12 may be a novel target in the treatment of myocarditis, as well as other T Helper 2 biased inflammatory processes.

                                                Could vaccination against LDL be a way to prevent atherosclerosis? Well, the next paper brings us one step closer to this dream. First author, Dr Gisterå, corresponding author, Dr Hansson from Karolinska School University Hospital and colleagues developed T-cell receptor transgenic mice to study LDL autoimmunity in a humanized hypercholesterolemic mouse model of atherosclerosis. A strong T-cell dependent E-cell response was induced by ODL leading to production of anti-LDL IgG antibodies that enhanced LDL clearance and ameliorated atherosclerosis. Results show that anti-LDL immuno-reactivity evoked three atheroprotective mechanisms, namely 1) antibody-dependent LDL clearance, 2) increased cholesterol excretion, and 3) reduced vascular inflammation, thus targeting LDL-reactive T cells may enhance atheroprotective immunity, and vaccination against LDL components may be an attractive way to prevent atherosclerosis.

                                                MicroRNAs regulate nearly all biological pathways and dysregulation of MicroRNAs is known to lead to disease progression. However, are there cell type specific effects of MicroRNAs in the heart? Co-First authors, Drs Rogg and Abplanalp, corresponding author, Dr Dimmeler from Goethe University Frankfurt, and colleagues assessed MicroRNA target regulation using MicroRNA 92a3p as an example. Their data showed that MicroRNAs have cell type specific effects in vivo which would be overlooked in bulk RNA sequencing. Analysis of MicroRNA targets in cell subsets disclosed a novel function of MicroRNA 92a3p in endothelial cell autophagy and cardiomyocyte metabolism. These findings may have clinical applications for the fine tuning of autophagy and metabolism to mitigate tissue damage in patients with cardiac disease.

                                                The next paper establishes a mechanism by which cardiac inflammation may be initiated in response to hemodynamic stress, but in the absence of significant cardiomyocyte cell death. Co-First authors, Drs Suetomi and Willeford, Co-Corresponding authors, Drs Brown and Miyamoto from University of California San Diego, and their colleagues used conditional cardiomyocyte-specific calcium calmodulin-regulated kinase Delta all CaM kinase II Delta knockout mice to demonstrate that cardiomyocytes generate inflammatory chemokines and cytokines and are the initial site of NLRP3 inflammasome activation. They further identified a causal role for CaM-Kinase II Delta-mediated activation of NLRP3 inflammasome and inflammatory responses in macrophage recruitment, cardiac fibrosis, and development of heart failure induced by pressure overload. Their elegant mouse experiments revealed sites and mechanisms of proinflammatory gene and inflammasome activation within cardiomyocytes which could serve as targets for early intervention or disease prevention.

                                                Are there different metabolomic effects between PCSK9 inhibitors and statins? First author, Dr Sliz, Corresponding Author, Dr Würtz from Nightingale Health Limited in Helsinki, Finland, and their colleagues quantify 228 circulating metabolic measures by Nuclear Magnetic Resonance Spectroscopy for over 5300 individuals in the PROSPER Trial at six months post randomization. The corresponding metabolic measures were also analyzed in eight population cohorts, including more than 72,000 individuals using a specific PCSK9 inhibitor SNP as an unfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Scaled to an equivalent lowering of LDL cholesterol the effects of genetic inhibition of PCSK9 on these 228 metabolic markers were generally consistent with those of statin therapy. Alterations of lipoprotein lipid composition and fatty acid distributions were also similar. However, discrepancies were observed for very low-density lipoprotein or VLDL lipid measures where genetic inhibition of PCSK9 had weaker effects on lowering VLDL cholesterol compared with statin therapy. Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation, where a statin treatment weekly lowered this marker of inflammation. Thus, if VLDL lipids have an independent causal effect on cardiovascular disease risk, the observed discrepancy on VLDL lipid lowering could contribute to differences in cardiovascular risk reduction between statins and PCSK9 inhibitors for an equivalent reduction in LDL cholesterol. Moreover, these results exemplify the utility of large-scale metabolomic profiling with genetics and randomized trial data to uncover potential molecular differences between related therapeutics.

                                                The final original paper this week demonstrates a novel biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases. Co-First authors, Dr Mosley and Benson, co-corresponding authors, Dr Wang from Vanderbilt University Medical Center and Gerszten from Beth Israel Deaconess Medical Center, and their colleagues employed a virtual proteomic approach linking genetically-predicted protein levels to clinical diagnosis in more than 40,000 individuals. They used genome-wide association data from the Framingham Heart Study to construct genetic predictors for more than 1100 plasma protein levels. They validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in more than 41,000 genotyped individuals in the eMerge Cohort. They tested associations for each predicted protein with more than 1100 clinical phenotypes. These associations were validated using directly-measured protein levels and either LDL cholesterol or subclinical atherosclerosis in the Malmo Diet and Cancer study. Using this virtual biomarker strategy the authors identified CLC1B and PDGFR Beta as potential circulating biomarkers of atherosclerosis and validated them in an epidemiologic cohort. Thus, these results demonstrate that a virtual biomarker study may efficiently identify potential biomarker disease associations, and that wraps it up for our summaries. Now for our feature discussion.

                                                Accelerated diagnostic protocols for testing are used everywhere. They're designed to improve the quality and value of chest pain risk stratification. However, many of them lack sufficient prospective safety and effectiveness data. We're so pleased to have a paper today that provides such important data on one of these accelerated diagnostic protocols for chest pain, and it's the HEART Pathway. To discuss this, I've got the corresponding author of today's featured paper, Dr Simon Mahler from Wake Forest School of Medicine, as well as our Associate Editor, Dr Deb Diercks from UT Southwestern. Simon, could you start by just telling us, what is the HEART Pathway?

Dr Simon Mahler:             Sure. Yeah, it's an accelerated diagnostic protocol. It's based on an accelerated diagnostic protocol called the HEART Score. We use a modified version of the Heart Score. We actually use a HEAR score, and that stands for the history, EKG, Age, and risk factors. That is combined with two troponin measures at 0 and 3 hours. We also factor in whether or not the patient has had prior coronary artery disease or has an acute ischemic EKG. So, to be low-risk you have to have a HEAR score of 0-3. HEAR is an acronym. You get points for each of those categories. If you have less than 3 points that's a low score. You have to have a low score, a non-ischemic EKG, no history of prior coronary disease, and two troponins less than a 99th percentile at 0 and 3 hours to be considered low risk and recommended for early discharge. If you don't meet any of those criteria then you are considered non-low risk and appropriate for further in-hospital evaluation.

Dr Carolyn Lam:                That's great. Could you just tell us what you did to give us some real-world safety and effectiveness data on this.

Dr Simon Mahler:             Yeah, so we had done a single-site randomized controlled trial. That was published in 2015 in Circulation: Quality and Outcomes, and really showed some promising results. We received some funding to do an implementation trial. So, this is the results of our implementation study. It's a before and after study. What we did was we sought to implement a HEART Pathway as a clinical decision support tool, integrated fully into our electronic medical record so that when providers see the patient with chest pain and order a troponin they interact with a HEART Pathway tool that guides them through the HEART Pathway risk assessment and then provides real-time decision support regarding their treatment and disposition decisions based on whether or not the patient has a low-risk assessment or a non-low-risk assessment. The design of the study was we collected data on all patients with chest pain and troponin order for one year while we worked on how we were gonna build this tool and embed it, and then we had three month watching period where we built the tool into the electronic health record across our three sites. Then, we had one year where we were post implementation where we collected data and looking at the difference in outcomes, particularly looking at both safety and utilization outcomes before and after use of the HEART Pathway.

Dr Carolyn Lam:                That's just such a clever design. Just give us a summary of the results before I ask Deb to chime in here.

Dr Simon Mahler:             There's a few really important things that we found. Probably the most important thing was the safety data that came out of this study. We had some good safety signals on prior studies. They didn't have enough sample size to really have a good precision around the safety point estimate, so in this study we had over 4000 patients in our post-implementation cohort, and about 31%, 30.7%, of those patients were classified as low-risk by the HEART Pathway. Among those patients that were classified by low-risk, the rate of death and MI, the composite outcome at 30 days, was 0.4%. Typically for these accelerated diagnostic protocols we want them to have an adverse cardiac event rate less than 1%, so a finding of 0.4% with a confidence in our role that doesn't extend beyond 1% that was a really important finding that really confirms the safety of this strategy.

                                                The other thing that we found which was interesting was that the use of the HEART Pathway was actually associated with detecting more myocardial infarctions during the index visit, which means that possibly the HEART Pathway use improved the recognition of those patients that were presenting with MIs. It's possible that without using the HEART Pathway some of those cases may have been missed. Finally, we were able to demonstrate that use of the HEART Pathway as a clinical decision support tool was able to decrease hospitalizations and some other utilization metrics such as stress testing and possible length of stay.

Dr Carolyn Lam:                Oh, that's awesome, Simon. I said it earlier. I'm gonna say it again. Thank you so much for publishing this wonderful work with Circulation. I really think that implementation, science, and decision support tools you've got that all in this paper, just beyond even the actual topic. Deb, take us behind the scenes a little bit with how we reacted as editors to this paper, please.

Dr Deb Diercks:                 Well, I think that overall, we were really excited about this paper. It really does add a real, real context to something we were really discussing and wondering about. I think one of the great things about the implementation, and Simon, please comment on this, is the diversity of the places that you actually used this in. I mean, most of us when we look at papers there's always a fear that it won't be able to be generalized to real-world practices. Correct me if I'm wrong, but you really applied it to just a wide variety of Emergency Departments that really support that this could be used anywhere.

Dr Simon Mahler:             Yeah, I think that's a really important point, that we did this across our system so that included a large academic busy Emergency Department that sees over 100,000 patients per year, all the way, basically to a smaller 12,000 per year, essentially almost a free-standing Emergency Department at the time that we started our study; it now has inpatient bed capacity, and then a suburban/rural hospital, as well, with about 30,000 patient visits per year. We extended beyond kind of the typical kind of comfort zone of large academic centers and into smaller community Emergency Departments as well.

Dr Deb Diercks:                 One of the things that this manuscript nicely articulated is that you kind of break it into the HEAR and then the troponin.

Dr Simon Mahler:             Right.

Dr Deb Diercks:                 Things change in the US with troponin. How do you think that's gonna impact how you guys apply this Pathway in the future?

Dr Simon Mahler:             It's a big topic of discussion right now, what to do with these Pathways. Are these Pathways still needed with the availability now of high-sensitivity troponins in the United States? I think that for many years as we've kind of followed data coming out of Europe we've been anxiously awaiting the arrival of these tests in the U.S., and there's a lot we can learn from the European data so far. Most of that data suggests that the high-density troponins are best used still in the context of a Pathway or an accelerated diagnostic protocol.

                                                I think that this particular study was conducted just using contemporary troponins, particularly given the time frame of the study in which we were accruing patients from 2013 through 2016, but I think it's still gonna be highly relevant, because I think that best practices are gonna still require us to use some sort of structured framework with high-sensitivity troponins. Now, it does remain to be seen a little bit what the best Pathway is gonna be to incorporate that. My take on this is that I believe that clinical decisions support tools or decision aids integrated with high-sensitivity troponins is going to be the best way to go. I'm a little bit skeptical about troponin-only approaches.

Dr Deb Diercks:                 That's a great summary. I don't think it's time to throw out all the value of that risk stratification tool, and I think your study showed that how it can easily be incorporated into what we do in a manner that doesn't really negatively impact the work flow, which I think is so important.

Dr Simon Mahler:             You know, we did a smaller study where we looked at the performance of the HEART Pathway with high-sensitivity assays. We studied it with both the Roche troponin high-sensitivity troponin T and the Abbott high-sensitivity I, and at the 99th percentile it actually made very little difference in terms of the performance of the HEART Pathway. What the potential advantages of incorporating high-sensitivity assays is that you probably no longer need a 0 and 3 hours, evaluation can be condensed. I think there's a lot of really interesting questions that availability of high-sensitivity troponins has created, and I think that there's gonna be a lot of emerging evidence over the next few years about new Pathways, and what are the best ways to fully take advantage of these higher-sensitive assays because, frankly, most of the decision aids that are currently in use they were developed using contemporary troponins, and they may not fully take advantage of high-sensitivity troponins. We may see modifications of our Pathway, and it will interesting to see kind of how things evolve as we study the impact of high-sensitivity troponin.

Dr Carolyn Lam:                Wow, exciting work ahead. Just one last question regarding the future. So, you followed up the patients in your study for 30 days. Am I wrong? Any plans to follow them up longer, and do you think such data are needed?

Dr Simon Mahler:             Yeah, we actually followed them for a year. Our primary analysis was through 30 days, and so we do have one-year data on all of our patients, and so we'll be doing a secondary analysis looking out to a year. Yeah, you can look forward to that coming up hopefully in the next six months or so.

Dr Carolyn Lam:                That is awesome. Thank you so much, Simon. Thank you so much, Deb. Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2018.

Nov 19, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Is there a unique lipoprotein profile for incident peripheral artery disease as opposed to coronary or cerebral vascular disease? Well, you're just gonna have to wait for our feature discussion to find out. That's coming right up after these summaries.

                                                Our first original paper this week tells us that gene variance known to be associated with idiopathic and peripartum cardiomyopathy are also associated with preeclampsia. First and corresponding author Dr Gammill from University of Washington and colleagues studied 181 participants with confirmed preeclampsia from the Preeclampsia Registry in BioBank. Saliva samples were collected for DNA isolation and whole exome sequencing was performed to detect rare variants in 43 genes known to be associated with cardiomyopathy.

                                                Results were compared with data from two controlled groups, unrelated women with a gynecological disorder, sequence using the same methods and instruments, as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium.

                                                The results showed that women who developed preeclampsia are more likely to carry protein altering mutations in genes associated with cardiomyopathy, particularly, the TTN gene which encodes the sarcomeric protein titin. Thus, detecting these gene variants may allow more specific diagnosis, classification, counseling and management of women at risk.

                                                Prior trials have shown that nonsteroidal anti-inflammatory drugs or NSAIDS confer cardiovascular risk. Now this has been postulated to be due to enhanced formation of methyl arginines in the kidney that would limit the action of nitric oxide throughout the vasculature. However, the next original paper in this week's journal suggests that this may not be correct. First author, Dr Ricciotti, corresponding author, Dr FitzGerald from University of Pennsylvania Perelman School of Medicine and colleagues, used multiple genetic and pharmacological approaches to disrupt the COX 2 pathway in mice and analyze plasma from patients taking NSAIDS.

                                                However, they did not observe an increase in methyl arginines. In contrast, they did observe an increase in plasma asymmetric dimethylarginine or EDMA in mice-rendered hypertensive by infusion of angiotensin II at a dose that also caused renal impairment. After a four week washout period following the infusion of angiotensin II, blood pressure, creatinine, and ADMA levels all fell back to normal levels.

                                                Celecoxib-treated mice also exhibited increased ADMA and plasma creatinine in response to infusion of angiotensin II and their levels also returned to normal thereafter. Thus, it seems likely that the previous reported elevations in ADMA reflected renal dysfunction rather than a direct consequence of COX 2 deletion or inhibition. The authors end by suggesting that the most plausible mechanism by which NSAIDS confer a cardiovascular risk, is by suppression of COX 2 derived cardioprotective prostaglandins such as Prostacyclin rather than by enhanced formation of methyl arginines.

                                                The next original paper identifies new targets with the potential to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia. Co-corresponding authors, Dr Ola and Eichmann from Yale University School of Medicine and colleagues looked at SMAD4, which is a downstream effector of transforming growth factor-beta/bone morphogenetic protein family ligands that signal via activin-like kinase receptors.

                                                The authors generated a tamoxifen inducible postnatal endo-fetal specific SMAD for a mutant mouse and showed that SMAD4 prevented flow-induced arterial venous malformations by inhibiting casein kinase II. The uncovered pathways provided novel targets for the treatment of vascular lesions in hereditary hemorrhagic telangiectasia related juvenile polyposis patients carrying SMAD4 mutations.

                                                The next original paper provides important data for the accurate diagnosis of long QT syndrome. Long QT syndrome can be a challenging diagnosis partly because the optimal method for QT assessment is not unequivocally established. QT experts advocate manual measurements with a tangent or threshold method.

                                                In today's paper, first and corresponding author, Dr Vink from Academic Medical Center University of Amsterdam and colleagues, aimed to assess similarities and differences between these two methods of QT interval analysis among 1,484 patients with a confirmed pathogenic variant in either KCNQ1, KCNH2 or SNC5A genes from 265 families. Both QT measurement methods yielded a high inter and intra reader validity and a high diagnostic accuracy.

                                                Using the same current guideline cutoff of QTC interval 480 milliseconds, both methods had similar specificity but yielded a different sensitivity. QTC interval cutoff values for the QT measured by the tangent method was lower compared to that measured by the threshold method. Plus, values were different depending on the correction for heart rate, age, and sex.

