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Feb 27, 2017

Dr. Carolyn L.:                    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. On our podcast today we are discussing the role of diastolic stress testing and the evaluation of heart failure with preserved dejection fraction, a really hot topic indeed, but first here's your summary of this week's issue.

                                                The first study tackles the obesity paradox in cardiac surgery, where morbidity and mortality are lower in obese patients. This study sought to ask the question, "Is this due to reverse epidemiology, bias, or confounding?" To answer this question, Dr. Maris Kelko and colleagues from University Leicester in United Kingdom used two separate analysis. One, registry data from the National Adult Cardiac Surgery Registry and two, a systematic review in meta-analysis of studies. Of more than 400,000 patients in the cohort study and more than 550,000 patients in the systematic review, the authors found a U shape association between mortality and body mass index classes, where lower mortality was observed in overweight and obese class one and two patients, relative to normal weight patients, and mortality was increased in underweight individuals.

                                                Now, the obesity paradox has been attributed to reverse epidemiology where the survival benefit associated with obesity is thought to actually reflect worse outcomes in the underweight patients who also had frailty, cachexia, or severe chronic disease. However, in the current study, counter to the reverse epidemiology hypothesis, the protective effects of obesity were less in patients with chronic renal, lung, or cardiac disease and greater in older patients as well as in those with complications of obesity, such as metabolic syndrome and atherosclerosis. Furthermore, adjustments for important confounders did not alter the results. The authors therefore concluded that obesity is associated with lower risks after cardiac surgery with consistent effects noted in multiple analysis even after attempting to address residual confounding and reverse causation.

                                                The authors even went as far as to suggest that their findings do not support common practice where weight loss is recommended prior to surgery or where very obese patients are refused surgery in the morbidly obese. These provocative findings are discussed in an accompanying editorial by Doctor's Carnethon and Kahn from Northwestern University. While the editorialists agree that this well-designed study highlights an important knowledge gap, they pointed out that the obese class two patients had nearly five times greater risk for deep sternal wound infection and 25% higher likelihood of needing renal replacement therapy.

                                                In such patients additional intervention in the perioperative period may still be indicated and include weight loss recommendations and postoperative surveillance for complications. Thus, a more cautious final recommendation may be for future studies to prospectively assess weight loss interventions prior to elective surgery in the context of overall surgical risk as assessed by the EuroSCORE or STS models.

                                                The next paper describes mechanistic studies showing for the first time that nucleoside diphosphate kinase suppresses cyclic-AMP formation in human heart failure. In this paper by First Authors, Dr. Abu Taha and Hagemann, corresponding authors Dr.'s Tobref and Weilend from the Heidelberg University in Germany, the authors performed biochemical studies of nucleoside diphosphate kinase and G Protein signaling in human and rat tissue samples, assessed the functional impact of nucleoside diphosphate kinase C on cyclic-AMP levels and contractility and isolated red cardiomyocytes and determined that in vitro effects of these nucleoside diphosphate kinases on contractility in zebra, fish and mice.

                                                They identified nucleoside diphosphate kinase as the critical isoform for the regulation of G Protein function and cyclic-AMP levels in the heart with important consequences for cardiac contractility. The increased nucleoside diphosphate kinase membrane content in human heart failure could potentially counteract a fading beta adrenoceptor response in the early stages of heart failure by increasing the amount of G Alpha stimulatory proteins in the plasma membrane. However, by switching from stimulatory to G Alpha inhibitory to activation, nucleoside diphosphate kinase may play a role in heart failure progression by reducing cyclic-AMP levels, typical for end-stage human heart failure.

                                                The study, therefore contributes to a better understanding of the molecular processes, underlying alter G Protein signaling in heart failure, and may help to develop new heart failure therapies.

                                                The next study tested the hypothesis, that high intensity interval training is superior to moderate continuous training in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure and reduced ejection fraction.

                                                Doctor Ellingson and colleagues from the Norwegian University of Science and Technology, performed a multicenter trial, comparing twelve weeks of supervised interventions of high-intensity interval training at 90 to 95% maximal heart rate, moderate continuous training at 60 to 70% maximal heart rate, or a recommendation of regular exercise in 261 patients with heart failure and ejection fraction less than 35%, in New York Heart Association class II or III status.

                                                The primary end point of change in left ventricular end-diastolic diameter from baseline to twelve weeks was not different between the high-intensity and moderate continuous groups. There was also no difference between the high-intensity and moderate groups in peak oxygen uptake, although both were superior to the recommendation for regular exercise. None of these changes were maintained at follow up after 52 weeks. Serious adverse events were not statistically different. However, training records showed that 51% of patients exercised below the prescribed target, during supervised high-intensity interval training, and 80% above the recommended target in those with moderate continuous training. Given that high-intensity interval training was not superior to moderate continuous training, in reversing remodeling or improving secondary end points, and considering that adherence to the prescribed exercise intensity based on heart rate was difficult to achieve even in the supervised setting.

                                                The authors concluded that moderate continuous training remains the standard exercise modality for patients with chronic heart failure.

                                                The final paper tells us, that brain emboli after left ventricular endocardial ablation may be more common than we knew. First author Doctor Whitman, corresponding author Doctor Marcus and colleagues from University of California studied eighteen consecutive patients, scheduled for ventricular tachycardia or premature ventricular contraction ablation, over a nine month period. Twelve patients undergoing left ventricular ablation were compared to a control group of six patients, undergoing right ventricular ablation only. Heparin was administrated with a goal activated clotting time of 300 to 400 seconds for all left ventricular procedures. Pre impulse procedural brain magnetic resonance imaging was performed on each patient within a week of the ablation procedure. The authors found that seven of the twelve patients, or 58% undergoing left ventricular ablation, experienced a total of sixteen cerebral emboli, compared with none among patients undergoing right ventricular ablation. Seven of the eleven patients undergoing a retrograde approach to the left ventricle, developed at least one new brain lesion. Thus, more than half of patients undergoing routine left ventricular ablation procedures, experienced new brain emboli after the procedure, even in the absence of clinically apparent stroke.

                                                Future research is critical to understanding the long-term consequences of these lesions and to determine optimal strategies to avoid them. This is further discussed in an editorial entitled "The Sound of Silence". How much noise should we make about post ablation silence strokes? By Doctor Z and Vora from Stanford University. Well, those were your summaries, now for our featured discussion.

                                                I am so thrilled to have with me two special guests to discuss the topic of the diagnosis of heart failure preserved ejection fraction or HFpEF. As you all know, that's my favorite topic and I have favorite people with me today. First, the corresponding author of our feature paper, Doctor Barry Borlaug from Mayo Clinic, Rochester, Minnesota. And, for the first time on the podcast, Doctor Mark Drazner, Senior Associate Editor from UT Southwestern. So, welcome Barry and Mark.

Barry Borlaug:                    Thank you Carolyn.

Mark Drazner:                   Thank you, great to be here.

Dr. Carolyn L.:                    So, Barry, you talked about the role of stress diastolic testing, shall I call it, in the  diagnosis of HFpEF in your paper. Could you tell us why you looked at it and what you found?

Barry Borlaug:                    Sure, Carolyn. When you have dyspnea and fatigue and you got a low EF, it's pretty easy to make the diagnosis of heart failure reduced EF, but we've been struggling for years with making the diagnosis of dyspnea, whether it's HFpEF or not in people with normal ejection fraction. And that's because physical and laboratory and clinical signs of high filling pressures and congestion, are either difficult to see or only present during stress, like physical exercise, in patients. So that's really what motivated us to pursue this study.

                                                We took patients, that were referred to our cath lab for invasive hemodynamic exercise testing, so we directly measured filling pressures, PA pressures and cardiac output reserve, to get a gold standard assessment, whether people have heart failure or not. And then we performed simultaneous echocardiography and blood testing to measure NT-proBNP levels, and then we just looked at what we could figure out. Can you accurately discern HFpEF patients from patients without cardiac dyspnea, using these non invasive estimates.

                                                We saw that a lot of people, with, for example, NT-proBNP levels that are low enough to be where most would consider HFpEF excluded, actually had HFpEF. And we saw that there were modest correlations between non-invasive echocardiographic estimates of filling pressures, specifically the E to E Prime ratio, and directly measured left heart filling pressures. But when we applied the criteria that had been initially proposed, we saw poor sensitivity to make the diagnosis with exercise. And this was largely related to the difficulty with getting all of the different echocardiographic indices, that are currently examined as part of the diastolic stress testing non-invasively. Next, we looked at just adding the exercise E to E Prime, which is an estimate of filling pressures, and when we used the cut-point, that's already been proposed, according to contemporary data, we found that this substantially improved the sensitivity to identify HFpEF, but there was a bit of a trade-off in that specificity decrease.

