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.