                                                The authors provided an adjusted cutoff values specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for long QT syndrome at has been made available as an aid in the interpretation of the QT interval.

                                                The next original paper demonstrates for the first time that thrombin mediated signaling may play a role in diet-induced atherogenesis. Co-first authors, Dr Raghavan and Singh, corresponding author Dr Rao from University of Tennessee Health Science Center and colleagues, used a mouse model of diet-induced atherosclerosis and molecular biological approaches and explored the role of thrombin and its G protein coupled receptor signaling in diet-induced atherosclerosis.

                                                They found that thrombin-induced CD36 expression and foam cell formation required protease activated receptor 1, G alpha 12, Pyk2, GAB 1, and protein kinase C theta dependent activating transcription factor 2 activation. Thus, inhibition of thrombin G protein coupled receptor signaling could be a promising target for the development of new drugs in reducing the risk of diet-induced atherogenesis.

                                                The next study provides insights into the long- term association of LDL cholesterol with coronary heart disease mortality in individuals at low tenure risks of atherosclerotic cardiovascular disease. First and corresponding author, Dr Abdullah, from VA North Texas Medical Center and UT Southwestern Medical Center and colleagues studied more than 36,000 subjects in the Cooper Clinic Longitudinal Study cohort who are at low tenure estimated risk of atherosclerotic cardiovascular disease. In other words, a low tenure risk of less than 7.5%. They've followed these patients for more than two decades.

                                                Results showed that LDL cholesterol and non-HDL cholesterol at or above 160 milligrams per deciliter were independently associated with a 50 to 80% increased relative risk of cardiovascular disease mortality. The associations between LDL cholesterol and cardiovascular disease mortality were more robust when follow up was extended beyond the traditional 10 year estimated risk period.

                                                The associations remain significant in those with an estimated tenure atherosclerotic cardiovascular disease risk of less than 5%. These data suggests that LDL cholesterol levels at or above 160 milligrams per deciliter in individuals deemed to be at low tenure atherosclerotic cardiovascular risk are associated with worse long term cardiovascular disease mortality. These findings, along with other observational data and data extrapolated from clinical trials, support further consideration of appropriate LDL cholesterol thresholds for lipid lowering interventions in individuals categorized as low short-term risk.

                                                The final paper this week uncovers a novel therapeutic target for the prevention and treatment of thoracic aortic aneurysms. First author, Dr Nogi, corresponding author Dr Shimokawa from Tohoku University Graduate School of Medicine and colleagues, used genetically modified mice to show a pathogenic role of the small GTP binding protein, GDP dissociation stimulator in the development of angiotensin 2 induced thoracic aortic aneurysms and dissection. Down regulation of this protein contributed to dysfunction of aortic smooth muscle cells and hence oxidative stress, and matrix metalloproteinase activities in the pathogenesis of thoracic aortic aneurysms and dissection.

                                                Local over expression of this small GTB binding protein GDP dissociation stimulator around the thoracic aorta inhibited aortic dilatation and rupture in deficient mice. And that wraps it up for this week's summaries. Now for our feature discussion.

                                                Atherosclerosis has been considered a systemic process, meaning that when we see a disease in one vascular bed, we assume that that's a risk marker for disease in other vascular territories, and that they share pathophysiology, they share risk factors. However, if we think about it, the prior studies have all been sort of focusing on coronary and cerebral vascular disease, but today's feature paper changes that a bit because it addresses a key knowledge gap in peripheral artery disease risk, and interestingly suggests that there may be a unique lipid profile that's related to peripheral artery disease.

                                                This is gonna be an exciting discussion and I have the first author, Dr Aaron Aday from Vanderbilt University Medical Center currently. We have our editorialist, Dr Parag Joshi from UT Southwestern, and our associate editor, Dr Anand Rohatgi from UT Southwestern. Welcome gentlemen and Aaron, could we start with you sharing about your study?

Dr Aaron Aday:                 So, as you mentioned, a lot of the previous epidemiologic data on atherosclerosis have been primarily in coronary artery disease and stroke, and when we looked at peripheral artery disease or PAD, there seemed to be some subtle differences. So for instance, total cholesterol on HTL cholesterol seemed to be the strongest risk factors for future peripheral artery disease and in terms of LDL cholesterol, the data are somewhat mixed. Some have found a weak association, some have actually found no association. And so building on that, we wanted to see if using nuclear magnetic resonance spectroscopy, we could elucidate more details about the litho protein pathways associated with peripheral artery disease.

                                                And we did this in the women's health study which is a prospective cohort study of women free of cardiovascular disease, the baseline, they were aged 45 and older. And what we've found in terms of the standards with their profiles, we again found that there was no association between LDL cholesterol and future peripheral artery disease, whereas certain standard lipid measures like HDL cholesterol were strongly associated with PAD, and then using the Endemol spectroscopy tool, we found that actually, small LDL particles and total LDL particles were concentrations of both of those markers, were strong risk factors for future PAD and other measures like total HDL particle concentration were even more strongly associated with future PAD than coronary artery disease.

                                                So essentially the signature associated with future peripheral artery disease, had some important differences than that for a composite of coronary artery disease and stroke.

Dr Carolyn Lam:                Aaron thanks for that. That's beautifully described and just so intriguing. Parag, could you tell us how should we be thinking about results like this?

Dr Parag Joshi:                   It's a great paper and it really highlights a new and unique approach in that we ... Peripheral artery disease as an isolated incident event is fairly understudied I guess we could say and so, this is a really nice paper to start choosing out some of the risk factors for that. I think overall, when we think of peripheral arterial disease in general, I think historically, we've thought of it as similar pathophysiology, you know LDL particles and perhaps other particles depositing in the arterial space. But this does highlight some important differences that might exist and I think one of those seems to be that maybe this is more a signature of elevated remnant lipoproteins or triglyceride rich remnant lipoproteins, small dent LDL particles, low HDL, that sort of metabolic syndrome type patterns that we look at as a high risk factor that may be more contributory to peripheral artery disease than coronary disease, or at least more specific to peripheral artery disease.

                                                I guess one of my main questions about that from your work Aaron is, how can we be sure this isn't just a pre-clinical marker of diabetic patients which we know have this type of pattern?

Dr Aaron Aday:                 Sure, it's certainly a possibility. I think what's notable in the cohort, at least a time enrollment. And there was a very little diabetes and actually there was a much greater prevalent of metabolic syndrome. So in my mind, it may be more of a metabolic syndrome specific marker rather than necessarily down the diabetes pathway, but it's certainly something that needs to be explored further.

Dr Parag Joshi:                   I wonder whether women's health studies such a healthy cohort that I wonder if this is picking up some signal before the answer to diabetes or as you said, metabolic syndrome, you know which certainly suggests an insulin resistance pattern and we know the association of diabetes with peripheral artery disease is stronger and so I wonder if this may be a sort of earlier way of picking that up.

Dr Aaron Aday:                 It may be. I think one thing to notice is the outcome of peripheral artery disease that we're using. So it is symptomatic disease. So, we're not picking up a lot of ulcers that are developing in the future, it's more the claudication and then people who've undergone revascularization. Certainly diabetics have both of those as well but I think that may suggest it's not fully unexplained by developing diabetes than peripheral artery disease further down the line.

Dr Parag Joshi:                   Yeah that's a great point.

Dr Carolyn Lam:                Yeah great questions, great thoughts. Anand, what about you? Did you have questions too?

Dr Anand Rohatgi:            I think from my perspective and thinking about it for circulation and its readership, we found this really interesting for several reasons. Number one, I think is, as you all have discussed, peripheral arterial disease just is not as well characterized and you can see that here in over 25,000 people, add about a 100 a bed, so I think in younger folk, it takes a lot of people to study, to be able to really understand kind of the pathophysiology of peripheral arterial disease.

                                                The other thing that they think they really shed some light on is how this is happening in women in particular and in women, of course as we know have been understudied in all cardiovascular diseases, but in particular, diseases like this which are less common. It's really insightful to see that these lipid abnormalities in women are contributing to peripheral arterial disease more so than your typical LDL cholesterol management and interestingly enough, most of the women who had PAD events in this study, did not have other cardiovascular events.

                                                They really just had PAD events exclusively and I thought that was really intriguing, and the use of this advanced lipoprotein testing, this NMR modality has been very useful in terms of biology and research, and I think that's the case here where we really go under the hood Carolyn, as you said, and get kind of deep dive, the lipid metalobles on abnormalities. And I think Parag and Aaron hit the nail in the head that this is really capturing an insulin resistance of phenotype and what I really liked about this is, instead of studying people who are 70, 80 years old and a lot of things are sort of clustering, a lot of diseases are clustering and they're manifesting all at the same time, it's very hard to tease apart the effective age.

                                                Here, we captured women in their 50s and middle aged, just as they have kind of gone through menopause and this adverse metabolite's phenotype starts to rise in women. And then we could follow them over time and see what the natural history of that is, and the women who have this phenotype go on to have this devastating consequence, this peripheral arterial disease. One of the questions I had then, Aaron for you is, what do you think the implications are from these findings? Does it mean that in terms of diagnostics, we should be doing more advanced testings looking at LDL and HDL type particles with NMR or some other mortality? Does it change therapies with new therapies beings studies right now? What do you think the implications are from your work?

Dr Aaron Aday:                 That's important right. I think you mentioned this and I see the inter marked tool in this study, is really a way to try to dig further into the biology of peripheral artery disease as a form of atherosclerosis. I think that we already know patients who are extremely high risk or PAD, those are patients with diabetes, smoking history, metabolic syndrome et cetera., and as you can see in a patient population in 28,000 middle aged women who are pretty healthy, we only had just over a 100 PAD events.

                                                So, I think even if you were to scale this up in terms of cost, I'm not sure that that would necessarily be a viable option for patients, but I think it does suggest that truly focusing on LDL in a very high-risk patient population, meaning patients with PAD, or we may not be fully addressing their risk. And so I think this is a need to highlight that important gap, think about other therapeutic options and we'll soon have ongoing trials, triglyceride low in therapy that may be particularly beneficial in this patient population and so that's how I see this being used.

Dr Anand Rohatgi:            That makes a lot of sense and particular because in middle aged women like this, your standard risk score algorithms will not really capture that they're at increased risk, even if they smoke, just because they're women and they're younger and so, I think this really is a call to arms to more refined risk assessment in these women.

Dr Parag Joshi:                   Aaron, do you think there's actually a difference in the biology in the peripheral arteries compared to the coronary and cerebral vascular beds, or is there data to kind of look at that or maybe histopathological data to look at that?

Dr Aaron Aday:                 We know there's a lot of overlaps, so I don't wanna suggest that PAD is not a former atherosclerosis. I think one limitation is that the primary animal model for PAD is the hyperCKemia model. That doesn't fully recapitulate what's happening in a limb with PAD and so I think that has been one limitation in understanding the biology. But I think what we're starting to see in some clinical trials that have come out in the last couple of years or starting to see a somewhat different signal for therapies in patients with PAD so for instance, in 48, we actually saw that there was a greater benefit to LDL lower [inaudible 00:21:00] inhibitors than for coronary disease. We now have the compass trial results, again, more events, higher risk among these patients but for their benefit, add on River Oxodine therapy, we've seen lymph events or lymph signals in the SGLP2 inhibitor trials. So, I think we're starting to get a sense that there may be something else on top of the traditional ascariasis biology that may be a potential target on down the road.

Dr Parag Joshi:                   I think it's really a fascinating biological question of how these different territories might actually differ in their pathophysiology. I think it's a really a nice time to look at this. Also I think, Anand and Aaron both mentioned ongoing trials. The omega 3 fatty acid trials I think reduce it, will be soon to be presented and hopefully published in the next month or so. It would be nice to see if they evaluate peripheral events in that group, I'm sure they will.

Dr Carolyn Lam:                Indeed, these have been just such great thoughts and discussion. Nothing really much to add there. I suppose I could say something cheeky like for the first time, and I never thought I'd say it on the podcast, I feel kind of bad that there are no men included in this trial but anyway, I just learnt so much from this. I just wanna thank you gentlemen for a great discussion.

                                                Thank you, listeners, for joining us today and don't forget to tune in again next week to Circulation on the Run.

Nov 12, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                This week's feature discussion focuses on first and man pilot study results of pericardiotomy and its influence on left ventricular diastolic reserve with volume loading. Very fascinating implications for heart failure with reserved ejection fraction, coming right up after these summaries.

                                                Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. But what are the underlying mechanisms and potential therapeutic approaches to this? Well, in today's paper from co-first authors Drs Sun and Yao, corresponding author Dr Chang, and colleagues from UT Southwestern Medical Center, the authors examine the status of cardiac autophagy and its role during sepsis pathogenesis using a rodent lipopolysaccharide-induced sepsis model. They've found that forced overexpression of Beclin-1 in the heart promoted autophagy and mitophagy, protected mitochondria, improved cardiac function, and alleviated inflammation and fibrosis after a lipopolysaccharide challenge. Whereas, haplosufficiency for Beclin-1 resulted in the opposite effects. For the more injection of a cell permeable Tat-Beclin-1 peptide improved outcomes in lipopolysaccharide-challenged animals. Thus promoting Beclin-1-dependent signaling may be a novel and effective intervention to alleviate organ dysfunction caused by maladaptive autophagy during severe sepsis.

                                                The next paper presents important experimental data that causes us to consider the potential cardiovascular hazards of anti B-cell activating factor immunotherapy, which is currently approved for the treatment of autoimmune systemic lupus erythematosus. You see, genomic data has shown that B-cell activating factor receptor pathway is specifically essential for the survival of conventional B lymphocytes, which is a key driver of coronary heart disease. However, in today's paper from co-first authors, Drs Tsiantoulas and Sage, corresponding author Dr Binder and colleagues from Medical University of Vienna, the authors reported an unexpected finding that B-cell activating factor neutralization increased atherosclerotic plaque size and complexity despite efficient depletion of mature, conventional B lymphocytes. Furthermore, the authors provided evidence suggesting a novel B-cell independent anti-inflammatory property of B-cell activating factor. They showed that the expression of the alternative B-cell activating factor binding receptor, transmembrane activator and CAML interactor in myeloid cells limited atherosclerosis thus showing novel atheroprotective pathways. Thus, these results introduce a new perspective with respect to the potential cardiovascular hazards that may be associated with the long term blockade of B-cell activating factor in chronic inflammatory settings. There is a need for more refine therapeutic approaches targeting the B-cell activating factor pathway.

                                                Vascular smooth muscle cells are known to possess remarkable plasticity undergoing fundamental phenotypic switches from a differentiated to a dedifferentiated state in response to vascular injury or remodeling. However, what are the underlying cellular processes by which vascular smooth muscle cells maintain their cell identity? Well, in today's paper from co-first authors Dr Yao, Yu and Li, corresponding Dr Wang from Fu Wai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking University Medical College. The authors applied single cell RNA sequencing to analyze disease human arteries and identified histone variant H2A.Z as a key histone signature that maintains vascular smooth muscle cell identity. H2A.Z occupied genomic regions near vascular smooth muscle cell marker genes and it's occupancy was decreased in vascular smooth muscle cells undergoing dedifferention. H2A.Z expression was dramatically reduced at both messenger RNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescued injury-induced loss of vascular smooth muscle cells identity and new intima formation. Together, these data introduced dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions and implied that H2A.Z may be a potential intervention known for vascular diseases.

                                                What is the causal role of body mass index and cardiovascular health in young adults? In the next paper from first and corresponding author Dr Wade from University of Bristol in United Kingdom and her colleagues. The authors used a combination of conventional multivariable regression analyses, Mendelian randomization and subsample recall by genotype methodologies. Recall by genotype is a novel approach that exploits the random assortment of alleles through meiotic cell division at conception to inform genetically base recall and enables the collection of precise phenotypic measures in smaller studies while maintaining statistical power and ability for causal inference. The authors use these methods to estimate the causal effect of body mass index on gross level and detail cardiovascular health in healthy participants from the Avon longitudinal study of parents and children at age 17 years as well as in an independent sample from the same cohort study at age 21 years.

                                                Their results showed that higher body mass index was likely to cause worse cardiovascular health specifically higher blood pressure and higher left ventricular mass index even in youth. Higher body mass index also resulted in increased cardiac output in the recall by genotype study which appeared to be solely driven by stroke volume, as neither the Mendelian randomization nor the recall by genotype analyses suggested a causal effect of body mass index on heart rate. These consistent results support efforts to reduce body mass index from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using a recall by genotype methodology.