Dr. Carolyn L.:                    That's so cool. So let me summarize some of these take-home messages here. First of all, using just rest echo. I was really impressed to see that rest echo indices alone only identifies a third to maybe up to 60% of the patients you found with invasively proven HFpEF. So, we may be specific, but we're really missing quite a number of patients. And then if you exercise them, what your data is really showing is that it's better to exercise them and use this data for the negative predictive value, isn't that what you're saying?

Barry Borlaug:                    You know, the exercise is really the gold standard, so it gives you both, the negative and positive. With the echocardiography, relying on the exercise E to E Prime ratio, that was really helping us, as you say, Carolyn, with the higher negative predictive value. So most people, that had HFpEF, in this series, where we could get adequate, highly controlled environments, adequate diagnostic echocardiographic data, most people that ended up having HFpEF fit those criteria, we could see an elevation in this E to E Prime on exercise, so it did provide good negative predictive value.

Dr. Carolyn L.:                    These are just such important data, because I think we're all still struggling with how to make this diagnosis of HFpEF. Mark, could you just share some thoughts on whether you think this is going to really change practice, even change guidelines?

Mark Drazner:                   I think, if you read this paper, you would recognize it, that it's certainly a critical question that we're all facing, how to make the diagnosis of HFpEF. And all of their guidelines that have been advocated, there really wasn't much data, and these really are the best data out there. So, certainly, it's [inaudible 00:15:41] me a direction of changing practices. Barry says, certainly, the approach will need to be validated, I think, before it reaches high level guidelines, but certainly I think it's a step in the right direction, and points the way towards the future in terms of improving our ability to diagnose HFpEF. And really, that's why both reviewers and [inaudible 00:15:59] this is such an important paper.

Dr. Carolyn L.:                    Right. Barry, I have a quick question for you though. Doing exercise echo, not easy. E to E Primes are all over the place usually. How easy was it? How feasible was this test?

Barry Borlaug:                    So, first I'd like to say that we have outstanding, very well-trained, very highly skilled research scenographers, here at Mayo doing this. In very controlled environment, we're providing plenty of time for them to obtain images and that's going to be a question moving forward, because not everybody in clinical practice has that capability. But with that said, in this very controlled environments, skilled scenographers, we were able to measure the exercise data during low level exercise about 85 to 90% of the time and at peak exercise about 75 to 80% of the time. So, it's fairly feasible, but even in this best case scenario, we can't get it on everybody.

Mark Drazner:                   Even in the [inaudible 00:19:49] echo lab, the recommended approach by the ASE with the four measures. How many times they were not able to acquire all those images, are necessary for those four techniques and so, here you have a [inaudible 00:20:03] of AS echo lab not being able to do that, and being transparent about that, and [inaudible 00:20:08] to the community, saying that, although these are ideal measures, even the [inaudible 00:20:12] perhaps you can't acquire them. I think that was another important point that came out of this and then lead to the focus on the E to E Prime.

Barry Borlaug:                    I couldn't agree more. You got one of the world renowned labs, very skilled scenographers doing imaging, and we're still not able to get it all in each patient, and that just points to the difficulty of getting really high quality diagnostic images, and a lot of time you need the next level test, when that happens. And invasive exercise testing is really that test, the gold standard.

Mark Drazner:                   When you get echos from the outside and you look at the E to E Primes, are you confident that the data, that's generally acquired, is gonna be acceptable for this [inaudible 00:20:50]?

Barry Borlaug:                    Yes and no, I mean I'm always a little bit concerned, but it's not just being a control freak, you know, wanting to see everything, but I think that if it's a still frame doppler, tissue doppler spectrum, you can see that the sample volume is in the right place, and it's really unequivocally normal or abnormal, I feel pretty good about that. Not as good as when they get a full dedicated study here.

Mark Drazner:                   Of course, the gold standard is also difficult. The invasive measurement.

Barry Borlaug:                    Yes it is, I didn't [inaudible 00:21:18] that, but we've been doing a lot of invasive exercise tests for the last ten years now. And we do like 250 a year here, so we're really quite [inaudible 00:21:28] but we have all hands on deck in the lab. We have a couple technicians running gas samples around, all over the place. Somebody is on the medgraphics card, measuring oxygen consumption. We've got a nurse in there, that's helping out, so it's complicated, and of course we're using the micromanometer catheters for the pressure assessments, because you get so much more artifacts from width and under damping and over damping with the pressure tracing, so that's also not easy to do if you say.

Mark Drazner:                   So maybe for practicing cardiologists it's gonna be hard to duplicate that and perhaps spend the energy in terms of doing the exercise echo techniques off the speed, for example. Perhaps, it's another message.

Barry Borlaug:                    I would agree completely. And I think that again, when you do that, if you do a really high quality exercise echo and it's still not quite definitive, then you can refer on to a center that does have that capability, because obviously it's just reality, not everybody is going to be able to do this. Not every place has the size and resources to be able to do these really advanced tasks.


Dr. Carolyn L.:                    And do you apply exercise echo now in making your diagnosis? How do you use this data, for yourself, clinically?

Barry Borlaug:                    We started to think about this, and I think that the best case scenario where the  people, that really have an intermediate pretest probability, based on their clinical characteristics. Somebody has jugular distension and a very high NT-proBNP level, and edema, you really don't need further testing, you know that that's going to be HFpEF. And if somebody has no risk factors, and everything is stone cold normal, they don't.

                                                But in some of these people that have some signals, but they don't quite meet criteria, we are doing this, again, if they have adequate echocardiographic images at rest. And then we're looking really carefully at the exercise echocardiography data, one concern from this data, I want to make sure people are very circumspect and really critically looking at the quality of their data, because we shouldn't over-interpret equivocal findings. And as you said earlier, E to E Primes can be all over the map, they're very difficult to obtain during exercise. But I think that if everything looks very high quality and is definitely abnormal or definitely normal, that can be helpful. More so, if it's normal. We     did see more false positive, so if it is abnormal, we did suggest that you may want to perform further confirmatory testing, because of the higher false positive rate with exercise echo.

Mark Drazner:                  

                                                I would say for the listeners, they should take a look at his figure six, which really is a nice diagnostic algorithm, where Barry shows, or advocates, for taking patients with intermediate probability and then using this to restratify that, using [inaudible 00:19:40] approach. I know that, that figure resonated with the editors and the reviewers dramatically, so I'd encourage listeners to take a look at that.

Dr. Carolyn L.:                    Listeners, you heard it right. [inaudible 00:22:36] Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.


Feb 20, 2017

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. I am so excited to be discussing the diabetic HFpEF or heart failure with a preserved ejection fraction phenotype, with world experts and new insights from the I-PRESERVE Trial. That will just be in a moment and here are your summaries first.

                                                The first paper in this issue is a systematic review and meta-analysis of risk factors for Co-Arctation of the Aorta on pre-natal ultrasound. In this paper by first author Dr. Familiari and corresponding author Dr. D'Antonio and colleagues from Arctic University of Norway, the authors performed a systematic review of 12 studies on 922 fetuses with echo-cardiography, and found that those with a post-natal diagnosis of co arctation had significant differences in several cardiac morphological parameters compared to cases without co arctation. The presence of a co arctation shelf, or hypoplastic arch, was associated with a significantly increased risk of co arctation. Furthermore, they reported multi-parametric diagnostic models that were associated with an increased detection rate. Thus, this paper tells us that assessment of left inflow and outflow tracts prenatally may help in stratifying the risk of co arctation.

                                                The next paper reports pre-clinical data that truly represents a paradigm shift in our understanding of vascular resident endothelial progenitors in tissue regeneration. In this paper by first author Dr. Patel, corresponding author Dr. [Cossroterrani 00:02:00], and authors from Royal Brisbane and Women's Hospital in Australia, the authors studied protein expression levels of common endothelial markers in mice using flow cytometry. They discovered an endovascular progenitor cell in vivo that is present in normal endothelium in the aorta and lungs and activated in vessel walls during various endogenic situations, such as in the placenta, skin wound healing, and tumors. They further define at a molecular level an entirely novel endothelial hierarchy from an endovascular progenitor cell to a mature different-shaded endothelial cell via complete RNA sequencing. They further clarify the linage of endothelial progenitors in their origin by using bone marrow transplantation and vascular-specific, lineage-tracing mouse models, showing that the endovascular progenitor cells were derived neither from bone marrow nor from hematopoietic progenitors. This discovery of an endovascular progenitor cell will have significant implications for the development of endothelial progenitors as a cell therapy.

                                                The next paper addresses the chicken or egg question regarding the association between obesity and atrial fibrillation, and this is done using Mendelian randomization to define a causal association between body mass index and atrial fibrillation. In this study by Dr. Chatterjee and colleagues from Massachusetts General Hospital, the authors looked at more than 50,000 European individuals without atrial fibrillation at baseline and showed that genetic variance associated with increasing body mass index were significantly associated with an increased risk of atrial fibrillation. The association between genetically determined obesity and atrial fibrillation persisted even after adjustment for traditional atrial fibrillation risk factors, such as hypertension, diabetes, coronary artery disease, and heart failure. Taken together, these data are consistent with a causal association between increasing body mass index and incident atrial fibrillation. These findings therefore support the primordial prevention of obesity as a significant public health target to combat the expanding global burden of atrial fibrillation.

                                                The last paper provides contemporary estimates of the stroke burden in China, a country which bears the biggest stroke burden in the world. In this paper by doctors Wang and Fagen from the Capital Medical University in Beijing, China and Auckland University of Technology in New Zealand, and colleagues, the authors reported results of a nationally represented door-to-door survey conducted in 2013 in 155 urban and rural centers in 31 provinces in China, totaling 480,687 adults. They found that the age standardized prevalence was 1,115 per 100,000 people, incidence rate was 247 per 100,000 person years, and mortality rates were 115 per 100,000 person years. The stroke prevalence estimates in 2013 were greater than those reported in China three decades ago, especially among the rural residents. Finally there was a north to south gradient of stroke in China, with the greatest burden observed in the northern and central regions. Well, that wraps it up for our summaries. Now for our discussion.

                                                For our featured discussion today, we are talking about my favorite topic and of course that is HFpEF, or heart failure with preserved ejection fraction, and I am so thrilled to have with us today Dr. John McMurray from University of Glasgow, who's the corresponding author of our featured paper referring to diabetes in patients with HFpEF and really talking about the novel results from the I-PRESERVE Trial. Welcome, John!

John McMurray:               Thank you Carolyn, it's always a pleasure to speak to you.

Carolyn Lam:                      Oh, I have been waiting for this one, and I'm so excited I don't know where to begin, but how about with this? Diabetes and HFpEF, first of all, haven't we spoken to death about co-morbidities in HFpEF? And secondly, what makes this paper special? Because we've heard about diabetes and HFpEF from CHARM, from DIG, from Relax, so tell us: why the interest in diabetes and HFpEF?

John McMurray:               Sure, Carolyn. I think you and I have been interested in diabetes and heart failure, that terrible combination, for a long time. But I think there's a lot more interest in it today because, of course, we've had several new clinical trials with interventions to lower blood glucose that have showed both beneficial and potentially harmful effects on the development of heart failure. But really what these trials have highlighted is just how common heart failure is as a complication of diabetes. And we strongly suspect, though we don't know for sure of course, but we strongly suspect that most of that heart failure developing amongst patients with diabetes is probably heart failure with preserved ejection fractions. So, I think the context currently is that what's different about our study compared to the ones that you mentioned is that in I-PRESERVE we measured a number of things that were not available in, particularly, the large clinical trials previously. So, in I-PRESERVE we measured natriuretic peptides, we looked at health-related quality of life, and maybe most importantly of all we had a large echo-cardiographic sub study. So I-PRESERVE is quite different than DIG-Preserved and CHARM-Preserved, and of course a lot larger than the RELAX HFpEF study.

Carolyn Lam:                      I was the associate editor managing your paper and I was so excited about this that I invited an editorial as well by Brian Lindman, and he's got this beautiful table that summarizes what your study really adds to the literature, and I think it's so critical. Could you start by summarizing? What are the main findings?

John McMurray:               Well, I-PRESERVE, as you know, was a trial of just over 4,000 individuals with HFpEF defined clinically and with an ejection fraction of 45% or above. There was actually a trial comparing the angiotensin receptor-blocker [inaudible 00:09:17] placebo, though in fact there is no difference in morbidity and mortality between those two treatment groups. So we've looked, as you said, at the patients who had diabetes and compared those to the patients who didn't have diabetes. I think there was some very interesting novel information; if you look at the two subsets of patients, they actually don't differ in terms of age and sex and, importantly, in left ventricular ejection fraction.

                                                But there are other differences that you would expect; for example, many more of the patients with diabetes were obese. But interestingly, and despite that, the patients with diabetes had higher, significantly higher, NT-proBNP levels. So as you know, obesity tends to be associated with lower rather than higher natriuretic peptide levels, so here we were finding higher natriuretic peptide levels in a subset of patients who were actually, by and large, more obese. And there was no difference in other things that might have accounted for that difference; natriuretic peptides, for example, there was no difference in the proportion of patients who had atrial fibrillation.

                                                So that was important, and that's also important when we come to think of outcomes because of course the previous studies reporting worse outcomes in patients with diabetes had not adjusted for natriuretic peptides because they by and large weren't available in the large prior trials. So that, of course, could have accounted for some of the worse outcome.

                                                Some of the other things, features, maybe to pick out in terms of baseline characteristics ... one was that these patients had many more features of congestion, so patients with diabetes had more edema, more often had a raised jugular venous pressure and so on, and that's interesting given some of the recent clinical trial data that we might come back to. And even though the [inaudible 00:11:22] class distribution was not different between patients with diabetes and those without, what was very different was health-related quality of life, which was much worse in patients with diabetes than those without. Now you could if you chose to, Carolyn, look at that as saying that physicians weren't assessing worse functional status or symptomatic status in the patients with diabetes, but the patients were certainly self-reporting a much worse health-related quality of life.

                                                So those were the, sort of, clinical characteristic differences. We did, as I said, have an echo-cardiographic sub study. There were 745 patients in total in the trial who had a detailed echo study, and there were perhaps more modest differences than I might have expected (and I'd be interested in your opinion about this) in patients with diabetes. So they had a somewhat greater, statistically significantly greater left ventricular mass, they had increased early diastolic mitral inflow velocity through E, they certainly had increased E over E prime increased left atrial areas, so there was some left ventricular remodeling and there was some evidence of increased left ventricular filling pressure, maybe diastolic disfunction. But the differences were not very striking; they were there, and as I said previously, ejection fraction (which most of us regard as perhaps not a very good measure of systolic function) was similar between the two groups. We didn't look at more sophisticated and [inaudible 00:13:09] measures of systolic functions so those could have been different, we just don't know.

                                                So that's the baseline clinical features and baseline echo-cardiographic findings. And then, of course, we followed these patients for a median of just over four years and what we found was that the cardiovascular and all cause mortality was about twice as high in patients with diabetes as in those without. And if you adjust for conventional clinical variables, including NT-proBNP, which is individually the most powerful predictor of outcome, you only very slightly attenuate that greater risk associated with diabetes. The risk of heart failure and hospitalization was also about doubled in an unadjusted analysis, but that was more attenuated in the adjusted analysis. But you've also got to remember that, of course, the patients with diabetes were not surviving as long, so the very fact that they had a substantially higher risk of heart failure and hospitalization despite a shortened longevity is important.

                                                Then lastly, again I think a fairly unique aspect of this study was that we then added the echo-cardiographic findings into the multi-variable model [inaudible 00:14:33] because it was only a subset of patients in which we had echo-cardiographic measurements. The statistical reliability of this is not as robust as in the main model, but what we saw was that there was more attenuation of the risk associated with diabetes when you added in the remodeling and diastolic dysfunction findings that we saw in the echo-cardiographic sub study. So that's a summary, I think, of the key points.

Carolyn Lam:                      John, I was really impressed and struck by the consistency of the message, which is what I really appreciated. What you added to the field was this consistent message that the diabetic HFpEF just had more signs of fluid overload in general, be it clinical, be it by NT-proBNP, be it by echo. And I thought that was something you said it was a moderate difference by echo; it was enough to be convincing to me, and I really appreciated that. The fact that adding the echo findings attenuated the significance ... you know we went back and forth about that quite a bit together, didn't we?

John McMurray:               We did.

Carolyn Lam:                      I think at the end it is consistent, it is useful information. It tells me that perhaps some of these outcomes are mediated by this access fluid, to me, at least part of it. And I think that is how we ended up expressing it in the final paper.

John McMurray:               I think you are absolutely spot on, Carolyn, because I don't think I had anticipated that the features of congestion would be so different. And you are correct in that, of course, correlates very well with natriuretic peptides, with the left atrial enlargement and so on.

                                                And then of course (and this is clearly extrapolation) but then of course it makes one wonder about some of the trials with diabetes drugs that we've seen. The TZDs, glycosomes, which calls a little bit of fluid retention, of course precipitating heart failure, and then the opposite recently with the SGLT2 inhibitors which of course are diuretics, and those drugs preventing the development of heart failure.

                                                And it does make me wonder if the diabetic phenotype maybe was a little bit of renal dysfunction, some subtle renal dysfunction, is a sodium and water avid phenotype state and that it doesn't take very much to tip those patients into frank heart failure and perhaps we need to think (and I think you might have been alluding to it) think about insuring that we adequately diurese these patients given that in this study where people were supposed to be optimally treated, clearly there was still a lot of evidence of residual fluid overload.