                                                Older adults undergoing aortic valve replacement are at risk for malnutrition, however, what is the association between pre-procedural nutritional status at midterm mortality? First author, Dr Goldfarb, corresponding author Dr Afilalo from McGill University in Montreal, Quebec, reported results of the FRAILTY-AVR prospective multicenter international cohort study conducted between 2012 and 2017 in 14 centers in three countries. This study included patients 70 years and older who underwent transcatheter aortic valve replacement or surgical aortic valve replacement. The mini nutritional assessment short form was assessed by trained observers pre procedure with scores seven or less out of 14 being considered to be malnourished. The short performance physical battery was simultaneously assessed to measure physical frailty. The authors found that malnutrition was associated with higher one-year mortality and 30-day adverse events following aortic valve replacement via a transcatheter or surgical approach. While malnutrition and frailty were interrelated, the integration of nutritional assessment resulted in improved predictive value for frail patients. Clinical trials are needed to determine whether pre and post procedural nutritional interventions can improve clinical outcomes in these vulnerable patients.

                                                Do newer generation ultra-thin strut drug-eluding stents improve clinical outcomes over contemporary thicker strut stents? First and corresponding author, Dr Bangalore from New York University's School of Medicine and colleagues search PubMed, Embase and Central and identified 10 trials that randomized more than 11,650 patients and evaluated three newer generation ultra-thin strut drug-eluding stents, that is defined as a strut thickness less than 70 microns, versus thicker strut second generation drug eluding stents and reported clinical outcomes. They found that newer generation ultra-thin strut drug-eluding stents were associated with a 16% reduction in target lesion failure, which was a composite of cardiovascular death, target vessel myocardial infarction or ischemia-driven target lesion revascularization evaluated at one year follow-up. Ultra-thin strut drug-eluding stents reduced the risk of target-lesion failure driven by a reduction in myocardial infarction and also a qualitatively lower rate of stent thrombosis compared to contemporary thicker strut second generation drug-eluding stents.

                                                Ambient air pollutants are known to be associated with increased cardiovascular morbidity and mortality, however, what is the association between air pollution and cardiac structure and function? First and corresponding author Dr Aung from Queen Mary University of London and colleagues performed a cross-sectional analysis of a large population free of preexisting cardiovascular disease in the UK Biobank population study. They found that higher past exposure to fine particulate matter and nitrogen dioxide were associated with larger cardiac biventricular volumes. Proximity to major roads, a surrogate for chronic air pollution exposure, was additionally associated with higher left ventricular mass. These associations between ambient air pollution and at first cardiac phenotypic changes, in individuals without prevalent cardiovascular disease, suggest that air pollution should be recognized as a major modifiable risk factor which needs to be targeted by a public health measures.

                                                The final original paper this week is the first study to demonstrate a causal link between atrial fibrillation and the NLRP3 inflammasome, which is an innate inflammation signaling complex. Co-first authors, Drs Yao and Veleva, corresponding author Dr Li from Baylor College of Medicine and colleagues assessed MLRP3 inflammasome activation by immunoblot in atrial whole tissue lysates and cardiomyocytes from patients with paroxysmal or long-standing persistent atrial fibrillation. They found that NLRP3 inflammasome activity was increased in these patients. To determine whether cardiomyocytes specific activation of NRLP3 was sufficient to promote atrial fibrillation, they established a cardiomyocyte specific knock in mouse model which expressed constitutively active NLRP3. These mice developed spontaneous premature atrial contractions, an inducible atrial fibrillation, which was attenuated by a specific NLRP3 inflammasome inhibitor. Cardiomyocyte-specific knockdown of NRLP3 suppressed atrial fibrillation development in these mice. Thus, these results establish a novel pathophysiological role for cardiomyocyte NLRP3 inflammasome signaling with a mechanistic link to the pathogenesis of atrial fibrillation, and suggests that inhibition of NLRP3 may be a potential novel atrial fibrillation therapy approach.

                                                And that brings us to the end of our summaries.

                                                Now for our feature discussion.

                                                Is pericardiotomy going to be our next treatment for heart failure with preserved ejection fraction or HFpEF? I have the first and corresponding author of a very intriguing research letter. Dr Barry Borlaug from Mayo Clinic in Rochester, Minnesota, joining me today to tell today about his great paper. Barry, welcome back to the show. You are amazing. Congratulations on yet another wonderful publication. So, could you set us up. Those of us who don't think about this every day. The hemodynamics of what pericardiotomy does. Tell us what was the rationale of doing this study?

Dr Barry Borlaug:              You know, it's interesting. We think about intracavitary pressures on the left side ventricle and the left atrium causing congestion and pulmonary hypertension. We think that this is all related to left ventricular issues, but about 30 or 40% of the pressure is actually related to external restraint on the heart as mediated by the right ventricle across the septum and the pericardium and external pericardial contact restraints. In animals, we've known since back in the late 1970s, that with the chest open, if you open up the pericardium, which we know in HFpEF, on average, is shifted up and to the left. It's stiffer. This effect really comes into play more at higher heart volumes. It doesn't have as much of an affect at lower heart volumes like might be absorbed with rest. It's even been rumored that in some species like greyhounds, illicit dog racers, would actually cut away the pericardium so these dogs could race better. It's actually been shown that they can experimentally, in a paper in the 1980s, that they can exercise the higher peak VO2. They have a higher cardiac output response, because the heart is better able to utilize the Frank-Starling relationships to augment ventricular filling and ejection at fuller pressures.

Dr Carolyn Lam:                Oh my goodness. I didn't know that latter fact about the racing dogs. Could I ask you something? We've talked about this before back in the day. When you say the left side the filling pressures go up when there's pericardial restraint, remember we used to talk about a parallel shift upwards versus true intrinsic stiffening ... diastolic stiffening. You still do mean that parallel shift upwards, right?

Dr Barry Borlaug:              That's right. If it was purely an increase in stiffness, we would expect it to sort of rotate, pivot from the bottom left up, but what we see, and in human data, we published a number of years ago, most of the increase in LV end-diastolic pressure is a parallel shift upward in the diastolic pressure volume relationship. That really suggests that there's an increase in restraints on the heart. That's why we think that that's an important target and it's possibly more remediable to treatment since we're having such tough luck changing the viscoelastic properties of the left ventricle, not that we shouldn't be doing that, but this might be something different that we could do that might give us a little bit more of a benefit in terms of filling pressure reduction.

Dr Carolyn Lam:                True. True. But the way you describe it too, it does mean that we may be talking about, I hate to say this but, specific subsets or types of HFpEF, where that may play a bigger role and I'd just like to bring the audience to your incredible paper that I think that I've cited a gazillion times already on the obese HFpEF phenotype. Do you want to remind everyone about that because I think there you really [inaudible 00:16:30], didn't you that ventricular interdependence played a big role.

Dr Barry Borlaug:              So, in people with obese HFpEF, which is now becoming by far one of the most dominant. Oh God. We did a study that compared them to non-obese and we see that the obese patients have a bit more plasma volume expansion, a bit more cardiac remodeling, right heart enlargements, increase of LV mass and an increase in epicardial fat. What all this does is increases the total heart volume in the pericardial space. Because the pericardium doesn't appear to grow as much as the heart volume, this increases the coupling between the right and left heart. Some people, perhaps like the obese phenotype of HFpEF, might be more poised to derive benefit from approaches to therapeutically remove this excess pericardial restraint.

Dr Carolyn Lam:                Okay, now you just have to get down to telling us what you did. This was a first in man pilot study. Drum roll everybody. You gotta listen up. This was so cool.

Dr Barry Borlaug:              This physiology just got us thinking that maybe we could do this to help our patients with HFpEF. First we tested this in dogs, then with pigs with features of HFpEF and it seemed to work there so the next step was to show that it might work in people. We took people that were already going to get their pericardium open, so people that were referred for cardiac surgery. We wanted to choose people that had risk factors for HFpEF and diastolic dysfunction but maybe not necessarily diagnosed HFpEF.

Dr Barry Borlaug:              We took people who were referred for aortic valve replacement for AS, coronary artery bypass grafting or both and consented them ahead of time, put catheters into them to measure hemodynamics and then we measured resting hemodynamics with the chest open, but pericardium intact, because the changes that we see occur predominantly when there's an increase in volume load to the heart, we then had to stress the system. Now we can't have them exercise cause they're under general anesthesia with an open chest. You achieve that by elevating their legs and giving them a little saline bolus, so we had a pressure at rest, pressure with saline load.

                                                Then we asked our surgeons to open the pericardium, which they do obviously to gain access to the heart for cardiac surgery and we repeated the same assessments and intervention. What we saw was that the resting filling pressures, again these people did have diastolic dysfunction, the resting pulmonary wedge pressure was about 16. With the volume load maneuver, it increased to 25 when the pericardium was intact. After we had opened the pericardium, the increase in wedge pressure, which was our primary endpoint, was reduced from an increase in nine millimeters of mercury down to an increase of only three millimeters of mercury. So that verified our hypothesis that the pericardium contributed and that we could prove total cardiac diastolic reserve, if you will, just by removing that pericardial restraints.

Dr Carolyn Lam:                Wow. I love the figures, by the way, that you've drawn as always they illustrate that so beautifully. And listeners, this is a research letter, so there's that one central figure that you must get your hands on right away. Now Barry, I think the first question is this wasn't really HFpEF patients right? Let's be very clear with the audience who these were though and then you did a subset analyses though, a further analysis that showed this may apply more to people with higher wedge at rest. Could you elaborate?

Dr Barry Borlaug:              Absolutely. While these people, and Carolyn, I think you know as well, I think a lot of people probably have HFpEF that they have a sort of occult HFpEF, that's not been diagnosed maybe because unfortunately, not everybody else thinks about this diagnosis. When you look at the charts very carefully, and found out about 13 of the 19 patients complained of significant dyspnea based on chart review. Of those 13, 10 had other indicators that according to current criteria would give them the diagnosis. When we looked at this at this very post hoc, sort of exploratory subset, we actually saw that these patients, even though they didn't necessarily have a clinic diagnosis of HFpEF, that these patients actually responded even more favorably to the effects of pericardiotomy in their greater reduction in the increase in wedge pressure. When we plotted in the figure that you mentioned, we plotted the change in the increase in wedge pressure, it was really the patients that had the greatest increase with volume loading initially that derived the most benefit. That makes sense because those were the people where the pericardium and the restraint is the becoming most operative, when the heart is most distended and congested.

Dr Carolyn Lam                 Maybe one quick last question. What next Dr Borlaug? Gosh, you just keep coming up with one thing after another with the animals. I noticed that it was a non-invasive pericardiotomy. I'm reading between the lines here. What are you going to do next? Do you think this is ready for prime time?

Dr Barry Borlaug:              As usual, you're reading correctly between the lines. We have filed a patent awhile back for this and we have a device that can achieve a pericardial modification or an anterior pericardiotomy without the need for open heart surgery, so that you don't crack the sternum. It's done from a subxiphoid approach and we've actually just received some funding to start doing this under an IDE, which we will need to work with the FDA. We hope to do and start testing this in patients that have HFpEF and then look at the acute hemodynamically affects. Then we'll also begin to explore the safety and potential efficacy using other indices like imaging, exercise capacity and things like that.

Dr Carolyn Lam:                That is just so cool. I think that one of the immediate take home messages for me now though is when we see patients who we think have HFpEF, have a low threshold to look for evidence of constriction. I would say that we may miss the diagnosis of people who legitimately have constrictive pericarditis and may need to benefit from this. I think it's one of those hidden diagnosis, so that's one thing. And then the next thing, if I could just ask you, are there any patient populations that you say should not undergo this? And I say this because I remember back in the day again, when we were experimenting with dog models, this is just gestalt okay, but I thought that the dogs who had right-sided heart failure, severe right-sided heart failure, needed that pericardium to lean on, and if you released it, the dilatation on the right side would just be inexorable because there is no pericardium to rein them in. Do you get what I mean? I don't know. I'm just curious if you have any patient population right now that you're already thinking I'm not going to include in my trial.

Dr Barry Borlaug:              Yeah. That's a very important point, Carolyn. We would not want to apply or test initially certainly this therapy where eccentric cardiac remodeling is a problem because we know that there is a little bit of eccentric dilatation even in people after a regular cardiac surgery with pericardiotomy. Marty Molenter showed that, in a paper back in the 1980s, you have a patient who already has some dysfunction, we would hypothesize that they may get a bit worse, so we would not want to test this in people with the right ventricular dysfunction, right ventricular enlargement phenotype of HFpEF. We would not want to give this to people with HFrEF. Remember with HFrEF, we wanted to do just the opposite. We tested this years ago with the ACORN trial or older studies wrapping the latissimus dorsi around the heart to cause reverse remodeling so this is really something that would maybe work more for people with smaller stiff hearts, HFpEF, where that concern that they're going to dilate and get low EF heart failure either on the left or on the right side. We would want to focus more on the small hearts and away from those people with dilation.

Dr Carolyn Lam:                That is so great. Thanks so much Barry for letting us under the hood. Congratulations once again. These are just great papers. Keep them coming. Well listeners. I'm sure you enjoyed that as much as I did. Don't forget to tune in again next week.


Nov 5, 2018

James de Lemos:              Welcome everyone to Circulation on the Run my name is James de Lemos, I am the executive editor for Circulation based at UT Southwestern in Dallas and I will be filling in for Carolyn today as we discuss this year's surgery themed issue. I would like to welcome Dr Marc Ruel, the chairman of cardiac surgery at the University of Ottawa and a long-time editor of the Circulation of surgery themed issue, as well as Dr Tim Gardner, professor of cardiac surgery at The University of Pennsylvania and our leader at Circulation on the editor team for issues related to cardiac and vascular surgery. Marc and Tim, welcome and thanks for all your tremendous work in this issue.

Dr Marc Ruel:                    Thanks James for having us.

Dr Tim Gardner:               Thank you. Glad to be here.

James de Lemos:              Why don't we start Marc with your thoughts on how this issue comes together, how it came to be, you picked the papers and how we ended up with this terrific issue.

Dr Marc Ruel:                    It’s been a really important year for surgery and for this issue, as some of you may know the supplement which used to be the old designation of this issue has been changed to the surgery themed issue in about 2014 or so where the new Circulation leadership and what we tried to do every year is to bring the very best, not only of cardiovascular surgical science but also of clinical care and pearls around clinical and surgical care. So, I think this year we have had probably more than 60 submissions sent to us. Tim and I have looked at those very closely and you as well, James, we really wanted to get the feedback and the approach from not only cardiac surgeons but also from cardiologists and cardio vascular care specialist around those. We've tried to select the best of science and also some papers that we feel would be very useful with regards to providing new clinical pearls for surgeons and anyone in the circle of care around cardiovascular surgery.

Dr Tim Gardner:               If I could just add, James, of course we have other papers that have been submitted by surgeons that are published or that deal with cardiac surgical or vascular surgical topics during the year, this particular issue is very much focused on cardiac surgery but throughout the year we have plenty of submissions of manuscripts by surgeons about surgery about surgically related topics and so on. So, I am actually kept quite busy reviewing and commenting and consulting on manuscript submissions of Circulation. There are plenty of papers over the course of the year that relate to surgical topics.

James de Lemos:              Wonderful, I think you will see, as we talk about these papers, really that what Marc and Tim are talking about in terms of papers that are broadly relevant to cardiac surgeons and cardio vascular providers really rings true. Let’s walk through the issue, its set up like most of our issues begins with a couple of opinion pieces, a brief frame of reference, articles about important topics. Marc, do you want to talk about the Domanski paper, talk about revascularization for ischemic cardiomyopathy?

Dr Marc Ruel:                    Absolutely, we've asked experts, namely Mike Farkouh and Micheal Domanski, to provide us where their thoughts regarding the optimal treatment on patients with LV dysfunction and severe coronary disease. What many of us would call an ischemic cardiomyopathy, which may be construed as a misnomer or as an accurate term, I will not debate on this today, but certainly it remains a very vexing clinical problem. I think we could all agree that the last niche where we still see very high in terms of treatment for coronary disease this is probably mortality and kind of an inability to provide for a tangible result.

                                                Once LV dysfunction has set in and the present of CAD the outcomes are poor, and it took years and literally almost ten years for the STICHES trials to show a benefit for surgical treatment. This is relatively all study now and it has to be put in context and I then that Mike and Mike are doing this extremely well in terms of providing the caveat, for instance, STICHES at its inception added had a 5% mortality rate around CABG, so we know that the modern outcome are probably better than that. It’s very difficult to actually decipher what sound be the mainstay of treatment for each challenging patient and I think the frame of reference provided by Dr Farkouh and Domanski is extremely useful in helping with that.

James de Lemos:              Tim we have another frame of reference that is also provocative. Trying to make a case that we think about in patients with hypertrophic cardiomyopathy with obstruction early surgical procedures to relieve the obstruction. Do you want to tell the readers a little bit about this opinion piece and what your thoughts on it are?