Carolyn Lam:                      I absolutely agree, and yes you read my mind that I was going to allude to the implications for therapies that have a diuretic effect, you know, like the SGLP2 inhibitors and in fact this was discussed in Brian Lindman's editorial, which is a must read.

                                                Just another question though. What do you think of peripheral mechanisms contributing to all this?

John McMurray:               Yeah, obviously there is the kidney aspect that we saw a relatively small difference in estimated GFR. Of course that only tells you one aspect of renal function and the nephron in diabetes may well be sodium avid maybe more likely to retain water. So certainly the kidney as a peripheral mechanism might be very important.

                                                And then of course the blood vessels, I mean there's no question that patients with diabetes have more abnormal endothelial function probably have got enhanced vascular stiffness. And of course we know from a long time ago at least in HFrEF (I'm not so sure about HFpEF) but in HFrEF there's evidence that some of the vascular stiffness you see in patients with HFrEF is actually due to sodium in the vessel wall and there's some beautiful old-style clinical physiology experiments showing that if you diurese patients with HFrEF you restore vasodilation you restore basal motor responsiveness. It could also be true in HFpEF though of course patients with HFpEF and many other reasons to have vascular stiffness.

                                                So yes, peripheral mechanisms may well be important. Your humoral abnormalities may be more pronounced in patients with HFpEF and diabetes compared to those without diabetes. We don't know because I'm not sure that's been measured very often. Certainly natriuretic peptides are, but what about things like the angiotensin system and arginine/vasopressin and the sympathetic nervous system. You know, there's still so much to study looking at patients with heart failure with and without diabetes because they're really quite distinct. And whatever's going on it makes a big difference the way those patients feel, what they can do, and what happens to them.

Carolyn Lam:                      Yeah, and your study really establishes that. Congratulations once again John, it's just been such a delight chatting with you.

John McMurray:               Likewise, Carolyn.

Carolyn Lam:                      Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and turn in next week!



Feb 13, 2017


Dr. Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our podcast is taking us to Japan today where we will be talking about aspirin for primary prevention in patients with diabetes. First, here's your summary of this week's issue.

                                The first study provides insight into the development of neurologic injury in patients with single ventricles undergoing staged surgical reconstruction. In this paper by Dr. Fogel and colleagues from the Children's Hospital of Philadelphia, the authors recognize that single ventricle patients experience greater survival with staged surgical procedures culminating in the Fontan operation, but experience high rates of brain injury and adverse neurodevelopmental outcome. They therefore studied 168 single ventricle patients with MRI scans immediately prior to bi-directional Glenn, prior to the Fontan, and then three to nine months after the Fontan reconstruction. They found that significant brain abnormalities were frequently present in these patients and that the detection of these lesions increased as children progressed through staged surgical reconstruction. In addition, there was an inverse association of various indices of cerebral blood flow with these brain lesions. This study therefore suggests that measurement of cerebral blood flow and identification of brain abnormalities may enhance recognition of single ventricle patients at risk for poor outcomes, and possibly facilitate early intervention.

                                The next paper uncovers a unique mechanism underlying arrhythmogenesis and suggests that the anti-epileptic drug valproic acid may possibly be repurposed for anti-arrhythmic applications. In this paper by first authors Dr. Chowdhury and Liu and corresponding author Dr. Wang and colleagues from University of Manchester UK. The authors used mouse models and human induced pluripotent stem cells derived cardiomyocytes to discover a new mechanism linking mitogen activated kinase-kinase 7 deficiency with increased arrhythmia vulnerability in pathologically remodeled hearts. Mechanistically, mitogen activated kinase-kinase-7 deficiency in the hypertrophied hearts left histone deacetylase-2 unphosphorylated, and filamin A accumulated in the nucleus, which then formed an association with kruppel-like factor 4 preventing its transcriptional regulation. Diminished potassium channel reserve caused repolarization delays resulting in ventricular arrhythmias, and the histone deacetylase-2 inhibitor, valproic acid restored potassium channel expression abolishing the ventricular arrhythmias. This study therefore provides exciting insights in developing a new class of anti-arrhythmics specifically targeting signal transduction cascades to replenish repolarization reserve, all for the treatment of ventricular arrhythmias.

                                Does the Mediterranean diet improve HDL function in high risk individuals? Well, the next paper by first author Dr. Hernaiz, corresponding author Dr. Fito and colleagues from Hospital Del Mar Medical Research Institute in Barcelona, Spain addresses this questions. The authors looked at a large sample of 296 volunteers from the PREDIMED study and compared the effects of two traditional Mediterranean diets, one enriched with virgin olive oil, and the other with nuts to a low-fat control diet. They looked at the effects of these diets on the role of HDL particles on reverse cholesterol transport, HDL antioxidant properties, and HDL vasodilatory capacity after one year of dietary intervention. They found that both Mediterranean diets increased cholesterol efflux capacity and improved HDL oxidative status relative to the baseline. In particular, the Mediterranean diet enriched with virgin olive oil decreased cholesterol ester transfer protein activity, and increased HDL ability to esterify cholesterol, paraoxonase-1, arylesterase activity, and HDL vasodilatory capacity. They therefore concluded that adherence to a traditional Mediterranean diet, particularly when enriched with virgin olive oil, improves HDL function in humans.

                                The final study tells us that among hospitalized medically ill patients, extended duration Betrixaban reduces the risk of stroke compared to standard dose enoxaparin. In this retrospective sub-study of the APEX trial, Dr. Gibson and colleagues from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts randomized 7,513 hospitalized acutely ill patients in a double-dummy, double-blind fashion to either extended duration of the oral Factor Xa inhibitor Betrixaban at 80 mg once daily for 35 to 42 days, or standard dose subcutaneous enoxaparin at 40 mg once daily for 10 days all for venous thromboprophylaxis. They found that the extended duration Betrixaban compared with enoxaparin reduced all cause stroke by almost one half with a relative risk of 0.56 equivalent to an absolute risk reduction of 0.43 percent and number needed to treat of 232. The effect of Betrixaban on stroke was explained by a reduction in ischemic stroke with no difference in hemorrhagic stroke. The reduction in ischemic stroke was confined to patients hospitalized with acute heart failure or non-cardioembolic ischemic stroke.

                                This paper is accompanied by an editorial by Drs. Quinlan, Eikelboom, and Hart in which they articulate three reasons that they think these results are important. First, the results demonstrated an unexpectedly high rate of new or recurrent ischemic stroke during the first three months in hospitalized medical patients receiving standard enoxaparin prophylaxis, the rate being even higher in patients presenting with heart failure or ischemic stroke. Secondly, the data demonstrated for the first time that a NOAC reduces the risk of ischemic strokes in patients without known atrial fibrillation. Thirdly, the effects of Betrixaban on stroke were dose dependent, all of the benefits were seen in those who received the 80 mg dose, whereas the 40 mg dose did not provide advantages compared with enoxaparin or placebo. While these results are encouraging, the editorialists also warn that these are based on a post-hoc analysis and should be considered hypothesis generating.

                                Well, that brings it to the end of our summaries. Now for our feature discussion.

                                Today our feature discussion focuses on the exciting 10-year follow up results of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes, or JPAD trial. I am simply delighted to have with me first and corresponding author Dr. Yoshihiko Saito from Nara Medical University, Japan. As well as a familiar voice on this podcast, Dr. Shinya Goto associate editor of Circulation from Tokai University in Japan. Welcome gentlemen!

Dr. Goto:             I am very pleased to have this opportunity. I am always enjoy listening your podcast, and this is very interesting topic of aspirin in prevention cardiovascular event in patients with diabetes, type II diabetes.

Dr. Lam:               I couldn't agree more, because the burden of cardiovascular disease globally is actually shifting to Asia, and the burden of diabetes especially, is one of the fastest growing in Asia. So a very, highly relevant topic indeed. Could I start, Yoshi, by asking you: these are the 10 year follow up results, what inspired you to take a re-look at the original JPAD results and to report this 10 year result?

Dr. Saito:              The American guidelines said that low-dose aspirin is recommended to the type II diabetes patient for the primary prevention of cardiovascular events who are older than 30 years old, and who are not contraindicated to aspirin. That meant that almost all type II diabetes patients were recommended to low dose aspirin. However, at that time there was no direct [inaudible 00:09:49] evidence for it. So we connected the prospective randomized control trial that examined the effects of the low dose aspirin on primary prevention of cardiovascular events in type II diabetes patients without preexisting cardiovascular disease. The name of this trial, JPAD trial, that stand for the Japanese Primary Prevention of Atherosclerosis with aspirin in Diabetes. We enrolled 2,539 patients who were assigned to the low dose asprin group or the no aspirin group. So we followed them with a median follow up period of 4.4 years.