Dr Tim Gardner:               Sure James, this is a really nice frame of reference article from both doctors Martin and Barry Maron and then their European contributor Paolo Spirito and the point of their opinion paper is that the surgical art for managing this very difficult obstructive cardiomyopathy syndrome has reached the point where we really shouldn't wait until patients are in extremist or in class 3 or 4 status in term of syndromic problems and can consider earlier surgery for these patients. They make the very important point which I think we have to except is that for patients to do well with this operation they need to be in a center where there is experienced surgery and experienced surgeons, but the point is now that the state of the art for managing obstructive cardiomyopathy is as such that good result are obtained and patients should be offered this surgery when appropriate, but earlier, in order to avoid the challenges of end stage cardiomyopathy and difficulty relieving the obstruction, so this is a really important opinion piece. It’s great to see our cardiology colleagues who are experts in this field make this point based on well published data from centers like the Mayo Clinic.

James de Lemos:              Moving now to the original articles, we've got 5 original articles, maybe Marc we can start with your thoughts on 2 articles related to revascularization, one in coronary disease and one identifying a really novel approach for treating type A aortic dissection with malperfusion.

Dr Marc Ruel:                    I think that's well said James, the first of these original papers will be likely somewhat controversial. The first author is Dr Bo Yang and essentially it is a series from Michigan where they look at just shy of 600 patients with acute Type A Aortic Dissection, of whom 135 were identified to have malperfusion syndrome. Essentially defined by the authors as something slightly different than malperfusion per say but really malperfusion accompanied with evidence of necrosis in one of the organs.

Their approach has been new and somewhat controversial in that they have brought these patients first to the interventional radiology suite in order to fenestrate in many cases or at least open the culprit artery or the culprit perfusion territory that leads to malperfusion syndrome and then depending on how the patient is doing they would then proceed to open repair as soon as 24 hours afterwards or they may wait longer in someone where there is no sign of improvement yet prior to moving to the ER, so they have found this has not only improved the results with regards to in hospital mortality after operative repair type A aortic dissection, but also to allow them to better discern or differentiate should I say between patients in whom malperfusion may lead to a futile situation and who then may be avoided from undergoing a very complex and difficult OR so would argue this is probably the first such large organized, well documented series of such an approach and I think it will lead to some head scratching, this being said it must be remembered that the goal standard for Type A aortic dissection is dealing with the intrapericardial aorta first and hoping that the perfusion gets better from this and everyone knows that the results of this approach are not fantastic.

We know that even in the best centers, including the latest data from Germany such an approach has about a 20% mortality rate so clearly there are ways that we can improve with Type A aortic dissection and this paper may be a strike in the right direction.

James de Lemos:              The other revascularization paper addresses that, I would say also a quite controversial topic which is how many atrial grafts are optimal in patients that are undergoing surgical revascularization?

Dr Marc Ruel:                    This is a paper from Toronto where the Ontario ICES database was used and several papers actually dozens and dozens of papers have come out previously from this well established and well allocated database. Steve Fremes who is the senior author and one of his trainees, Dr Rocha and the team of authors got together and decided to look at the impact of 3 versus 2 arterial grafts in patients undergoing cabbage with regards to survival. They have very nice, very compelling follow up information and they basically carry out 2 exercises.

First, they wanted to see if the 3,000 patients or so had 3 or more arterial grafts had a better outcome than the 8,000 patients or so who had 2 arterial grafts and frankly they found there was no significant difference with regards to survival at 8 years and freedom from MACCE at 8 years. However, when they compare those 9 or 8,000 patients or so who had 2 arterial grafts to the rest of 40,000 or so patients who had 1 arterial graft and completions with veins they found that again there was a survival benefit. This last finding is not new and its obviously subject to indication biases as well as expertise bias as we've seen in many of the observational perspectives studies around multiple arterial grafting. But I think the concept of comparing 2 versus 3 arterial grafts is very novel in surely in this paper is being addresses with very high scientific related from the numbers and the quality of the follow up that's been brought to the exercise.

James de Lemos:              I've really been struggling, I love your thoughts and Tim, your thoughts on how to reconcile the data in space. I really am having a hard time getting my head around what seems to be conflicting data about the number of arterial grafts in what an optimal CABG looks like in 2018 with the evidence that we have. What are your thoughts on that question?

Dr Tim Gardner:               I think that this supports the concept that 2 arterial grafts whenever possible for some patients, younger patients perhaps 3 but I think the important point is, multiple arterial grafting should be attempted and carried out whenever possible. I leave the is 3 better than 2 to some future study or future review that can be more precise about that.

Dr Marc Ruel:                    This being said I think we don't view efficiently coronary surgery as being an area of expertise and many centers including very strong academic centers may not necessarily marry the concept that coronary surgery has to be something with the dedicated expertise. I think when we look at those observational perspectives series we see the effect of it may be the expertise bias, but it may be more than just 2 or 3 arterial grafts, they may be the whole wrapping of care that comes with it including optimizing beta blockers and managing diabetes etc. So, I think it may be more than purely conduits but definitely, as Tim said, 2 arterial grafts are probably better than just 1 and the jury is still out on whether 3 is better than 2.

James de Lemos:              Excellent. Switching gears now Tim, an area that obviously you have tremendous experience and expertise we've got 2 innovative papers addressing surgery for individuals who have congenital heart disease. Can you update us on what we are publishing here?

Dr Tim Gardner:               Sure, the one study focuses on the risks of pulmonary valve surgery in adult patients who underwent a correction of tetralogy of Fallot earlier in life. This is a growing population actually we refer to as young adult with congenital heart disease and in many centers they are more numerous in terms of the patients groups than infants because this group has been successfully treated early in life, but this particular group of patients, patients who have had tetralogy of Fallot repaired and end up with what the author calls right ventricular outflow disfunction generally regurgitation through the outflow tract pulmonary valve sometimes obstruction, these patients then face significant clinical challenges in death from heart failure, right ventricular failure or arrhythmias in their late 20's and 30's. We have been focusing now on the timing and the type of pulmonary valve replacement.

Dr Tim Gardner:               Now there is catheter replacement options available, but when to do this and how to minimize risk is really the focus of this one paper that describes a four multi-center study looking at predictors of risk for these patients. Sort of a hypothesis generating paper, but it is an important study none the less, focusing on how to identify patients with right ventricular out flow tract dysfunction and who should have pulmonary valve replacement and when that should optimally be done. It a very good study. The other important study that we have is that the other age spectrum of neonates and this is a study that is based on a review of data from the pediatrics heart health information systems database, led by the group at the Children's Hospital Philadelphia.

Looking at variations in pre-operative care and management of neonates with transposition of the great arteries. This was a little controversial actually when we reviewed it among the editors because the suggestion is that earlier surgery this would be in the first week of life and more perhaps aggressive use of atrial balloon septostomy seems to improve outcomes. This is a generally low risk population, the point of the paper is that these pretty good results can be improved by paying more attention to the timing of surgery and the appropriate use of balloon septostomy. It’s sort of a quality improvement perspective based on a large database and I think it’s a very nice study and undoubtedly creates additional attention to this particular area.

James de Lemos:              Marc, our last original paper is a really novel issue engineering approach to creating vascular conduits, can you tell the readers briefly what happens to her in this paper?

Dr Marc Ruel:                    Indeed. It’s a paper from Stanford, from Joe Woo’s lab and the first author is Daniel von Bornstädt. Essentially, as you say it’s a very innovative novel approach to try to recreate a bioengineered blood vessel. We surely know there's quite a need for such off the shelf conduits, not only in cardiac surgery but also in vascular and vascular surgery and even for things such as AV fistulas and others. It’s really interesting to see that this is what I would call transitional science at its best and surgeons have had an important role over, as you know, centuries in helping develop this and many discoveries have come from surgical labs, especially a few decades ago.

In any case, what Joe and his team have performed is to try to use clinically applicable methods to derive and create a bioengineered blood vessel and they started first with human aortic smooth muscles cells and skin fibroblasts which are literally easy to get and they used those to constructs bi-level cell sheets, they then used a 22 gauge angiocath needle so that the sheets would be wrapped around this in order to lead to a tubular vessel construct. Then the next problem has been traditionally that those bioengineered vessels would burst out with atrial pressure. What Joe's team came up with is to use a commercially available adhesive, so a glue essentially, which is dermabond which typically we use after any form of surgery to keep the incision together and they put dermabond on the surface of this sheet wrapped around an angiocath needle to act as a temporary external scaffold. They then led this into a bioreactor and implanted it in series of 20 rats as a femoral artery interposition graft. The results were excellent. Essentially, patency was perfect and there was a full vascular maturity with all 3 layers of blood vessel that you would expect including an intima that had been formed as a result of the experiment.

I think this is all very promising because none of the methods here are involving something that would have non-autologous issues, or you could easily see this being used with a patient’s own cells in order to achieve an autologous. I think this is obviously small vessels, there are 22-gauge needle is not a big conduit, you’re not going to bypass an LED with this, but I think it’s a start and it’s all done using transitional or clinically applicable methods. I guess the next step would be moving to a large animal model and certainly I think we should stay tuned to see where this leads us.

James de Lemos:              I think that's exactly my thinking as well about that discussion and really leads us into some of the issues that come up in the review paper that you are a co-author on new strategies for surgical revascularization. I think this basic in translational science piece is designed to address some of the limitations of current revascularization and you all did a really beautiful job covering some new more clinically ready strategies in your papers. Can you just tell us very briefly what you all covered in that review paper?

Dr Marc Ruel:                    Indeed, this is a paper that was kind of aiming at being a state of the art around CABG and rapidly the focus was reshaped towards kind of new strategies around surgical myocardial revascularization. Initially we have a section on OPCAB on this and that and minimizing the inflammatory effects of the pump and quickly it became apparent that the desire of Circulation and this themed issue was to focus it more on really what are the up and coming improvements around surgical coronary revascularization. This paper focuses on essentially 4 main areas. One is hybrid coronary revascularization, the second one is less invasive coronary surgery, the third one is the use of multiple arterial grafts to which we eluded a little earlier during this podcast and fourth is the use of an aortic coronary surgery, essentially meaning bypass surgery performed without any manipulation of the aorta.

James de Lemos:              As we think about innovation in terms of conduits, the procedure itself, the other aspect that's covered in our last paper is can we make the procedure safer perhaps by modifying our use of anti-platelet therapies based on meshment of the platelet phenotype and Tim do you want to bring us home by just telling us a little bit about what we learned from Paul Gurbel and his group of platelet experts?

Dr Tim Gardner:               Well we learnt a lot about platelet science and appropriately so Dr Gurbel is a well-recognized expert in platelet physiology or platelet management and this is a really quite a challenging area because many of our patents come to surgery especially for coronary surgery already on platelet inhibitor agents and what Dr Gurbel and his co-authors showed in this paper is that although there is somewhat limited data there can be and should be platelet function testing and with an appropriate understanding of platelet inhibition drugs that we may be able to limit the time between removal of these or discontinuation of these platelet inhibitor drugs and the necessary surgery which will improve outcomes and reduce bleeding in patients requiring urgent CABG surgery. It’s a very useful update and it is a good example of a paper that isn't written by surgeons, but really applies very much to the cardiac surgical treatment of coronary artery disease

James de Lemos:              I really like the very practical tables and figures that lay out the potential tests that surgeons or anesthesiologists may consider for assessing this and even how one might implement. I would like to bring us to conclusion now, first I want to acknowledge, Sara O'Brien at the Circulation office for her amazing work together with Marc and Tim pulling this issue together, making sure that we have a consistent high quality issue with wonderful figures and tables and it really came together beautifully and thank you both for joining me today and the podcast I think it’s obvious that we've got an issue that all of you listen to this podcast need to actually pull out the issue or download it because we have a co-host of wonderful papers to look at and cardiac surgery thriving at Circulation. As we've talked about this is the tip of the iceberg, this themed issue, we've got great content coming, issue after issue. We are already open for business next year’s issue, so please send us your best cardiac surgery research. Please pay attention to these important papers and apply them in your practice because I think many of them are already directly applicable.

Marc given your leadership role in the issue do you want to bring us home and make any concluding remarks?

Dr Marc Ruel:                    I think your points are very well taken James and I want to reintegrate that if I speak on behalf of the cardiovascular surgical community, we are very thankful to the leadership with Circulation. James, Joe, Tim and many others and obviously the support from the staff in clearly establishing that cardiovascular surgery is a very important therapeutic mentality and the overall scope in the broad scope of cardiovascular therapeutics.

Dr Carolyn Lam:                You've been listening to Circulation on the Run. Don't forget to tune in again next week.


Oct 29, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue provides much long awaited healthcare resource utilization and cost implications in the MOMENTUM 3 randomized controlled trial of a magnetically levitated cardiac pump in advanced heart failure. All of this coming right up after these summaries.

                                                The first original paper this week provides important mammalian data on the acute effects of phosphodiesterase type 1 inhibition on the heart. Now phosphodiesterase type 1, or PDE1, is known to hydrolyze cyclic AMP and cyclic GMP in the heart. However, what's important to understand is that data from rodents may not be applicable to humans because rodents express mostly the cyclic GMP favoring PDE1A isoform, whereas human hearts predominantly express PDE1C isoform which has a balanced selectivity for cyclic AMP and cyclic GMP.

                                                In today's paper, first author Dr Hashimoto, corresponding author Dr Kass from Johns Hopkins University School of Medicine and colleagues, determined the acute effects of PDE1 inhibition on PDE1C expressing mammals, dogs and rabbits, in normal and failing hearts. They found that selective inhibition of PDE1 with ITI-214 induced positive inotropic, lusitropic, chronotropic, and arterial vasodilatory effects in dogs and rabbits. These effects occurred via cyclic AMP modulation and were observed in failing hearts. ITI-214 contractile increase was insensitive to beta adrenergic blockade or heart rate increase, but inhibited in vivo by adenosine receptor inhibition. Furthermore, isolated myocytes revealed differences between PDE1 and PDE3 inhibition. Wherein PDE3 inhibition, augmented beta receptor agonism and calcium transients, whereas PDE1 inhibition enhanced function without calcium increase. These findings have important clinical implications for ITI-214 which has completed phase 1 trials and may provide a novel therapy for heart failure.

                                                We know that macrophages are involved in foam cell formation in atherosclerotic plaques, but our next paper tells us we may now have a way to therapeutically modify this. Co-corresponding authors Dr Wei and Schober from Ludwig Maximilian's University Munich elucidated the role of microRNA generating enzyme Dicer in macrophage activation during atherosclerosis. They showed that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited, whereas lipid filled foam cell formation was exacerbated in Dicer deficient macrophages due to impaired mitochondrial fatty acid oxidative metabolism. MicroRNA biogenesis promoted the degradation of fatty acids by mitochondrial respiration in macrophages, which in turn reduced intracellular lipid storage and limited atherosclerosis. Thus, reducing foam cell formation in atherosclerotic arteries by enhancing energy metabolism through microRNA mediated fatty acid oxidation may be a promising approach for the treatment of atherosclerosis.

                                                The next study evaluates how aortic stiffening relates to resting cerebral blood flow and cerebral vascular reactivity in older adults. First and corresponding author Dr Jefferson from Vanderbilt Memory and Alzheimer's Center and her colleagues studied participants free of clinical dementia, stroke, or heart failure, including 155 older adults with normal cognition and 115 mild cognitive impairment. They found that greater thoracic aortic stiffening quantified by cardiac magnetic resonance was associated with lower cerebral blood flow in cognitively normal older adults. Aortic stiffening was associated with reduced resting cerebral blood flow in the presence of preserved reactivity and associated vasodilatory capacity, particularly among participants without hypertension. ApoE4, a well-known genetic susceptibility risk factor for Alzheimer's disease, modified the results with stronger effects among carriers in the temporal lobes, where Alzheimer's disease pathology is known to first evolve. In summary, greater aortic stiffening related to lower regional cerebral blood flow and higher cerebral vascular reactivity in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow for earlier detection and targeted interventions to prevent or mitigate the onset of more serious cerebral vascular damage associated with greater aortic stiffening.

                                                Aortic valve replacement for aortic stenosis is usually timed according to the development of symptoms, but could the timing be too late once irreversible myocardial scar has developed? Co-first authors Drs Musa and Treibel, corresponding author Dr Greenwood from University of Leeds and their colleagues found that in patients with severe aortic stenosis, focal myocardial fibrosis determined by cardiac magnetic resonance imaging was present in over 50% of patients and was associated with a two-fold higher late mortality. Focal scar was independently associated with all cause and cardiovascular mortality, after both surgical and transcatheter aortic valve replacement. In severe aortic stenosis, late gadolinium enhancement appears to be a useful biomarker of left ventricular remodeling, and its presence is associated with worse long-term outcomes following aortic valve intervention. Thus, in severe aortic stenosis, late gadolinium enhancement may be a useful biomarker of left ventricular remodeling, and its presence may be associated with worse long-term outcomes following aortic valve intervention.