                                The results of the original JPAD trial were that low dose aspirin reduced CV events by about 20%, but the reduction could not reach statistical significance. So I don't know the exact reason, but one is the reason is low statistical power, because event rate was about one-third of the anticipated. Another reason is that low dose aspirin really could not reduce cardiovascular events. So we decided the extension of the follow up of the JPAD trial to elucidate the efficacy and safety of long term therapy with low dose aspirin in type II diabetes patients. This extension study was named the JPAD 2 study. We followed them up to the median follow up period of more than 10 years.

                                In this time the JPAD trial study, we analyzed the patients in a pod protocol method because the randomized control trial was ended after 2008. Finally, we analyzed the 992 patients in the aspirin group, and 1,168 patients in the no aspirin group who retained the original allocations throughout the study period. The primary endpoint were composite endpoint of cardiovascular events including sudden cardiac death, the fatal and the non-fatal coronary artery disease, fatal and non-fatal stroke, peripheral vascular disease, and aortic dissection. This end point is the same as the original JPAD trial. The main results are the primary endpoints, 15.2% of patients occurred primary endpoints in aspirin group, and 14.2% in the no aspirin group occurred in the primary endpoints. So the primary endpoints rate is singular in both groups, with the hazard ratio is 1.14 with a 95% CI is 0.91 to 1.42 with a p value of 0.2 by log-rank test. So the low dose aspirin therapy could not reduce cardiovascular events in the type II diabetes mellitus.

                                We also analyzed these data by intention to treat analysis, the results is singular. Again, the low dose aspirin therapy could not reduce the cardiovascular event in type II diabetes mellitus. However, I was told the hemorrhagic events, total hemorrhagic events was singular in both groups, but gastrointestinal bleeding of about 2% in the aspirin group but only 0.9% in no aspirin group. That means our gastrointestinal bleeding is doubled in the aspirin group compared with no aspirin group. This is the main outcome of the JPAD and JPAD-2 trials.

Dr. Lam:               Thank you so much Yoshi, and really congratulations on such a tremendous effort. I completely applaud the idea of looking at the 10 year follow up trying to address the issue of whether or not it was a lack of power that limited JPAD-1, but what you found really reinforced what you found in JPAD-1, which is low dose aspirin did not reduce cardiovascular events in the diabetic group. They're still huge numbers, I'm so impressed that 85% of the treatment assignment was retained. Then furthermore you even showed increased gastrointestinal bleeding with aspirin. So really remarkable results. Can I just ask, are you surprised by the results, and how do you reconcile it with what was found in the general population studies like the Physician Health Study, or the US Preventive Services Task Force, where they really seem to say that primary prevention aspirin works in the general population when your risk is a certain amount?

Dr. Saito:              I think that we studied only the type II diabetes patients, so it is not clear that our results are applied to the general population, but our results is very much similar to the current European guidelines and American guidelines.

Dr. Lam:               That's a very interesting point about diabetic versus non-diabetic population and the utility of low dose aspirin. Shinya, you brought this up before. What do you think?

Dr. Goto:             For the primary prevention population cohort study, aspirin demonstrated 25% reduction of cardiovascular event. We are not recommending aspirin for primary prevention due to the balance of bleeding and cardiovascular protection, absolute risk. In Yoshi's paper, in patients with type II diabetes aspirin evened that [inaudible 00:16:13], and that is very important message he had shown in this long term outcome randomized trial.

Dr. Lam:               Do you think that there are some pathophysiologic differences when you study a diabetic versus non-diabetic population?

Dr. Goto:             Yes, that is a very important topic, and we have very nice review paper by Dr. Domenico and Fiorito. In patients with diabetes the platelet time over becomes relatively rapid as compared to general population. New platelets come to blood and COX-1 inhibition by aspirin cannot reach to enough level in diabetes patient. Still, this [inaudible 00:16:57] hypothesis, very interesting hypothesis.

Dr. Saito:              I think so, I think so. That review that proposed the same concept, their higher dose of aspirin as possibly effective for diabetic patient.

Dr. Lam:               That's interesting. Are you planning any future studies Yoshi?

Dr. Saito:              Yeah, maybe two times study.

Dr. Goto:             But anyway, the event rate is currently very low than the old [inaudible 00:17:28]. So the sample size should be huge. Huge sample size is needed for the primary prevention setting to analyze the effect of aspirin, so the number needed to treat in the primary prevention setting is more than 1000. If diabetes patient, aspirin is resistant to aspirin so the number needed to treat is getting larger. So the sample size is getting larger and larger. That is not practical to perform that clinical trial.

Dr. Lam:               That's a very good point that the contemporary trials like yours are really challenged by the low event rates because of improved preventive treatment across the board like high dose statins, like very, very low LDL targets, and so on. That's a good point. Actually, could I ask both of you gentlemen, and maybe Shinya you can start, can you let us know what is it like to perform such a large rigorous clinical trial in Japan? It must be a lot of effort. Could you give us an idea?

Dr. Goto:             In Japan, medical care system is a little bit different from the U.S. Every patient covered by the homogeneous health care system so it means it is rather difficult to conduct a clinical trial. I appreciate the effort by Professor Saito, Yoshi, it is extremely difficult to conduct the study. Japan is relatively small island, patient stick to the clinic so the long term follow up with relatively low follow up can be expected. [inaudible 00:19:15] number of patients is a challenge, and Yoshi did succeed it. We can do that and due to the baseline therapy is quite homogenous, impact of the clinical care like this has very strong impact.

Dr. Lam:               Exactly, and I share your congratulations once again to Yoshi for really tremendous effort, important results. Thank you so much Shinya for helping with this paper, and for really highlighting how really important it is. Did anyone have anything else to add?

Dr. Saito:              Yes, I have one thinking, in respect to the Japanese clinical trials. I think the Japanese evidence, as derived from Japanese clinical studies is getting better and better in quality. Almost all Japanese clinical trials enrolled only Japanese patients, so the way the Japanese not so good at to organize the international clinical trial because of the, one is the language problem, and the other is funding problem. In Japanese funding agency, the AMED, that is similar to the NIH in United States, but AMED is not so strong as NIH so that they cannot give a bigger budget to the Japanese clinicians. That is another problem to organize a big clinical trial. The funding [inaudible 00:20:49] apprenticeship without holding investigators are very, very important to be better clinical situation in Japan, I think so.

Dr. Lam:               Thank you for listening to Circulation on the Run, don't forget to tune in next week.


Feb 2, 2017


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 Centre and Duke-National University of Singapore.

                                                Today is special, special, special because here with me is the editor of special populations and that is Dr. Sharon Reimold from UT Southwestern, who is the editor handling the special issue for Go Red For Women.

                                                Welcome, Sharon.

Dr Sharon Reimold:         Thank you, Carolyn. I'm happy to be here.

Dr Carolyn Lam:                This is so cool. Just us ladies chatting about issues that we need to be talking about.

                                                Now first of all, this is the first time that Circulation is doing a focus issue for Go Red for Women. Could you tell us a little bit more about that?

Dr Sharon Reimold:         Sure. The Go Red for Issue campaign has been around for many years. The editorial staff realized that we really hadn't had an entire issue devoted to cardiovascular issues in women. We decided several months ago to try to make this a reality and asked for submissions of articles and we’re delighted to see the interest that our cardiologists across the country had, as well as across the world, in submitting their research for consideration in this issue.

Dr Carolyn Lam:                I know. There are seven original papers. There are review papers. There are research letters. It's an amazing issue.

Dr Sharon Reimold:         We had hoped to focus on a lot of different areas in which heart care in women is influenced. We're really quite delighted that we had papers on pregnancy, papers related to strategies to get women involved in trials. We were able to look at novel risk factors in women, and also, have an excellent review about arrhythmias in women versus men that I think everyone will want to take in.

Dr Carolyn Lam:                Yeah. Congratulations once again right off, but let's jump straight into this set of twin papers that deal with post MI outcomes and sex differences. There've been quite a number of publications on this. What makes these two papers special?

Dr Sharon Reimold:         I think these papers are special because they're trying to think more deeply into why women tend to get re-hospitalized after a heart attack more often and what are the reasons that they're getting readmitted.

                                                For instance, it seems that women, as we know, may get a variety of different symptoms that are their equivalent or anginal equivalent after they've been in the hospital and also before they were in the hospital. I, personally, suspect that when somebody comes to the hospital with chest discomfort and they've recently had a heart attack, then often times, they get readmitted and re-hospitalized.

                                                These papers are starting to look at mechanisms, why this happens. I think this will be the bridge to the point where we figure out what can we about this, to hopefully, make men and women more equal in this regard.

Dr Carolyn Lam:                That's so true and well put. I also found very, very interesting and important that paper that really highlighted the importance of coronary flow reserve and microvascular ischemia, not just obstructive disease. Can you say a few words about that paper?

Dr Sharon Reimold:         Sure. It's been known for a long time that if you perform catheterizations on men versus women with similar presentation ... Women may not have as much obstructive disease. This particular manuscript explores coronary flow reserve and identifies this as being part of the difference between men and women in that regard. That, obviously, could have important implications for the clinical care of these patients.

Dr Carolyn Lam:                I like that. All these papers really took what we may have known a bit before, but took them to a deeper level and in a very novel way. So important. You mentioned some of the novel aspects that were also explored in the issue, the pregnancy related factors, in fact, novel risk factors that we should be taking note of in women. Do you want to comment on a few highlights?

Dr Sharon Reimold:         The relationship of pregnancy complications to long term, both maternal and offspring health has been around for a while, but really, we don't know very much about it. We, certainly, have known previously that women with preeclampsia, or those who have significant hypertension, or diabetes in pregnancy may have later problems when they are in middle age or older.

                                                What we are learning from some of these new entries into the research domain is that women who have premature labor and delivery are also at risk for having complications, and this sort of fits in the middle. It's not just preeclampsia, or hypertension, or diabetes. It's that you delivered earlier. Then moreover, we have a couple of research focused letters that describe arrhythmias in pregnancy and what happens to those women during pregnancy. I think we all have seen young women come in and have symptoms, but we really don't know what their outcome has been because any single physician probably just sees a few of them. This highlights arrhythmias as a issue in that population.

                                                We also looked at other articles that focused on other risk factors for heart disease, ranging from breast arterial calcification to traditional biomarkers that we may be drawing in hospital, BMP, troponin, and such. There's a nice manuscript that focuses on hormone changes in women and how they're associated with development of cardiovascular disease. So a fairly broad look at a variety of different risk factors that we don't think about when we're simply asking, "How old are you? What's your blood pressure? What's your diet? Do you have diabetes, and do you have lipid disorders?"

                                                What I would hope that we would get out of this is to open all of our minds and our approaches to patients to think about asking about their pregnancies, did they have any complications, figuring out if they have any hormonal issues, and then being free to consider whether or not the woman that you have in front of you actually has obstructive disease or perhaps has issues with abnormal flow reserve.

Dr Carolyn Lam:                Exactly. I would, actually, add to that, also, looking at our commonly used cardio metabolic biomarkers with the lens of realizing that there are important sex differences in all these biomarkers. That was a very nice paper, corresponding author, Dr. James de Lemos. All these papers are just so practical.

                                                I'm actually going to switch tracks now, Sharon, because I really want to talk about this final paper. All I need to do is read the title of the editorial and it’ll be self-evident. "Women are less likely than men to be full professors in cardiology. Why does this happen and how can we fix it?" I love that you invited this editorial. Could you tell us a bit about the paper that sparked this editorial and your thoughts on this?

Dr Sharon Reimold:         Yes. The original article has as its first author, Dr. David Blumenthal. It's an article that's one of a series of manuscripts that looked at academic cardiologists and looked at faculty rank where they were able to gather data on sex differences, clinical productivity, research funding, publications, et cetera. They have looked at other disciplines other than cardiology, but this particular manuscript focuses on cardiologists. What it demonstrates is that we are getting, perhaps, a little bit more women in at the assistant professor level, but there’s still a significant lag at the full professor level.

                                                In fact, in many centers if you query development offices, there's probably at least a seven year lag between women and men in terms of making it through the whole spectrum. While perhaps, this is not new conceptually, I think it does quantitate it for us and it highlights the concept that this is an issue now, similarly to what it was 25 years ago when I was a cardiology fellow.

                                                The interesting compliment to this is the editorial by Dr. Karns and Dr. Bairey Merz which tries to go into why does this happen and how can we fix it. They took a very academic approach to their editorial in terms of looking at data and then talk about implicit bias and how even a very small degree of implicit bias will cause men to be promoted, perhaps more in a faster manner than in women, and also bring up some things we don't even think about. One of the best ones was the concept that you advertise for a new position as a cardiologist. If you advertise for someone and you list the skills you want and what you want to build, then that's a more gender neutral way to approach a job. If you advertise for a dynamic, outgoing, I don’t know, vigorous sort of person, and there are ads out there that read like that, you are, inadvertently, advertising for a man, most of the time.

Dr Carolyn Lam:                Male characteristics.

Dr Sharon Reimold:         Yeah. They talk about that. Then they obviously end up with how can we fix it? I think that's a real challenge.

                                                There are some data within the field of literature for development that suggest that mentoring and coaching are important, but that they don't necessarily push people up the ladder very rapidly. There are some places, for instance, our University of Texas system now that is very interested in the concept of sponsorship. That someone sponsors another individual, could be male or female, to get involved and pushes them ahead, not pulls them, so that they have opportunities for faster career development and success. In any event, I think this compliment of paper and editorial really highlights an issue that, while not necessarily affecting female patients, certainly affects cardiology as a destination career.

Dr Carolyn Lam:                I agree. I think part of the how to fix it is simply by being aware and acknowledge the issue. That is exactly what we’re doing in these papers. I love that they are academically written. Like you said, you read a lot about these gender biases in the popular press, but it's so refreshing to see it addressed in an editorial, in a beautiful paper, in circulation.

                                                Sharon, congratulations on just this excellent, excellent issue. Is there anything else you may want to highlight about the issue?

Dr Sharon Reimold:         I think that's the major thing. I think we moved a long way from the beginning of Go Red For Women as a campaign where we really wanted patients to be aware that hypertension or elevated cholesterol levels were an important issue. I think now is a time where we move forward. We’ll learn more about differences between men and women and we figure out how we can treat or account for these differences as we strive to make health care for all and cardiovascular care for all improve over time.

Dr Carolyn Lam:                Thanks Sharon. Everyone of you listening to this, go pick up this issue. I'm sure we've peaked your interest.

                                                Thank you for listening to Circulation On The Run. Don't forget to tune in next week.


Jan 30, 2017

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 Centre and Duke-National University of Singapore. Our featured discussion today relates to 20 year outcomes after mitral valve repair versus replacement for severe degenerative mitral regurgitation.

                                                But first, here's your summary of this week's issue. The first paper suggests that agonistic angiotensin receptor autoantibodies may be biomarkers of adverse outcomes. In this study from first author Dr. Abadir, corresponding author Dr. Fedarko, and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, authors developed a quantitative immunoassay for measuring agonistic angiotensin AT1 receptor autoantibodies in the serum.

                                                They then assessed its operating characteristics in a discovery group of 255 community dwelling adults from Baltimore and validated these findings in a second group of 60 individuals from Chicago. They found that AT1 receptor autoantibody levels were significantly associated with higher levels of inflammatory cytokines, weaker grip strength, slower walking speed, higher risk for frailty, more falls and increased mortality.

                                                Furthermore, chronic treatment with angiotensin receptor blockers, it attenuated the AT1 receptor autoantibody association with decline in grip strength and increased mortality. These results therefore suggest that followup studies and intervention trials in chronic inflammatory diseases should test whether AT1 receptor autoantibody levels can be used to stratify patient risk and whether they can be used to identify patients who may benefit from angiotensin receptor blocker treatment.

                                                The next paper suggests that baseline target mismatch on CT perfusion imaging may predict the response to tenecteplase in ischemic stroke. Dr. Bivard and colleagues from John Hunter Hospital University of Newcastle in Australia pooled two clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke.

                                                Baseline CT perfusion was analyzed to assess if patients met the diffused two target mismatch criteria. These criteria are absolute mismatch volume of more than 15 mL, mismatch ratio of more than 1.8, baseline ischemic core less than 70 mL and volume of severely hypoperfused tissue less than 100 mL.

                                                Among 146 pooled patients, 71 received received alteplase and 75 received tenecteplase. Overall tenecteplase treated patients had greater early clinical improvement by NIH Stroke Scale change and less parenchymal hematoma, but did not show a significant difference in three month patient outcome by the Modified Rankin Scale.

                                                74 of the 146 patients met target mismatch criteria. It was only among these patients with target mismatch that treatment with tenecteplase result in greater early clinical improvement and better late independent recovery than those treated with alteplase. In summary, tenecteplase may offer an improved efficacy and safety profile versus alteplase, benefits that are possibly exaggerated in patients with baseline CT perfusion defined target mismatch.

                                                The next study is the first to provide a comprehensive analysis of circulating metabolite levels and relate these to clinical outcomes in patients with pulmonary arterial hypertension. First author Dr. Rhodes, corresponding author Dr. Wilkins and colleagues from Imperial College London conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry in 365 patients with idiopathic or heritable pulmonary arterial hypertension and 121 healthy controls.