                                                The next study suggests that endogenous factor Xa activity may be irrelevant pharmacodynamic marker to guide Edoxaban dosing in future. First author Dr Yin, corresponding author Dr Giugliano from TIMI Study Group, Brigham and Women's Hospital in Boston, and their colleagues, describe the value of endogenous factor Xa activity as a pharmacodynamic marker, linking Edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. They showed that the extent of inhibition of endogenous factor Xa activity was influenced by Edoxaban dosing and clinical characteristics, and was associated with both antithrombotic benefit and risk of bleeding. The implications are that this approach of linking endogenous factor Xa activity to clinical outcomes may be used to guide dose selection in future clinical trials, to monitor patients in certain clinical scenarios, or to define the doses of oral factor Xa inhibitors in patients who require precise anticoagulation therapy.

                                                The next paper describes a novel multi-protein complex that plays a critical role in regulating cardiomyocyte survival. First author Dr Zhang, corresponding author Dr Yan from University of Rochester School of Medicine and Dentistry and colleagues, showed that phosphodiesterase 1C is activated by transient receptor potential canonical channel-3 derived calcium, thereby antagonizing adenosine A2 receptor cyclic GMP signaling and promoting cardiomyocyte death or apoptosis. Targeting these molecules individually, or in combination, may represent a compelling therapeutic strategy for potentiating cardiomyocyte survival.

                                                The final paper demonstrates a molecular link between two well-recognized biomarkers of fibrosis, Galectin-3 and Osteopontin. First author Dr Shirakawa, corresponding author Dr Sano from Keio University School of Medicine and their colleagues, showed that Osteopontin was almost exclusively produced by Galectin-3 high CD206 positive macrophages, which specifically appear in the infarct myocardium after a myocardial infarct. The interleukin-10-STAT3 Galectin-3 axis was essential for Osteopontin producing reparative macrophage polarization after myocardial infarction, and these macrophages contributed to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results therefore suggest that Galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling Osteopontin levels. And that brings us to the end of this week's summaries, now for a feature discussion.

                                                Left ventricular assist devices have truly revolutionized our management of advanced heart failure. In fact, these devices have allowed us to keep patients not just as a bridge to transplantation, but as destination therapy. The devices get better and better but also more and more expensive, and the problem is, that places a lot of strain on our healthcare systems. A lot of us are crying out for information on the cost effectiveness of these newer devices, and guess what? We have answers this week with our featured paper.

                                                I am delighted to have with us the first and corresponding author Dr Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as our senior editor Dr Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Hello, Mandeep and Biykem! I am so pleased to be talking about a subject really close to all our hearts. Mandeep, could you start by maybe sketching out the actual issue, and maybe reminding our audience what's the difference between the different types of left ventricular assist systems that you compared.

Dr Mandeep Mehra:       The era of left ventricular assist devices took a major therapeutic shift when we recognized that we could usher in continuous flow devices. These are devices that generate no peripheral pulse, they do not have systole and diastole. And these devices are small in profile, have very few moving parts, and there are several commercially available devices, two in the United States and up to three worldwide, that bear these characteristics.

                                                The HeartMate II device, which is a continuous flow device that flows blood in an axial format. The HeartWare, or HVAD device, which is a centrifugal flow pump, where the blood comes in and then is ejected at a 90 degree angle. The Jarvik 2000 pump that is still used in some areas, in many regions experimentally, and then the new kid on the block, the HeartMate 3 device, which is a centrifugal flow pump with some very unique technological characteristics.

Dr Carolyn Lam:                Nice! And now drumroll, please tell us what you found in your brilliant study this week.

Dr Mandeep Mehra:       First, I'd like to remind the audience that the MOMENTUM 3 trial which randomized patients to the HeartMate II versus the HeartMate 3 device, was called MOMENTUM 3 and was a two-year study. We presented the pivotal two year trials results in 366 randomized patients earlier this year in The New England Journal of Medicine, and this study showed that the HeartMate 3 was superior on the primary endpoint when compared to the HeartMate II. The primary endpoint was survival, free of a disabling stroke, or the need to replace the pump surgically for a pump malfunction. And much of that, Carolyn, was driven by the need for replacement of the pump because the HeartMate 3 pump has some unique features that reduce its proclivity for pump thrombosis.

                                                The HeartMate 3 pump is a frictionless pump. It's completely, magnetically, dynamically, born in the rotor. It has wider blood flow paths, so we don't see hemolysis with this pump. And this pump also has an artificial intrinsic pulse that has been created, that pulsates the pump in a 40 beats per minute configuration. So this was the primary trial result, and one of the lucky foresights that we had when we designed the trial was to embed, prospectively, economic analysis within this trial. We recognized that the cost effectiveness related issues and cost configurations with these devices would become very, very important as we scale into today's day and age of healthcare transformation. And the paper that is being presented in Circulation this week, really speaks to the health resource utilization and cost outcomes between the two devices.

                                                We found that the HeartMate 3 pump is actually a cost minimization device, and what that means, Carolyn, is that we have become very used to thinking of new technology as providing incremental costs. So we think that, "Oh, well, what incremental costs should society bear for the benefits as we allocate new technology?" And in this particular trial, what we found is that while the costs of the pump itself, the HeartMate II and the HeartMate 3, were kept the same, which means its operational implant costs were the same, pretty much. We found that the HeartMate 3 pump was associated with a reduction in healthcare resource utilization over two years and with a marked decrease in cost. And in fact, our estimate of cost reduction was in the range of about 65 thousand dollars less, compared to the HeartMate II, in favor of the HeartMate 3.

Dr Carolyn Lam:                Wow, Mandeep, first of all, congratulations on these remarkable findings. Biykem, I really have to bring you in here. What do you think of the implications of this?

Dr Biykem Bozkurt:         First, I would like to congratulate the authors for a very innovative approach. As Mandeep has stated, they prospectively collected very challenging billing data from the hospitals, and then also did a very complex analysis including the VRG, as well as looking at payer reimbursements for public versus private. And did a variety of subgroup analysis, which I thought was quite helpful in sorting out that perhaps the cost effectiveness was concurrent both from the Medicare, the public, as well as the private, or regardless of the intent for destination versus bridge to transplant.

                                                Probably the most important concept when you look at these close analysis is incremental cost effectiveness ratio, per quality of adjusted life year gained. Now, I do realize the current analysis doesn't allow us to infer the ICER benefit or the incremental cost effectiveness, which I think the investigators are planning to do with a thousand and more patients over a course of two years, which is going to be probably the more definitive. But as it currently stands, with what is provided by Dr Mehra and his colleagues is, we're probably reaching that sweet spot of what is construed as the cost effectiveness ratio of a cost.

                                                Let's say 100 thousand dollars over the course of a year, then I would like to ask Mandeep whether on the prediction will reach that threshold of less than 100 thousand dollars. Because the former studies, looking at the ICER ratios, or incremental cost effectiveness ratios for the DT destination therapies, usually we select somewhere around 200 thousand dollars. And I know that usually that is seen as a prohibited cost, and there was a discussion whether we would be able to reduce the cost by about half, either doing index admission and add subsequent hospitalizations. With the data Dr Mehra and his colleagues have shown, it looks like the re-hospitalization cost is about, approximately half, or reduced by 50%. Mandeep, any thoughts on that, on that sweet spot?

Dr Mandeep Mehra:       Yeah. I think, Biykem, you have articulated this extraordinarily well. And for the audience, since it's worldwide, I'd like to place a few things in perspective on how to think of economic modeling. First of all, the point I would make is that this is the first prospectively collected data that we have in the field, and as you pointed out, it was very, very difficult to pull this data together and is still very complex. But let's just think about what ICER really is. It all starts with what we consider to be health utility.

                                                For example, Carolyn, Biykem, and me less so, would have a health utility of 1.0, 1.0 means a perfect health utility number. And I know, Carolyn, you and Biykem are absolutely perfect so you would be a 1.0, I probably am not a 1.0. But a patient with advanced heart failure has a health utility of about .4, so that's only 40% of what is perfect. And when we place ventricular assist devices, whether you place the HeartMate 3 or the HeartMate II, the health utility actually jumps up to about .7. So it's not perfect yet, but it moves all the way up there.

                                                The incremental cost effectiveness ratios of implanting a device over time are calculated based on this health utility benefit, compared to the population of advanced heart failure. And the best current estimates of the HeartMate II are that ICER is about 200 thousand dollars, per quality adjusted life years gained, and this has been done by creating what's known as Markov modeling. A lot of that, by the way, is conjecture, it's not real information. It is predicted information, so one has to take that data with a grain of salt.

                                                Here in this health resource analysis for MOMENTUM 3, we actually looked at actual data. There are some estimates used in this analysis as well, where we did not have accurate billing forms available, but we focused on those things where we had very clear knowledge of the cost of outcomes. For example, we did not look at the costs of outpatient follow-up care. We mainly looked at the cost differences of hospitalizations. And what we essentially found here is that just looking at hospitalizations and differences between the two devices, the cost differential, whether it's Medicare which is public [inaudible 00:20:14], or whether it's commercial. It ranges somewhere between 50 to 65 thousand dollars of difference between the two devices.

                                                Now, if you assume that the ICER for the HeartMate II is accurately at about 200 thousand, and you reduce that ICER by about 50 to 60 thousand, the ICER would naturally come into the range of what you would consider to be about 135 thousand to 150 thousand dollars per quality adjusted life years gained for the HeartMate 3, compared to an advanced heart failure population. Once we look at it from that perspective, as Biykem pointed out, we are getting closer and closer to the societal norms.

                                                At one time-point, society used to think of a quality adjusted life years gained cost of 50 thousand dollars as something that would be acceptable to society, and this was seemingly based on the threshold for what dialysis provides in benefit. And now, we recognize that we have to really expand that to somewhere around 100 thousand more logically, or between 100 and 150 thousand for some technologies. The important thing I would say to you is that, that is society dependent. So what the United States considers to be a reasonable ICER, say 100 to 130 thousand dollars per quality adjusted life years gained, may not be the same that Great Britain would look at, or Sweden would look at, or another country would look at. And each country actually creates their own economic value propositions, and this will have to be taken into account as we think about this data as well.

Dr Carolyn Lam:                How cleverly and clearly articulated, thank you so much Mandeep. Just one last question for both you and Biykem, what do you think this implies for moving to less and less advanced heart failure with these left ventricular assist device systems? Biykem?

Dr Biykem Bozkurt:         It's an ever-expanding field, and as these devices are becoming smaller, lower profile with lesser complications and more affordable, probably the utilization will likely increase as we have been seeing. As you know, even the percutaneous non-durable device used, as well as our mechanical circulatory support durable devices are definitely increasing utilization. And thus, one may wonder not only the bridge to transplantation, but the destination therapy portfolio, or bridge to decision portfolio, may really increase as these devices become safer and more affordable.

Dr Carolyn Lam:                Wow, that's amazing. How about you, Mandeep, what do you think?

Dr Mandeep Mehra:       Carolyn, I couldn't have said it any better than what Biykem articulated. I do think that at least in the United States, as we reach the thresholds of cost effectiveness that we as a society accept, we will start to see a lot more widespread utilization, particularly for lifelong therapy or so-called destination therapy. I completely agree with that. I think that moving the needle to the less sicker population is still challenging, because there are complications with these devices that make that slightly difficult.

                                                There was a trial called the REVIVE-IT trial that was stopped midstream largely because of concerns about pump thrombosis, and that trial was looking at taking these devices to a less sick NYHA class 3 population and was stopped midstream. Now that the HeartMate 3 has pretty much resolved the issue of pump thrombosis, and even show a halfing in stroke rates with this device over two years, I think that that portfolio of evidence needs to be reopened. I would caution though, that until we have confirmatory randomized data in those less sick populations, the use to that population should still stay restricted.

Dr Carolyn Lam:                I don't think anyone could have said it better than both of you. Thank you so much for this very insightful and balanced conversation.

                                                Thank you so much for listening today. You were listening to Circulation on the Run, and don't forget to tune again next week.


Oct 22, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors.

                                                I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. The ORBITA Trial of percutaneous coronary intervention and stable single vessel coronary artery disease has to be one of the most hotly discussed in the cardiology world. The featured paper of this week adds important knowledge that will help us understand the physiology stratified results of ORBITA.

                                                Coming right up after these summaries.

                                                The first original paper this week provides novel mechanistic insights that may lead to a new treatment approach for obesity and hypertriglyceridemia. Co-corresponding authors, Drs Xiang and Xia from Central South University of Xiangya in China, looked at Reticulin 3, which is an endoplasmic reticular protein that has previously shown to play a role in neurodegenerative diseases.

                                                In the current paper, the authors show that over-expression of Reticulin 3 in mice induced obesity and a greater accumulation of triglycerides. Remarkably, increased Reticulin 3 expression was also found in patients with obesity and hypertriglyceridemia. They further showed that Reticulin 3 played critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Thus, these results suggest that inhibiting the expression of Reticulin 3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia in the future.

                                                The next study provides insights into the genetic determinates of residual cardiovascular risk in patients already receiving statins. First author Dr Wei, corresponding Dr Denny from Vanderbilt University Medical Center and their colleagues performed a genome-wide association study and identified that a variation at the LPA Locus was associated with coronary heart disease events during statin therapy and independent of the extent of LDL cholesterol lowering. The association of the LPA Locus with coronary heart disease events persisted in individuals with an LDL cholesterol less than 70 milligrams per deciliter. These findings, therefore, provide support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce coronary heart disease events in patients already receiving statins.

                                                The next paper provides important mechanistic results that help us understand pathways in atherosclerotic plague regression. Co first authors, Drs Mueller and Zhu, corresponding author Dr Fazio from Oregon Health and Science University and their colleagues have previously shown that mice lacking an LDL receptor with beta protein 1 in macrophages undergo accelerated atherosclerotic plague formation. However, in the current study they sought to explore the role of macrophage LDL receptor protein 1 during plague regression. They did this by placing EPO E deficient mice on a high fat diet for 12 weeks, then reconstituting their bone marrow using wall type or macrophage LDL receptor protein 1 deficient mice as donors, and finally switching them back to a chow diet for 10 weeks. The authors found that the lack of LDL receptor protein 1 expression in macrophages unexpectedly caused more atherosclerosis regression. Mice with macrophages lacking LDL receptor protein 1 showed less M1 macrophages in the plague and increased CCR7 dependent egress of macrophages from the plague. Thus, loss of macrophage LDL receptor protein 1 has a dual and opposite effect on plague biogenesis, depending on whether the plague is growing or shrinking.

                                                The next paper highlights the intercalated disc, which is a specialized intercellular junction, coupling cardiomyocyte electrical activity in forced transmission as a mechanosensitive signaling hub for causative mutations in cardiomyopathy. First author Dr Trembley, corresponding author Dr Small from University of Rochester School of Medicine and Dentistry and their colleagues showed that myocardin related transcription factors associated with desmosome proteins of their intercalated disc in both murine and human hearts. Genetic deletion of myocardin related transcription factors in cardiomyocytes led to rapid onset of dilated cardiomyopathy in response to pressure overload hypertrophy. Furthermore, myocardin related transcription factors were required for the maintenance of sacromere and intercalated disc integrity under pathological stress. These findings, therefore, provide a unique link between the intercalated disc and mechanosensitive transcriptional regulations. Since myocardin related transcription factors redistribute from intercalated disc in human heart failure, this may represent a novel signaling complex present in cardiomyopathic characterized by desmosome dysfunction.

                                                The next paper investigated the association of blood pressure with peripheral arterial disease events, using data from the ALLHAT Trial. Co first authors Drs Itoga and Tawfik, corresponding author Dr Chang from Stanford University School of Medicine and their colleagues found that both lower systolic blood pressure of less than 120 and higher systolic blood pressure of above 160 millimeters of mercury were both associated with higher rates of peripheral arterial disease events. Diastolic blood pressure less than 70 and a pulse pressure above 65 millimeters mercury were also associated with increased rates of lower extremity peripheral arterial disease events. Given that the recent revised blood pressure guidelines advocate lower systolic blood pressure targets for overall cardiovascular risk reduction, the authors called for future, further refinement of optimal blood pressure targets, specific for peripheral artery disease.

                                                The final original paper this week provides the first integrated atherosclerotic disease risk calculator to incorporate risk factors including high sensitivity C reactive protein, family history, and coronary artery calcium data. First and corresponding author Dr Khera from UT Southwestern Medical Center and colleagues used 3 population-based cohorts to develop Cox Proportional Hazards Models for the outcome of atherosclerotic cardiovascular disease. The derived Astro-CHARM model incorporated factors like age, sex, systolic blood pressure, total and HDL cholesterol, smoking, diabetes, hypertension treatment, family history of myocardial infarction, high sensitivity c reactive protein, and coronary artery calcium scores. The model performance was validated externally in a 4th cohort, and shown to improve risk prediction compared with traditional risk factor equations, and showed good discrimination in calibration in the validation cohort. A mobile application and web based tool was developed to facilitate the clinical application of this tool, and is available at

                                                And that brings us to the end of this week's summaries. Now for our featured discussion.