                                                They found that increases in circulating modified nucleosides originating from transfer RNAs, energy metabolism intermediates, tryptophan and polyamine metabolites and decreased steroids, sphingomyelins and phosphatidylcholines independently discriminated pulmonary arterial hypertension from controls and predicted survival. Furthermore, correction of metabolite levels overtime was linked to better clinical outcomes and patients who responded well to calcium channel blocker therapy had metabolic profiles comparable with healthy controls, thus these findings suggest that monitoring plasma metabolites overtime could be useful to assess disease progression and response to therapy in pulmonary arterial hypertension. Therapeutic strategies targeted against metabolic disturbances, particularly translational regulation and energy metabolism, may merit further investigation in pulmonary arterial hypertension.

                                                The final study takes a contemporary look at age associated changes in left ventricular diastolic function. Dr. Shah and colleagues from Brigham and Women's Hospital in Boston, Massachusetts related diastolic measures including tissue Doppler E prime, E to e prime and left atrial size, to the risk of heart failure hospitalization or death in 5801 elderly participants in the ARIC study. They further defined sex-specific 10th percentile limits in 401 participants free of cardiovascular disease or risk factors. They found that each diastolic measure was robustly associated with incident heart failure hospitalization or death. Reference limits for E to e prime and LA size were generally in agreement with existing guidelines, whereas limits for tissue Doppler E prime were substantially lower at 4.6 for septal E prime and 5.2 for lateral E prime in the ARIC study compared to 7 and 10 respectively in international guidelines. Compared to the guideline cut points, the ARIC base limits improved risk discrimination and reclassified over one-third of the study population as having normal diastolic function. These findings were further replicated in the Copenhagen City Heart Study.

                                                In summary, this study suggests that a decline in left ventricular longitudinal relaxation velocity occurs maybe as part of healthy aging and is largely prognostically benign. This supports the use of age-based normative values when considering an elderly population.

                                                Well, that wraps it up for the summaries, now for our featured discussion.

                                                Today we are discussing the very important result of the mitral regurgitation international database and we have with us today no other than the corresponding author Dr. Jean-Louis Vanoverschelde, and he is from University of Louvain in Brussels. Welcome Jean-Louis, I made it.

Dr Jean-Louis Vanoverschelde:  Hey, how are you?

Dr Carolyn Lam:                Thank you so much for joining us. Also joining us today is Dr. Victoria Delgado, associate editor from Leiden University Medical Center in the Netherlands. Welcome Victoria.

Dr Victoria Delgado:        Hello. Thank you very much for having me in this podcast.

Dr Carolyn Lam:                So, severe degenerative mitral regurgitation with flail leaflets, a very important condition and your study, Jean-Louis, really provides important clinically applicable information. Could you please address our clinicians out there with a take home message from your paper.

Dr Jean-Louis Vanoverschelde:  Well, the take home message is very easy, once this condition needs to be operated on, there are really two options, one which is to repair the valve and keep the native tissue and the other is to replace the valve and trash the native tissue if I can say so. The results of the study are really clear. There is a major survival advantage by repairing the valve as opposed to replacing it. So for everyone of those who have degenerative mitral regurgitation with flail leaflets, the best treatment option is mitral repair.

Dr Carolyn Lam:                Now these results came from a multi-center registry of thousands of patients. I was really struck with the duration of the study. I think that's something that's really novel. You had a 20 year follow up but also patients were recruited from 1980 all the way to 2005, am I right? So could you expand a little bit about the possibility of techniques changing during that period?

Dr Jean-Louis Vanoverschelde:  Although there has been subtle changes in the practice, the basic principle have remained the same. So we have not really accounted for these changes in the practice over time, with regard to what happened to mitral valve replacement, clearly the prostheses that were there 30 years ago are not the same as the ones that are currently implanted to the patients, but none the less when we performed an analysis, a sensitivity analysis to look at whether the results were different from 20 years ago compared to those that were more recent, we found exactly the same result.

Dr Carolyn Lam:                Yes, I thought that was a very important sensitivity analysis. Tell us a bit more about the propensity score matching as well because another thing people will be thinking is, you know, this is a registry, huge numbers very important but obviously there would be differences in indication for repair versus surgery.

Dr Jean-Louis Vanoverschelde:  For sure, the fact is that there are statistical means that allow you to mimic not to be the exactly the same as, but to mimic randomization and it is the propensity score matching. That means that you perform a prior analysis that will identify similar patients in the two cohorts and match them so that you are basically having the same kind of patients that are treated with two different ways. So it's not randomization but it’s getting close to randomization when you use cohorts like the one from the MIDA registry.

Dr Carolyn Lam:                Perfect. Victoria, did you take the same take home messages and are you applying this clinically? I noticed that you invited an editorial, a lovely editorial on this paper as well, so please share your thoughts.

Dr Victoria Delgado:        Yeah, I share the same take home message that Dr. Vanoverschelde has outlined. I think that this is very important article, it's a landmark article highlighting one of the most important things that mitral valve repair should be probably the standard of care for patients with severe mitral regurgitation without degenerative cause with a flail and the article basically what it does is also endorsing the recommendations of current guidelines highlighting the value of mitral valve repair. Of course that mitral valve repair should be performed in centers with experience and with good durability of these repairs, so the centers need to have a good heart team where they can analyze their results in such a way like the MIDA registry has done demonstrating a good durability of the repair.

Dr Carolyn Lam:                And do you have anything to add to that Jean-Louis?

Dr Jean-Louis Vanoverschelde:  No, I think basically Victoria very well summarized the basic features not only of the paper itself but also of the condition and what currently is in the guidelines. In fact, the guidelines have already said that we should be preferring mitral valve repair over replacement, but the data on which this was based were probably not as conclusive as the one that are provided by this analysis of our registry, so I think it's really reinforcing the idea that we should go ahead and try to perform repair as much as possible, now with a caveat of course that the surgeons need to be skilled enough to perform that. But with the type of differences that we see in survival between the two cohorts I think that if a surgeon does not feel comfortable with repairing the valve and would rather replace it, he might refer the patient to another surgeon that is capable of repairing the valve. The impact and outcome is such that I think this really supports the idea that the patient should be referred to high volume and skilled centers.

Dr Carolyn Lam:                Could you give us an idea of what kind of impact you're talking about, what kind of numbers that you see?

Dr Jean-Louis Vanoverschelde:  It's the same in all the analysis, whether it's in the overall population or in the matched cohorts by 20 years, we have something like 20 to 25% survival difference, absolute survival difference between the two groups. So it's a reduction of mortality approximately by half if you perform repair compared to replacement, and it is increasing with time, so it's not something that is only present in the first years but is increasing with time, so it's about 20 to 25% absolute difference between the two cohorts.

Dr Carolyn Lam:                That truly is remarkable. Congratulations again on such a landmark paper like Victoria said. Now to either of you, question that's a bit left field maybe, but what do you think the role is now for percutaneous techniques of mitral valve repair or replacement then?

Dr Jean-Louis Vanoverschelde:  That's an interesting question. I think that if you really look far away into the future probably everything at some point in time will be percutaneous. At this stage I’m not sure that the percutaneous technique able to mimic what we can do with surgery in terms of mitral valve repair. So, it's an alternative to surgery in patients who are inoperable. In those who can undergo a surgical mitral repair, my first choice will certainly be to go surgically rather than percutaneously, at least right now.

Dr Carolyn Lam:                Victoria?

Dr Victoria Delgado:        I also agree with those comments. I think that now we have a lot of possibilities to treat these patients but the most important thing is to have the entire clinical picture of the patient, to see the pros and cons of preparing the patient for surgery or for percutaneous valve. There should be also an integration of imaging to know which is the cause of the valve dysfunction and to see whether the anatomy could be easily repaired by surgery or instead if the patient has contraindication for surgery, if it could be repairable as well with transcatheter therapy. But then for that I think that is really important and this is what the editorial also highlights, the role of the heart team, where there are different specialist surgeons, clinical cardiologists, heart failure specialists, imaging specialists that can integrate the entire information of the patient in order to select the most appropriate therapy. But still for patients who do not have contraindications for surgery who have repairable valve and as you can see from this registry, the percentage of repairability is quite high, I would still refer the patient as well for surgical valve repair.

Dr Carolyn Lam:                You heard it right here. Thank you so much for joining us today and please don't forget to tune in next week.


Jan 23, 2017


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 Centre and Duke-National University of Singapore. In just a moment, we're going to be discussing new results of the pioneer trial, and the patient with atrial fibrillation who undergoes intracoronary stenting, a familiar conundrum. What's the role of NOACs? Is there still a role for full-dose triple therapy with warfarin? First, here's your summary of this week's journal.