                                                Gosh, I am learning for the first time today that it's terribly inconvenient to lose my voice when I am a podcaster. This is Carolyn Lam and our featured discussion that I am so excited about, but the cool thing is the thing we are talking about is so hot that you don't even need me to say anything. And what we are talking about is the ORBITA Trial. That was greeted with as much hype and hoopla and sensationalism since its publication in 2017. I am so proud to have the first and corresponding author Dr Rasha Al-Lamee from National Heart and Lung Institute Hammersmith Hospital in London. I also have Dr Ajay Kirtane from Columbia University Medical Center in New York Presbyterian Hospital and the Cardiovascular Foundation in New York as the editorialist for the paper. And finally, our associate editor Dr Manos Brilakis from UT Southwestern. Rasha, why don't you just take it away and just tell us, what is your paper focusing on in this week's issue?

Dr Rasha Al-Lamee:         The paper that was published in this issue in circulation is basically our second analysis of the ORBITA Trial, a substudy analysis. Essentially, looking at the primary endpoint and the secondary endpoints of ORBITA, and having a look at those patients from ORBITA and seeing whether there was any association between their invasive physiological assessment using FFR and ISR at the pre-randomization stage and seeing whether the level of ischemia on ISR or FSR was associated or predicted in the way in which they performed in terms of their endpoints. To see whether there was any difference in the placebo control efficacy of angioplasty in those patients who have more or less severe ischemia on their invasive physiological assessment.

Dr Manos Brilakis:            First off, that's a phenomenal paper, and I think she puts things into perspective. I know Ajay put an excellent tutorial. I think all of us were surprised about the findings. You would expect that the more ischemia, that you might see a little more response. Any thoughts as to why there wasn't such an association?

Dr Rasha Al-Lamee:         I think it's so difficult because, of course, as we all know from the primary paper that was published in The Lancet, in terms of the primary endpoint, which would be change in exercise time and the difference between the two groups, the difference is actually much smaller than we expected. And when we have such a small difference in exercise time, the ability to be powered enough to be able to split that endpoint based on stratification of invasive physiology becomes very difficult, and we're perhaps underpowered to be able to do that.

                                                Where we did see a very great effect in terms of the primary assessment in The Lancet paper was in stress echo ischemia. What we saw is those patients who had angioplasty were far more likely to have an improvement, or indeed, a normalization of their ischemia on their stress echo. Where we saw a big difference the two groups we were then clearly powered to be able to stratify those patients based on their invasive physiology, and for that secondary endpoint we saw that, in fact, tied to your stenosis or the lower your ISR or FRR, the more likely you are to have an improvement in stress echo, having had placebo controlled angioplasty.

Dr Manos Brilakis:            Ajay, I know you had a lot of things insight into the vision of the tutorial for the ORBITA Trial. What are your thoughts about the findings?

Dr Ajay Kirtane:                 I would, first of all, congratulate Rasha and the ORBITA team, there are others, for not only doing the main trial, but for conducting these detailed analyses, which were clearly set up ahead of time, and that's been one of the critiques of the trial is why were patients with normal-ish range FFRs included. Well, part of it was to test this hypothesis, and perhaps to show that there would be a correlation between the change in the FFR, if you will, and the endpoints that were measured.

                                                So, I think that that's the first part, that this is actually a scientific experiment, and a thoughtful one in doing so. I think exactly as Rasha said though, if there is a limited signal, with respect to the overall trial, then further subsetting is less likely to show a significant signal. I think that's exactly what the investigators found. The only other comment I would make though is, I would commend Rasha and the team for producing other analyses that are novel in this manuscript including the freedom from angina analysis, as well as responding to some of the earlier critiques of the trial and not using specific methodologies to adjust the baseline differences improves. Those are also included in this analysis.

Dr Manos Brilakis:            Yeah, absolutely, I think that was very enlightening to see, the freedom of angina. And I know there was some questions whether that might change the overall findings from the studies, so there is some quality of life benefit. Rasha, what is your thoughts about this? I mean, you must understand this study better than anyone else. People who have stable angina, should they undergo PCI or not?

Dr Rasha Al-Lamee:         I think the freedom from angina signal was very important, and obviously not something that we had pre-specified, so it wasn't reported in the primary analysis. We're obviously much more able now, since we've published that primary analysis to do secondary analyses and look at things that perhaps we haven't pre specified. And it's interesting to see that 20% more patients are free from angina having had angioplasty vs. placebo. Having said that, to me, it's a fantastic finding, but still a little unexpected. Much less than we might expect looking at unblinded data, or our unblinded clinical experience. I would have expected much higher levels from freedom of angina.

Dr Rasha Al-Lamee:         I think what we know, and what we've seen both from this paper, very importantly, and also the primary manuscript, is that the efficacy of angioplasty is very tightly linked to the improvement in ischemia. We've actually, in fact, got more papers that are coming out from our group recently. And that you can predictably tell your patients that if I sense a lesion that's causing a reduction in ISR or FFR, and potentially symptoms, then I will improve your ischemic burden.

                                                What I think is more tricky is how much I will relieve your symptoms, or make you feel better. That may be because symptom assessment itself is very tricky, and perhaps that actually just diagnosing cardiac angina is actually a very difficult thing. The easiest way to piece out improvement in symptoms is to find those patients who become free of angina because, of course, that's the binary end point. When we look at grades of symptoms, and whether their angina frequency improves, or whether the level of angina improves in terms of PCI, then I think it becomes much harder, especially in a blinded trial where, of course, when people come back, even with atypical chest pain, it will still be recorded as potentially angina because, of course, both the investigators and the patients have no idea what they've had done, which is quite different from real life where, of course, you are able to think more about whether this chest pain might indeed be from the heart or from other causes.

Dr Manos Brilakis:            Perfect, thank you very much. And I would completely agree with you that, the study was perfect. And, as Ajay said, it is something that we needed, and more of them should be done. And I think you are right that this is the best way to piece out the symptom improvement.

                                                Ajay, any final comments?

Dr Ajay Kirtane:                 I think that the toughest challenge with trials like this is to really enroll the patients that many of us as interventionists feel would really improve in terms of their symptom class. Even despite these efforts, if one looks at the baseline of anginal frequency in the trial, the means are relatively high, which suggest that the anginal burden, at least in terms of measurements through the anginal questionnaire is not that severe. One could argue that somebody has severe angina that is occurring all the time, that those are types of patients that are hard to randomize in a clinical trial.

                                                I think, at least my overview stepping back perspective of the context of ORBITA within clinical practice, is exactly that. The trial is an important scientific advance, but this does not encompass the answer for every single patient that comes to see us in the office that have a range of symptoms, very severe to less severe. That was something Rasha has been saying all along as well. It's not something that we could over extrapolate this to every patient that we see. So, I think that when the hype dies down, these types of scientific analyses will stand out. They emphasize the need for regular clinical research, and in that way, I think has generated a lot of attention not only to the clinical field here, but also the scientific pursuit of evidence. That's a really magical thing.

Dr Rasha Al-Lamee:         I think, if I can add to that Ajay, I think it's probably also sort of the assessment of symptoms is incredibly important. I think many of us, and I'll include myself in this, when we see a very tight stenosis, are happy to essentially correlate any level of symptoms to that tight stenosis. One thing I've learned from all this, I want to see reproducible angina that very much is textbook, cardiac caused chest pain, and the atypical anginas we see, perhaps some of that pain is not from that stenosis, but from somewhere else. Therefore, by fixing that stenosis, we don't necessarily make that pain go away.

Dr Manos Brilakis:            Absolutely, and I think you are absolutely, if it is something simple vessel disease, if it's something a little more straightforward, then I think you are right Ajay, that this is much harder, multiple vessel disease especially in people with reduced ejection fraction.

Dr Carolyn Lam:                You've been listening to Circulation on the Run! Don't forget to tune in again next week!


Oct 15, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Will artificial intelligence replace the human echocardiographer? Aha, well to find out the answer, you have to wait for the incredibly exciting discussion of today's feature paper coming right up after these summaries.

                                                The clinical benefits of the cholesterol ester transfer protein, or CETP inhibitor dalcetrapib depends on adenylate cyclase type 9, or ADCY9 genotype. However, what are the underlying mechanism responsible for the interactions between ADCY9 and CETP activity? In the first paper from today's journal first author Dr Rautureau, corresponding author Dr Tardif from Montreal Heart Institute, and colleagues used a mouse atherosclerosis model inactivated for ADCY9 and demonstrated that loss of ADCY9 protected from atherosclerosis and was associated with improved endothelial function, but only in the absence of CETP. ADCY9 in activation increased weight gain, adipose tissue volume, and feed efficiency, but only in the absence of CETP.

                                                This mouse model reproduced the interactions between ADCY9 and CETP activity observed in patients, and offers new mechanistic insights for the importance of ADCY9 in determining the responses to CETP inhibition. For example, the dal-GenE clinical trial is currently testing prospectively whether patients with coronary disease and the favorable ADCY9 genotype will benefit from dalcetrapib.

                                                The next study addresses the controversy around the cardioprotective effects of Omega-3 polyunsaturated fatty acids, and uncovers signaling pathways associated with eicosapentaenoic acid, or EPA supplementation that may mediate protective effects in atherosclerosis. First author Dr Laguna-Fernandez, corresponding author Dr Bäck from Karolinska Institute, and their colleagues showed that EPA supplementation significantly attenuated atherosclerotic lesion growth. They performed a systematic plasma lipidomic analysis and identified that 18 monohydroxy eicosapentaenoic acid was a central molecule formed during EPA supplementation. 18 monohydroxy eicosapentaenoic acid was a precursor for the plural resolving lipid mediator called resolvent E1.

                                                In the present study, a resolve in E1 was shown to regulate critical atherosclerosis related functions in macrophages through its downstream signaling receptor to transfuse protective effects in atherosclerosis.

                                                Are there racial differences and long-term outcomes among survivors of in-hospital cardiac arrest? In the next paper first and corresponding officer Dr Chen from University of Michigan and her colleagues performed a longitudinal study of patients more than 65 years of age who had an in-hospital cardiac arrest and survived until hospital discharge between 2000 and 2011 from the National Get With The Guidelines Resuscitation Registry whose data could be linked to Medicare claims data. They found that compared with white survivors of in-hospital cardiac arrest, black survivors had a more than 10% lower absolute rate of long-term survival after hospital discharge. This translated to a 28% lower relative likelihood of living to one year, and a 33% lower relative likelihood of living to five years after hospital discharge for black versus white survivors.

                                                Nearly one-third of the racial difference in one-year survival was dependent on measured patient factors. Only a small proportion was explained by racial differences in hospital care, and approximately one-half was the result of differences in care after discharge, or unmeasured confounding. Thus, further investigation is warranted to understand to what degree unmeasured, but modifiable factors, such as post-discharge care may account for the unexplained disparities.

                                                The next study provides insights into a novel mechanism of atherogenesis that involves protease-activated receptor 2, a major receptor of activated factor 10, which is expressed in both vascular cells and leukocytes. Co-first authors Dr Hara and Phuong, corresponding author Dr Fukuda from Tokushima University Graduate School of Biomedical Sciences, and their colleagues showed that in ApoE-Deficient deficient mice, protease-activated receptor 2 signaling activated macrophages and promoted vascular inflammation, increasing atherosclerosis.

                                                Furthermore, they showed that in humans, plasma-activated factor 10 levels positively correlated with the severity of coronary artery disease, suggesting that the signaling pathway may also participate in atherogenesis in humans. Thus, the protease-activated receptor 2 signaling pathway may provide a novel mechanism of atherogenesis and serve as a potential therapeutic target in atherosclerosis.

                                                The next paper tells us that biomarkers may help to predict specific causes of death in patients with atrial fibrillation. First and corresponding author Dr Sharma and colleagues from Duke Clinical Research Institute evaluated the role of biomarkers in prognosticating specific causes of death among patients with atrial fibrillation and cardiovascular risk factors in the ARISTOTLE trial.

                                                They looked at the following biomarkers: high sensitivity troponin T, growth differentiating factor 15, N-terminal pro-B-type natriuretic peptide, and interleukin 6. They found that sudden cardiac death was the most commonly adjudicated cause of cardiovascular death, followed by heart failure and stroke or systemic embolism deaths. Biomarkers were some of the strongest predictors of cause-specific death, and may improve the ability to discriminate among patients' risks for different causes of death.

                                                How do the complement and coagulation systems interact in cardiovascular disease? Well in the final original paper this week, first author Dr Sauter, corresponding author Dr Langer from Eberhard Karls University Tübingen, and their colleagues used several in vitro, ex vivo, and in vivo approaches as well as different genetic mouse models to identify the anaphylatoxin receptor C3AR and its corresponding ligand C3A as platelet activators that acted via intra -platelet signaling, and resulted in activated platelet fibrinogen receptor GP2B3A. This in turn mediated intravascular thrombosis, stroke, and myocardial infarction. This paper, therefore, identifies a novel point of intersection between the innate immunity and thrombosis with relevance for the thrombolic disease of stroke and myocardial infarction.

                                                That wraps up with week's summary. Now for our featured discussion.

                                                Can we teach a machine to read echocardiograms? Well today's feature paper is going to be all about that. I am so excited to have with us the corresponding author of an amazing, and I think, landmark paper, Dr Rahul Deo from the One Brave Idea Science Innovation Center and Brigham and Women's Hospital in Boston, as well as our associate editor Dr Victoria Delgado from Leiden University Medical Center in The Netherlands. Now let me set the scene here. We know that echocardiography is one of the most common investigations that we do in cardiology, and in fact even outside of cardiology, and it is hands down the most accessible, convenient tool to image the heart.

                                                Now let's set this up by remembering that echocardiograms are performed with machines, but led by echocardiologists like me. Now this is really scary Rahul because I think your paper is trying to say ... Are you trying to put people like me out of business?

Dr Rahul Deo:                    Definitely not. I think what I'm hoping to do is actually two things. One of them is, despite the fact that it's an accessible and safe tool, because it needs people like us, it's probably not used as often as ideally it could be. So part of our hope was to democratize echocardiography by being able to take out some of the expenses from the process so that we can hopefully get more simpler studies done at an earlier stage in the disease process. Because in many ways, at least from my experiences being an attending, it feels like if we could just have gotten to these patients earlier we may have been able to start therapy that could've changed the disease course, but our system can't really afford to do huge numbers of echoes on asymptomatic patients. Really we were trying to find some way of facilitating this by at least helping out on trying to quantify some of the simple things that we do with echocardiography.

Dr Carolyn Lam:                I love that phrase, democratizing echo. And you're absolutely right, if we could put it in the hands of non-experts and help them interpret them, we could really lead to detecting disease earlier, and so on and so forth. Wow. But everyone's wondering, how in the world do you go about doing that?

Dr Rahul Deo:                    One of the things that's really been amazing in these last five years or so is that the field of computer vision, so the field by which computers are trained to mimic humans in terms of visualizing, recognizing, identifying images, has really advanced, and incredibly rapidly. And one of the reasons for that is that the video game type of computing system, the same things that go into Playstations and such, have resulted in much, much more rapid computing. And that's allowed us to train more complex models.

                                                So that's one of the things that's changed, and also, it's just much easier to get our hands-on training data. So machines can be trained to do things, but they need lots of examples. And the harder the task, the more examples they need. So the widespread availability of digital data has made that easier, though I would say that it wasn't that easy to get our hands on enough echocardiography data to be able to train. But in general, almost any task where there's enough data has been solved on the computer vision side. So this has really been an exciting advance in these last few years. So we thought we could very well just used these same technologies on a clinical problem.

Dr Carolyn Lam:                Okay, but Rahul what are you talking about here? Like the machine's actually going to recognize different views, or make automated measurements? That's the cool thing, frankly, that you've written about because we know that the machines can already kind of do EF, ejection fraction, but you're talking about something way bigger. So tell us about that.

Dr Rahul Deo:                    Yeah, so there are many cute examples in the popular press about machines being able to recognize the differences between cats and dogs, or some breeds of dogs. And so if you think about things that way, it really shouldn't be that much more difficult to imagine recognizing between different views, which probably are much more dramatically different than different breeds of dogs. So you could really just take the same models, or the same approaches, give enough examples, label them, and then say figure out what the differences are.

                                                And I think one of the challenges with these systems is they're often black boxes. They can't tell us exactly what it is that they're using, but when it comes to something like recognizing whether something is an apical four chamber view or a parasternal long axis view, we actually don't care that much as to how it is that the computer gets there. We just wanted them to do it accurately, and that's one of the places for some of these computer vision models. It's a field broadly called deep learning, and it's just great at achieving complex tasks.

                                                So, once you recognize views, then the other thing that computers have been shown to be able to do is recognize specific objects within an image. For example, you could give an entire football field and you could find a single player within it. You could recognize where the players are, where the ball is, where the grass is. So computers can distinguish all those things too. And then once you know where something is, you can trace it and you can measure it. So in that sense it's very similar to what a human reader would do, it's just broken down into individual steps, and each one of those needs to be trained.

Dr Carolyn Lam:                You put that so simply so that everyone could understand that. That's so cool. You mentioned, though, accuracy. I could imagine that a machine would likely interpret one image the same way again and again, and that addresses something that we really struggle with in echo doesn't it? Because, frankly, one reader against another, we always know. Ejection fraction has got a plus minus seven or something, and then even within the same reader you could read the same thing and say something one day, and say something the other. So this is more than just automating it, is it?

Dr Rahul Deo:                    Yeah, so it's certainly making it more consistent, and the other thing that we were able to do, I mean once you can teach it to identify and traces the contours of the heart in one image you can have it do it in every single image within the video, and every single video within the study. So now, I mean it's quite painful. I know this from my own experience in terms of tracing these things, so a typical reader can't trace 150, 200, 300, 500 different hearts, that's not going to happen. So instead, they'll sort of sift through manually, pick one or two, and if there's variability from one part of the study to the other, that really won't be captured.

                                                And in this case, the computer will very happily do exactly what you ask it to do, which is to repeat the same thing again and again and again, and then be able to average over that, capture variability. So that's one of the tasks that is much more easy to imagine, setting a computer who won't talk back to you and won't resist and won't refuse to actually taking on the mundane aspect of just getting many, many, many more measurements. And that could happen not only in a single study, but also could happen more frequently. So you could imagine that, again, there's just not that resistance that's coming from having to have an individual do these things.

Dr Carolyn Lam:                Oh, my goodness, and not only does he not ... well he, machine, not say no, I mean they don't need to take time off or weekends off. We could get immediate reports directly. Oh my goodness. Victoria I have to bring you in on this. We knew as editors when we found this paper that this is something we just have to publish in Circulation that's going to be groundbreaking. Could you tell us a little bit more about what you think the implications of this is?

Victoria Delgado:              I think that this is a very important paper because it's a very large study and it's sets, I would say, three important questions that we deal every day in clinical practice. One is how to reduce burden in very busy echo labs by facilitating the reporting of the echoes and the interpretation of the echoes. Second: to have an accurate measurement and quantification of the images that we are acquiring, and third: this is recognition of the pattern.

                                                And I think that this very important, particularly in primary care because, for example in Europe here, echocardiography is not really in the primary care and the patients are being referred to secondary level hospitals or third level hospitals. That means that the waiting days sometimes is too long. If we train the general practitioners, for example, to do simple echocardiograms with the handheld systems which are also the technologies that are coming and are really available in your iPhone, for example, on your phone, you can get an echocardiographic evaluation of a patient that comes to a general practitioner.

                                                And if you don't have too much knowledge on interpretation, these tools that can have recognition of the pattern of the disease can trace a red flag and say, okay this patient may have this disease or may have this problem, you should consider sending or referring this patient to us at Leiden Hospital where he's going to have a regular check-up and a complete echocardiogram. That could lead to less burden in very busy labs and only refer the patients in a timely manner to the centers when they have to be referred, when the others can wait of can be referred much later.

                                                I think that that's important, and next two technologies that are coming now and it will be very important, some groundbreaking technologies. One is the handheld systems, the ones that you can have in your phone, the ones that you can have in your tablet for example. And the other one is going to be the artificial intelligence to, if not diagnose completely, at least to recognize the pattern that there is a pathology where we need to focus, and we need to act earlier.

Dr Rahul Deo:                    I think that one place we would like to see this used is in a primary care setting where you have individuals who have risk factors that we know would be risk factors, for example, for let's say heart failure with preserved ejection fraction. But really, my experience in that phase of clinical practice is there's a lot of resistance from patients to get on the medications. So hypertension is, at that point, often, I just got worked up because I had a hard time finding parking, and so on, and so on, where there's just a natural resistance.

                                                So if you could imagine having objective measures describing, let's say how their left atrium is doing at that point, how it looks the next year, what the change in therapy is doing, all these things, you actually can bring in that quantification at a low enough cost that makes it actually practical, then that would be one place we could imagine motivating or intensifying therapies on the basis of something like this.

                                                And I think one area we have to admit we didn't solve is we haven't solved the ability to facilitate getting the data in the first place. We do know that there are these focused workshops around trying to get some simple views, and more and more of our internal medicine residents are able to get some of these, but we can't dismiss that this is still an important challenge in terms of being able to get the images. What we want to do is say, well you can get some images and we can help you interpret them and quantify in an effort to try to motivate therapies being initiated or intensified in a way that's sometimes difficult to do in the current system.

Dr Carolyn Lam:                So, Rahul and Victoria, you both mentioned that one of the key aspects is the acquisition of the echo. Not just the machine that does it, but also who takes the images that will then be automatically analyzed. So, Rahul, do you think that sometimes you're going to invent something that will replace even the acquisition, or maybe even simplify it so that we may not need Doppler anymore?

Dr Rahul Deo:                    One of the things that we thought about was, we wanted to limit ourselves to views that might be easier to acquire, in part because we wanted to reduce the complexity of the study and yet still try to capture as much information as possible. And getting back to the first part of your question, you could imagine that recognizing a view is not that different from recognizing that a view is 10 degrees off from where it should be. You could imagine training a computer to do just that very same thing too. It could recognize a slightly off axis apical four chamber view and guide you into correctly positioning the probe, and you could even imagine a robotic system that does this and just takes the person out of it all together. In part because a very skilled sonographer can quickly look at something and say, oh I just need to tilt my wrist this way and move it this way. I was always humbled by that because I never could quite do that myself.

                                                But in the same way, and in the way, that's happening is that an image is recognized, and then the reference image is held in one's brain, and then they just know from experience what needs to be done to turn one into the other. But that very well-oiled machine could very well be taught to do that exact same thing too.

Dr Carolyn Lam:                Oh wow. That is just totally amazing. I know the listeners are being blown away by this just as I am. Let me just end by asking for any last words, Victoria and Rahul, of the clinical application of this. When are we going to have this primetime? What do you think?

Victoria Delgado:              I think that this is coming. This is one, for example, of the first studies showing the feasibility of this technology. In terms of accuracy, probably we need improvement, but that depends very much on the quality of the echocardiographic data that we obtain. And in the future, I think that we are going to rely more and more on this technology, and we will have the expert view for those cases that are ambiguous or where the technology has limitations. But in terms of accuracy, for example, I can imagine one of the clinical scenarios that we face in everyday clinical practice is the evaluation of the effect of the treatment in heart failure patients for ejection fraction, and in patients, for example, treated with chemotherapy to see changes in ejection fraction.

                                                That, if we do it manually as we do now, we know that we have limitations in terms of the own viability of the observer. If you leave it for artificial intelligence, maybe that viability may be reduced, and you may be better in terms of adjusting the medication if needed. Because you removed completely what would be the individual viability. So these are the fields that probably I see more and more application of this technology in order to improve the reproducibility of the measurements and accuracy. But yeah, for that we need probably very good image quality, and I see in echocardiography we always tend to say, yeah the image quality is not that good. I'm sure that echocardiography can give you much more than just using through the echocardiography. You can use contrast, you can use many other techniques in order to improve the image quality. And artificial intelligence, the better the image quality is, probably the better it's going to be as well, the accuracy of the measurements and the recognition of disease.

Dr Carolyn Lam:                Wow, and Rahul?

Dr Rahul Deo:                    I completely agree with Victoria. I think that we're going to have to be clever about where we incorporate something like this into the current clinical workflow. You have to choose your problem carefully, you have to understand it. Any system like this is going to make some mistakes. To figure out how to minimize the impact of those mistakes, and at the same time add benefit and potentially enable things that wouldn't even be done. So I think that the fun stuff is yet to come here in terms of really incorporating this in a way that can really change clinical practice.

                                                I want to add one thing that I really haven't mentioned. And we, at this point, really just focused on trying to mimic the stuff that we're already doing. Part of the motivation of this work is to try to potentially see things that we can't even see right now and try to potentially predict onset of disease or early latent forms of something that would really be difficult to detect by the human eye. And we've seen examples of that in some of the other fields around radiology, and I think that's going to be a place that would be augmenting beyond what we're even doing currently.

                                                But of course, the challenge is that the system has to be interpretable enough that we understand what it is that it's seeing, because otherwise I'm sure we'll be reluctant to embrace something clinically that we don't understand.

Dr Carolyn Lam:                You've been listening to Circulation on the Run. Don't forget to tune in again next week.


Oct 8, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.

                                                The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.

                                                The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.

                                                In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"

                                                Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.

                                                In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.

                                                Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.

                                                They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.

                                                That wraps it up for our summaries, now for our feature discussion.

                                                Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?

                                                Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.

                                                Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings?

Dr Richard Haynes:          So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.

                                                It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan.

Dr Carolyn Lam:                Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan?

Dr Richard Haynes:          That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way.

Dr Carolyn Lam:                Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that?

Matthew James:              Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease.

Dr Carolyn Lam:                Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right?

Dr Richard Haynes:          Eligibility was actually determined by the EGFR, the estimated GFR.

                                                Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm.

Dr Carolyn Lam:                Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm?

Dr Richard Haynes:          I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial.

Dr Carolyn Lam:                Justin, I mean you come from the heart failure world too just like me. What was your take?

Dr Justin Ezekowitz:        I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.

                                                Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well.

Matthew James:              Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.

                                                I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction.

Dr Richard Haynes:          I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients.

Dr Justin Ezekowitz         I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.

                                                I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.

                                                The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.

                                                The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published.

Dr Carolyn Lam:                You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages?

Braden Manns:                 Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes.

Matthew James:              I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population.

Dr Justin Ezekowitz:        So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely.

Dr Richard Haynes:          I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has.

Dr Carolyn Lam:                Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.

                                                Thank you very much to audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Oct 1, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                FDG-PET CT was recently introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, can we improve on its diagnostic performance? Well, to learn more you have to listen to the upcoming featured discussion, right after these summaries.

                                                Our first original paper this week describes a potential novel therapy for hypertension. In this study from first author Dr Hu, corresponding author Dr Soong, from Yong Loo Lin School of Medicine National University of Singapore, authors showed that galectin-1 is a key regulator for proteasomal degradation of CaV 1.2 channels. L-type CaV 1.2 channels are known to play crucial roles in the regulation of blood pressure. In a series of elegant in vitro and in vivo experiments, the authors showed that galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and thereby, exposing specific glycines for polyubiquitination. This mechanistic understanding provided the basis for targeting CaV 1.2 galectin-1 interaction and demonstrated the modulatory role that galectin plays in regulating blood pressure. The study, therefore, offers a potential novel approach for the therapeutic management of hypertension.

                                                Direct oral anticoagulants or DOACs, are surpassing warfarin as the anticoagulant of choice for stroke prevention in non-valvular atrial fibrillation. However, DOACs outcomes in elective peri-procedural settings have not been well elucidated and remain a source of concern for clinicians.

                                                The next paper in today's issue was a meta-analysis designed to evaluate the peri-procedural safety and ethicacy of DOACs versus warfarin. For author Dr Nazha, corresponding author Dr Spyropoulos, from the Feinstein Institute for Medical Research in Northwell Health at Lenox Hill Hospital in New York, reviewed the literature for data from phase three randomized controlled trials comparing DOACs with warfarin in the peri-procedural period among patients with non-valvular atrial fibrillation. Sub study from four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF. The short-term safety and ethicacy of DOACs and warfarin were not different in patients with non-valvular atrial fibrillation peri-procedurally. Under an uninterrupted anticoagulation strategy, DOACs were associated with a 38% lower risk of major bleeds compared to warfarin.

                                                The next paper presents results from the Sarcomeric Human Cardiomyopathy Registry or SHARE, which combined longitudinal data sets curated by eight international hypertrophic cardiomyopathy specialty centers to provide a better understanding of the factors that contribute to heterogeneous outcomes in lifetime disease burden in patients with hypertrophic cardiomyopathy. First and corresponding author Dr Ho from Brigham and Women's Hospital and colleagues analyzed longitudinal clinical information on 4,591 patients with hypertrophic cardiomyopathy. By examining the data set spanning more than 24,000 patient-years, the mortality of patients with hypertrophic cardiomyopathy was shown to be 3-fold higher than the general population at similar ages. The lifetime cumulative morbidity of hypertrophic cardiomyopathy was considerable, particularly for patients diagnosed before age 40 years and patients with sarcomere mutations. Atrial fibrillation and heart failure were the dominant components of disease burden. Thus, young age of diagnosis and the presence of sarcomere mutations are powerful predictors of adverse outcomes in hypertrophic cardiomyopathy. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.

                                                The final original paper this week provides molecular insights into atherosclerosis and it shows that defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Now, we know that atherosclerotic blocks demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine lesions. In today's paper, first author Dr Shah, corresponding author Dr Bennett from University of Cambridge and colleagues studied levels of 8-oxoguanine and its regulatory enzymes in human atherosclerosis. They found that human plaque vascular smooth muscle cells showed defective nuclear 8-oxoguanine repair, associated with reduced acetylation of the base excision repair enzyme 8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base excision repair defect in vascular smooth muscle cells alone markedly reduced plaque formation, thus indicating that endogenous levels of oxidative DNA damage in vascular smooth muscle cells promoted plaque development.

                                                And that brings us to the end of this week's summaries. Now for our feature discussion.

                                                Prosthetic valve endocarditis is a life-threatening complication. However, making a timely diagnosis of prosthetic valve endocarditis before the occurrence of severe complications is really difficult. Now, FDG-PET CT has recently been introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, previous studies reported only modest diagnostic accuracy and may have been hampered by confounders. But today's study, our feature study in Circulation, addresses this issue. We have none other than the corresponding author, Dr Ricardo Budde from Erasmus Medical Center in Rotterdam, the Netherlands, and our dear associate editor, Dr Victoria Delgado, who is in Leiden University Medical Center, also in the Netherlands.

                                                So please tell us, how does your study help us address this issue of the accuracy of FDG-PET CT

Dr Ricardo Budde:           What we actually did is that of course endocarditis is a relatively rare disease, so we had six hospitals in the Netherlands that collaborated on this study and in each of the hospitals we searched for PET CT scans that were performed in patients with a prosthetic heart valve, either because they were suspected of having endocarditis, or if they were meant for other purposes, for example oncological follow-up. Then we grouped all those CT scans together, interpreted the PET CTs anew by dedicated interpreters, and then compared the findings with the actual diagnosis in the patient, which of course is always difficult in endocarditis because to make the diagnosis is difficult. So, also, one year follow-up period was included in that to be absolutely certain whether the patient had endocarditis or not. By taking this whole cohort of patients, we were able to determine the diagnostic accuracy of PET CT, as well as by using a logistics model, identify confounders which influence the diagnostic accuracy of PET CT.

                                                I think the study that we did addresses several important aspects and the way it helps physicians in actually interpreting and implementing PET CT to diagnose endocarditis is two-fold. First of all, we identified confounders that have to be taken into account when interpreting and using the PET CT. For instance, low inflammatory activity at the time of imaging and the use of surgical adhesive during a prosthetic heart valve implantation are confounders which should be taken into account when interpreting the PET CT. Furthermore, the guidelines have always insisted on not to use or use it very cautiously PET CT within the first three months after prosthetic heart valve implantation. However, we showed that actually this period after implantation does not necessarily have to be taken into account as also a good diagnostic accuracy can be obtained within the first three months after implantation.

Dr Carolyn Lam:                Ricardo, that's wonderfully put. I don't do a CT, PET CT, routinely. In fact, I am echocardiologist and it used to be that infective endocarditis was diagnosed with echo. So Victoria, tell us, how does echo stand now with this information?

Dr Victoria Delgado:        That's a very good question but I think the guidelines set a very clear figure of how the diagnostic workup of patients with prosthetic valve endocarditis should be performed. An echocardiography is the first imaging technique. The point is that transthoracic echocardiography in patients with suspicion of prosthetic valve endocarditis is very challenging. In terms of ideal, echocardiography is probably the best imaging technique to do first to evaluate whether it is endocarditis or not. It's difficult, we have to take into account that for a specific prosthetic valve, particularly mechanical, the shadowing can make that we don't see the [inaudible 00:10:22] and sometimes it's difficult, particularly in the early phase immediately after implantation, all the inflammation can be confounder for presence of endocarditis. In those cases, I think that this study provides additional and important data highlighting which are the confounders when you use PET CT to evaluate depressions of endocarditis. I think that, when you take into account those confounders, the accuracy of this technique is very good in order to make or help in the diagnosis of these patients. So, echocardiography, I think that will remain as our first imaging technique to rule out [inaudible 00:11:10] we can see but in those cases where the diagnosis is not confirm or rule out with transthoracic and transesophageal echocardiography this study provides additional data and important data showing that PET CT is a valuable complementary imaging diagnostic test for these patients.

Dr Carolyn Lam:                Ricardo, would you agree with that because I think your study also emphasized that perhaps FDG-PET CT should be implemented early in the diagnostic workup to prevent the negative confounding effect of the low inflammatory activity? So how do we put this all together?

Dr Ricardo Budde:           Well actually, I agree with Dr Delgado that echocardiography is and should be the first-line test that you do if you have a patient that has a suspicion of endocarditis. I mean, the advantages of echocardiography are many and it's non-invasive, it's bedside-available if needed, it's patient-friendly, and it provides a huge amount of information so you should always start with echocardiography. However, sometimes it can be difficult by echocardiography, for the reasons just explained by Dr Delgado, and I think then PET CT should be considered. And when you want to do a PET CT, then you should do it early within the diagnostic workup.

                                                Actually, in the article, one of the figures is a flow chart which we provide, and it provides information on how we think PET CT can best be implemented in the workup of endocarditis. In this flow chart we also start with doing an echocardiography and also, importantly, consult the endocarditis time to make initial classification of whether it's a rejected, possible, or definite prosthetic heart valve endocarditis. After that, you can follow the flow chart and see when you can best implement PET CT, in our opinion.

Dr Carolyn Lam:                Indeed Ricardo, I am so glad you brought up this figure and listeners, you have to take a look at it. I can imagine that everybody will be using this and discussing it and how to incorporate this in the workflow. And indeed you do start with either transthoracic or transesophageal echo and blood cultures, so thank you for clarifying that.

                                                Now, for our clinicians out there, are there any situations you may be telling us to be a little more careful? Could you put it simply for us when it comes to the FDG-PET?

Dr Ricardo Budde:           You mean when not to perform a PET CT?

Dr Carolyn Lam:                Yeah, or when we have to be really careful about inaccuracies.

Dr Ricardo Budde:           I think, of course, the confounders that we indicate in the article, especially if bioglue has been used by the surgeon during the initial surgery. We know that bioglue can be seen on a PET CT as a false positive uptake of FDG and it's also important to note that this is a phenomenon that can persist for a very long time after a valve implantation. It could be for years, so especially that I think is a very important confounder to take into account and be careful when you interpret PET CT or use the PET CT and always read the original surgical report if it is available to obtain this information.

Dr Carolyn Lam:                That's wonderful advice. Victoria, do you have anything to add?

Dr Victoria Delgado:        No, I think that Dr Budde explained perfectly this figure that is key in the article and also how to evaluate patients with suspected endocarditis of prosthetic valve. One thing that sometimes we forget is starting from the first step that is a good clinical history which includes also a good evaluation of previous history and, if possible, what has been done in the patient. I think that this key information to understand the findings on the echocardiography, transthoracic or transesophageal, and the subsequent investigations that you are going to perform. Either CT which is considered, for example, when you have a definitive prosthetic valve endocarditis and you want to rule out potential complications such as abscess, for example, and if you perform a PET CT or other imaging modalities that then also indicate the presence of infection like, for example, [inaudible 00:15:26] leukocytes with PET, for example.

Dr Carolyn Lam:                And I just want to end up with one little point. Ricardo, how about the fact that part of your results don't corroborate the ESC guideline recommendations that they say you have to avoid FDG-PET in the recently implanted prosthetic valve. How do you feel it's going to play out for clinicians?

Dr Ricardo Budde:           Well, I think the 2015 ESC guidelines on endocarditis are a very important document. One must take into account that the inclusion of PET CT in the ESC guidelines was a major step, and some might say that it was a little premature to include the use of PET CT because the number of data that was out there were still relatively limited. I think it's something that we are learning along the way. Now that we are using PET CT more often we are more aware of what we do to findings that we get and also the findings that we have within specific timeframes after the implantation of a prosthetic heart valve. One of the things that I think is desperately needed also at the moment is to have a prospective study where we would do PET CT in patients after implantation of a prosthetic heart valve that do not show any signs of endocarditis where we do PET CT just to determine these normal uptake values. I think that would be a major contribution to the whole learning experience that we're currently having with implementing PET CT within prosthetic heart valve endocarditis.

Dr Carolyn Lam:                Indeed, and Ricardo your paper has added significantly to our understanding. Readers, remember, it's Figure 6 of our feature paper this week. It is a beautiful figure. Pick it up, take a look. In the meantime just thank you so much Ricardo and Victoria for joining me today.

                                                Listeners, don't forget to tune in again next week.


Sep 24, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Ticagrelor has shown superior efficacy to clopidogrel in the management of acute coronary syndromes. But what about in patients undergoing PCI for stable coronary artery disease? Well, our feature paper this week gives us answers to this question but you're going to have to wait to the feature discussion to hear these answers. That's coming up right after these summaries.

                                                Our first original paper this week shows that RBM20 mutation carriers have an increased risk of arrhythmias. You may recognize RBM20 as that splicing factor which targets multiple pivotal cardiac genes such as Titin and Calcium/Calmodulin-Dependent Kinase 2 Delta or CAMK2D. In today's paper first author Dr van den Hoogenhof and co-corresponding authors Dr Pinto and Creemers from Academic Medical Center Amsterdam, compared the clinical characteristics of RBM20 and Titin mutation carriers and used RBM20 knock out mice to investigate the downstream effects of RBM20 dependent splicing. They showed that loss of RBM20 disturbed calcium handling and led to more pro-arrhythmic calcium releases from the sarcoplasmic reticulum. Patients that carried a pathogenic RBM20 mutation had more ventricular arrhythmias despite a similarly depressed left ventricular function compared to patients with a Titin mutation.

                                                Targets of RBM20 splicing were enriched for calcium and ion handling genes, most notably CAMK2D and type 2 Ryanodine receptor. Loss of RMB20 induced an increased L-Type Calcium current density, intracellular calcium overload, increased sarcoplasmic reticulum calcium content and increased spontaneous calcium releases which all could be attenuated with treatment with an L-type calcium channel blocker. Furthermore, these results suggest that RBM20 mutation carriers should be closely monitored for potential electrical disturbances and cardiac arrhythmias even in the early stages of disease.

                                                Echocardiographic quantitation of degenerated mitral regurgitation is recommended in clinical guidelines but is it really scalable to routine clinical practice? First author Antoine, corresponding author Sorano from Mayo Clinic Rochester Minnesota and their colleagues looked at more than 3900 patients diagnosed with isolated mitral valve prolapse between 2003 and 2011 and to any degree of mitral regurgitation quantified by any physician or sonographer in routine clinical practice. They found that in multi-variable analysis routinely measured effective regurgitant orifice area was associated with mortality independent of left ventricular ejection fraction and systolic diameter symptoms or age and comorbidities. Furthermore, compared with general population mortality excess mortality appeared for moderate mitral regurgitation with an effective regurgitant orifice area above 20 squared millimeters and became notable with an effective regurgitant orifice area above 30 squared millimeters which then steadily increased with even higher levels of above 40. Thus, quantitation of degenerative mitral regurgitation is scalable to routine clinical practice with strong independent prognostic power when performed routinely by multiple practitioners.

                                                The next study identifies a novel mechanism of lipid homeostasis that is linked to a pseudo gene associated with the recently discovered apolipoprotein known as APOO. Co-first authors Montasser and O'Hare, corresponding author Dr Mitchell from University of Maryland School of Medicine in Baltimore, performed an array based association analysis in more than 1100 Amish subjects and identified a variant strongly associated with LDL cholesterol levels. They identified a founder haplotype on chromosome 5 which was associated with a 15 mg/dl increase in LDL cholesterol after recombination mapping, the associated region contained eight candidate genes. Using a zebra fish model to evaluate the relevance of these genes to cholesterol metabolism they found that the expression of the transcribed pseudo gene APOOP1 increased LDL cholesterol and vascular plaque formation. Thus, based on these data the authors proposed that APOOP1  regulates levels of LDL cholesterol in humans and represents a novel mechanism of lipid homeostasis.

                                                The Orion-1 trial demonstrated that inclisiran which is a small interfering RNA therapeutic that targets PCSK9 MRNA with [inaudible 00:05:42] produces significant LDL reduction. In today's study from Dr Ray from Imperial College London and colleagues, the authors described in detail the effect of inclisiran on prespecified secondary lipid and lipoprotein outcomes over time for up to 210 days and also described the individual variation and response in these measures. They found that a single 300 milligram dose of inclisiran  lowered non-HDL cholesterol at day 180 by 35% and a second dose at day 90 resulted in a 46% reduction at day 180. Similarly a single dose of 300 milligrams of inclisiran  reduced apolipoprotein B by 31% at day 180 and a second dose of 300 milligrams administered in day 90 reduced apolipoprotein B by 41%. Significant reductions in all atherogenic lipoproteins measured were sustained through today 210. Furthermore, every individual had a reduction of apolipoprotein B and non-HDL cholesterol at 180 days with the 300 milligram two-dose regimen of inclisiran. Thus, inhibiting the synthesis of PCSK9 through small interfering RNA may be a viable alternative to monoclonal antibodies with respect to effects on atherogenic lipoproteins and that brings us to the end of our summaries. Now for our feature discussion.

                                                Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndrome but it has not really been assessed in patients undergoing PCI for stable coronary artery disease. For our feature paper today it's going to shed some light and help us with this question and these are the results of the STEEL-PC trial. I'm so pleased to have with me right now the corresponding author Dr Robert Storey from University of Sheffield in the UK as well as our associate editor who managed this none other than Dr Stefan James from Uppsala University. Thank you.

                                                Rob, could you tell us what is the issue you tried to address and because your study is not that simple, we're not used to thinking about these pharmacodynamic and kinetic studies so could you explain a bit of what you did?

Rob Storey:                        Well it's quite a few concepts that we assessed in this study. We've got data from a number of studies showing that Ticagrelor both at doses of 90 mg twice daily and 60 mg twice daily is more reliable and superior P2Y12 inhibitor compared to clopidogrel. We've got this issue of very variable response to clopidogrel with some poor responders and some high responders and a range in between. That's fairly well established and part of this study was to get more data on the 60 mg dose of Ticagrelor in these stable CAD patients undergoing PCI and get some pilot data on clinical efficacy obviously this study was not part of clinical outcomes.

                                                But, there's another issue in terms of adenosine uptake so Ticagrelor has a relatively weak effect on adenosine uptake into red cells and other cells and this may or may not explain some of its clinical effects including some adverse effects such as dyspnea. We wanted to get a better idea of the impact of Ticagrelor at both these doses on adenosine uptake.

Dr Carolyn Lam:                Could I ask ... Okay this may be naïve. I'm not an interventional cardiologist but why would you expect something different in an acute coronary syndrome compared to stable coronary artery disease? Is there an underlying hypothesis there?

Rob Storey:                        Well there can be changes to their differences in platelet reactivity although those aren't particularly great and overwhelmed really by P2Y12 inhibitor like Ticagrelor which gives such reliable inhibition of the P2Y12 receptor. But, there have been a limited number of groups that have looked at adenosine uptake and so we wanted to get independent confirmation or not of whether Ticagrelor therapeutic concentrations impacting on adenosine uptake and get some ideas of whether it's affecting circulating adenosine levels. That's an important question in terms of understanding the mechanisms and actions of Ticagrelor.

Dr Carolyn Lam:                Got it. Thanks for breaking it down so nicely. So what did you find?

Rob Storey:                        What we found was surprisingly that we saw no impact of Ticagrelor at either dose and at any time point within a month after PCI on adenosine uptake. That is the circulating levels of adenosine and the rate at which adenosine is taken up by cells in the blood mainly red blood cells. The explanation for that really is that the therapeutic levels of Ticagrelor that you see are not sufficient to impact on adenosine uptake because it's a very weak inhibitor of the adenosine uptake pathway known as the MT1. The therapeutic levels are just not getting up to a high enough concentration to have a significant impact on that.

Dr Carolyn Lam:                Stefan, you've thought a lot about this. What did you think of the findings?

Stefan James:                    I think it's very interesting. Of course, the pharmacodynamic effects that you can measure by pretty simple means, the level of platelet inhibition, it should be similar in ACS and stable coronary artery disease and I think it's sort of confirming what Rob has been showing in other populations with ACS ... we have been very interested in trying to understand the additional mechanisms of action of Ticagrelor... try to understand the mortality rate without the benefit for Plato, for example. Was it only -- platelet  inhibition or were there other mechanisms? And, there is a specific Ticagrelor related side effect, dyspnea, which we would have been interested in understanding... is this a  mechanism of action? We can't really explain that.  There are other mechanisms and other effects that we have seen can also be explained by adenosine, so I thought it was very interesting and important to understand more about these mechanisms.  

Dr Carolyn Lam:                Yeah.

Stefan James:                    But I would like to ask you, Rob. Do you think this adenosine hypothesis now, is dead, or should we still try to explore this?

Rob Storey:                        Well of course in this study what we didn't look at was the adenosine kinetics in the tissue level which is where we hypothesize the dyspnea may arise from stimulation of C5 is in the lung tissue so we're missing that piece of information. It's still conceivable that very weak levels of ENT-1 inhibition may impact from adenosine levels in the tissue. We're not seeing a strong ENT-1 inhibition sufficient to raise circulating levels or something that we can pick up on this in vitro assay.

                                                I think it still remains an open question. We've got this sort of contradictory information from drugs like cangrelor and other drugs in development like Elinogrel  where we don't see an impact on adenosine but they still may cause dyspnea.  So I think it's a very open question still.

Stefan James:                    Do you think that your paper gives us additional strength to the hypothesis that the mortality benefit for ticagrelor as seen in Plato is explained by the platelet inhibition and the balance between the reduction in ...

Rob Storey:                        Well I think what we see really in all these studies is that Ticagrelor is a fantastically effective PTY12 inhibitor. It gives you the best level of platelet inhibition during maintenance therapy out of all the available PTY12 inhibitors. And clearly having such more reliable PTY12 inhibition than clopidogrel could still be driving a mortality benefit in high risk patients so we can't exclude the adenosine pathway contributing to some of the clinical effects but I think this sways me a little bit more to the position of thinking this is most of the benefits through platelet inhibition.

Dr Carolyn Lam:                Interesting. So you're on the cutting edge of this. What's the next step then?

Rob Storey:                        Clearly we can see that very effective and reliable P2Y12 inhibition is important and leads to clinical benefits and I think we need to implement that wherever we're using P2Y12 inhibitors. We need to take that message and use a more consistent therapy rather among those with associated with variable response which doesn't seem to make sense. I think this stable PCI population, their risk has fallen. And we see that in this study, quite a number of patients report a response to clopidogrel but no stent thrombosis.

                                                That really reflects, I think improvements in stent design and implantation techniques, so the implication is that maybe aspirin alone is enough to prevent stent thrombosis with modern techniques if you get a good result but in the higher risk patients particularly the ACS patients it's likely you need much more reliable platelet inhibition and that's why Ticagrelor really provides this security.

Dr Carolyn Lam:                So, Rob there is one thing you tested two doses and they seemed to be equivalent at least in antiplatelet inhibition, right? So what does this mean? Should we maybe preferentially use the lower dose from now on, is there still room for the higher dose? Could you share some insights there?

Rob Storey:                        Well I think one has to be cautious in not jumping to adopt a dose just on the basis of pharmacodynamic data but clearly what we show is that the 60 mg dose of Ticagrelor offers a very reliable and consistent level of PTY12 inhibition and that's likely to be very effective in preventing stent thrombosis in combination with aspirin. We also show signals that were also shown in the Pegasus study that the 60 mg dose may be better tolerated such as with lower levels of dyspnea.

                                                So, there is the option for off label use of the lower dose of Ticagrelor in those who cannot tolerate the high dose due to dyspnea because certainly they'll have better platelet inhibition down titrating from 90 to 60 and if they were to switch to Clopidogrel. So I think our study offers some comfort in terms of that aspect. The only caveat is that you have to be careful not to use strong CYP3A inducers such as some epilepsy drugs with Ticagrelor cause that can increase the metabolism and we did have one case of high platelet reactivity with strong CYP3A inducers so using a higher dose initially I think is a good idea. The label says 90 mg for 1 year following ACS and the 6 is licensed beyond one year as a down titration predominantly.

                                                Our study certainly gives some comfort that down titrating earlier if a patient can't tolerate the 90 for whatever reason, seems to be a justifiable thing. And the other thing is the European guidelines support the use of Ticagrelor off label in elective PCI and our study certainly gives some comfort that off label use and the low risk elective PCI patients of the 60 mg dose can be justified at least from a pharmacodynamic point of view.

Dr Carolyn Lam:                Well, thank you because that's exactly what our audience is loving to hear. How do these findings translate into the clinical practice - Would you have any other take home messages for the clinicians listening in?

Rob Storey:                        Well I think one thing we looked at also was troponin release which is very common after PCI. We didn't see an impact of PTY12 inhibition high levels on troponin  release and I think that sort of caveat in terms of that's not going to be the best measure in terms of surrogate for efficacy in the PCI population. The other question really is, how much of the platelet inhibition and how much of the adenosine effects of Ticagrelor influence the clinical outcomes and clearly the studies sways towards the platelet inhibition very consistent high level of platelet inhibition explaining most of the benefits.

Carolyn Lam:                      You've been listening to circulation on the run, don't forget to tune in again next week.


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