The first paper tells us about the clinical impact of left atrial appendage closure. Dr. Melduni and colleagues from the Mayo Clinic in Rochester, Minnesota, studied 9,792 patients undergoing bypass or valve surgery between 2000 and 2005. They used propensity score matching to estimate the association of left atrial appendage closure with early post-operative atrial fibrillation- defined as atrial fibrillation within 30 days of surgery- ischemic stroke, and mortality. They found that after adjustment for treatment allocation bias, left atrial appendage closure during routine cardiac surgery was significantly associated with an increased risk of early post-operative atrial fibrillation, and did not influence the risk of stroke or mortality.

They therefore concluded that it remains uncertain whether prophylactic exclusion of the left atrial appendage is warranted for stroke prevention during non-atrial-fibrillation-related cardiac surgery.

The next study provides pre-clinical evidence that genes on sex chromosomes may contribute to the sexual dimorphism of abdominal aortic aneurysms. That is, we well know that abdominal aortic aneurysm is a male-predominant disease. Now, in this paper, by first author Dr. Alsiraj, corresponding author Dr. Cassis and colleagues from the University of Kentucky, female LDL-receptor-deficient mice, with an XX or XY sex chromosome complement, were infused with angiotensin II for 28 days to induce abdominal aortic aneurysms. DNA microarrays were performed on the abdominal aortas, and to mimic the males, the female mice were administered a single dose of testosterone.

They found that an XY sex chromosome complement, in phenotypic females, profoundly influenced aortic gene expression profiles and promoted abdominal aortic aneurysm severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. The mechanisms for augmented abdominal aortic aneurysm severity in XY females included increased inflammation, augmented matrix metalloproteinases, and oxidative stress. These results, therefore, demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of aortic abdominal aneurysms. Sex chromosome genes may therefore serve as novel targets for sex-specific abdominal aortic aneurysm therapeutics.

The next two studies shed light on the mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism. In the first study, Dr. Watts and colleagues from University of Western Australia carried out a two-by-two factorial trial, of high-dose atorvastatin versus evolocumab on stable isotope tracer kinetics in 81 healthy, normal lipidemic, non-obese men.

They found that both atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL apoB, IDL apoB, and LDL apoB. On the other hand, evolocumab, but not atorvastatin, also decreased the production rate of IDL apoB and LDL apoB. The reduction of LDL apoB and LDL cholesterol was significantly greater with a combination versus either mono-therapy. In summary, they found that in healthy, normal lipidemic men, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism, and by reducing IDL and LDL production. The latter effects are incremental to statins.

The second paper to deal with this topic comes from Dr. Ginsberg and colleagues from Columbia University in New York, who studied 18 participants, this time 10 of whom were women, who completed a placebo-controlled two-period study, receiving two doses of placebo followed by five doses of alirocumab. These authors found that alirocumab decreased LDL cholesterol and LDL apoB by increasing IDL and LDL apoB fractional clearance rates, and by decreasing LDL apoB production rates. These results were consistent with increases in LDL receptors available to clear IDL and LDL from the blood during PCSK9 inhibition. These two papers are discussed in a beautiful accompanying editorial by Dr. Chris Packard from University of Glasgow. In his editorial entitled "Unpacking and Understanding the Impact of PCSK9 Inhibitors on Apolipoprotein B Metabolism." Those were your highlights! Now for our feature discussion.

Today we are going to be discussing one of the most common conundrums in all of cardiovascular medicine, and that is the care of patients with atrial fibrillation who also need percutaneous coronary intervention. Of course, both dual antiplatelet therapy and oral anticoagulation therapy would be indicated to reduce the risk of stent thrombosis and thromboembolism in atrial fibrillation, respectively. However, with the intensification of the anti-thrombotic regimen, there is the inevitable trade-off with more bleeding. Now, to discuss this, we have the first and corresponding author on a very novel study of the pioneer trial, and that is Dr. Michael Gibson, from Harvard Medical School and Beth Israel Deaconess Medical Center. We also have the editorialist for this very exciting paper, Dr. Deepak Bhatt from Brigham and Women's Hospital, and finally, we have Dr. Dharam Kumbhani, associate editor from UT Southwestern. Welcome, gentlemen!

Dr Deepak Bhatt:           Thank you.

Dr Michael Gibson:          Thanks.

Dr Dharam Kumbhani:   Thank you.

Dr Carolyn Lam:                So, Michael, could I start with you? This is a sub-study of the pioneer study. Could you tell us how this is different from the primary results, what were you looking for, and what you found?

Dr Michael Gibson:          As you know, as [inaudible 00:07:40] said, we have a lot of bleeding with conventional triple therapy, and we used two regimens to try and reduce that bleeding. One was a reduced dose of rivaroxaban, 15 milligrams, plus thienopyridine. The other strategy was baby dose rivaroxaban, 2.5 milligrams twice a day, plus DAPT. What we found in the overall study was a significant reduction in bleeding- from, say, 26.7% down to 18% for riva plus DAPT- that's the baby dose plus DAPT- and down to 16.8% for the 15 milligrams of riva plus the thienopyridine.

You'd have to treat about 11 to 12 patients to prevent one significant bleeding event. That's the mainstay. What we found in this very, very important sub-study is that that was associated with reduction in hospitalization. All-cause hospitalization was reduced, and cardiovascular hospitalization went down from 28.4% to about 20% for the two regimens. Bleeding with hospitalization went down, from 10.5% to about 6%. At the end of the day, you'd only have to treat 10 to 15 people to prevent one hospitalization, so from a health economic perspective, and from a patient viewpoint and hassle perspective, this was very important.

Dr Carolyn Lam:                In fact, Michael, I would say from a clinician-cardiologist perspective, these results are really very applicable. In fact, I really like, in the accompanying editorial, what Deepak wrote, that it may be one of those rare occasions where a sub-study provides very clinically meaningful information compared to the primary study. Deepak, would you like to elaborate a little bit more about that?

Dr Deepak Bhatt:             Sure. A really great point that you've raised. It wasn't, in fact, a sub-study we're talking about in Circulation. It was an analysis from the overall trial, looking at a different endpoint than the primary endpoint, the hospitalization, and the composite of hospitalization and mortality. I think that's a very important endpoint. If it were a heart failure trial, for example, that's the endpoint everyone would hone in on- mortality and hospitalization. The fact that that was significantly reduced, I think, is very clinically meaningful. Mike mentioned the economic implications, which for sure are there, by reducing hospitalizations and re-hospitalizations.

The impact on cardiovascular hospitalizations- the reduction there- I find particularly remarkable. The reduction in bleeding, of course, is good, and in its own right has a great deal of value, but the additional reduction in cardiovascular hospitalizations, I think, is quite reassuring for those that are worried about the efficacy of the two experimental regimens that he and his colleagues studied. Sure, the trial's not powered in each individual sub-group for rare events like stroke, but the fact that CV hospitalizations are not increased, and in fact reduced, tells me that this is a winning strategy or strategies.

Dr Carolyn Lam:                Right. Michael, another issue, though- this is open label, and I suppose one of the criticisms could be that there is a bias for clinicians managing patients on the traditional Vitamin K antagonist to maybe hospitalize patients more for some reason. What is your response to that?

Dr Michael Gibson:          That is always the criticism of an open label trial, but again, the events were adjudicated, and for the heart events, that's done in a blinded fashion, so it's reassuring that there was a blinded assessment of the heart events.

Dr Carolyn Lam:                True. How about comments on generalizability? I mean, what do you think? Trial setting, real world ...

Dr Michael Gibson:          Yeah, I think that's one of the advantages. This was very much a real-world kind of study. It was truly done throughout the world. We had a very broad entry criteria. Anyone who was getting a stent put in- you didn't have to have ACS, although about half the patients did. The only real exclusive criteria was you couldn't have any bleeding or be profoundly anemic. You couldn't have a stroke or [TIA 00:11:58] in the past. Other than that, it made real-world practice in a lot of ways.

Dr Dharam Kumbhani:   This is Dharam. If I may ask both the other people on the call, is ... Rivaroxaban is not FDA approved, in these doses, for use. I'm wondering if they might provide some comment, given the benefit that we see in this trial, overall, what their thoughts are and what the next steps might be.

Dr Carolyn Lam:                Sure. Maybe Michael, then Deepak?

Dr Michael Gibson:          Yeah, that's a good point. It is important to point out that you'd need to check the prescribing information in your country. In some countries- I think it's about 54 countries- the 2.5 milligram dose is available. It is approved for ACS, but is not approved for a-fib. Then, you have a dose of 20 milligrams that's approved worldwide for a-fib, but there are some countries- it's important to note, in some countries, 15 milligrams is the full dose that's approved- say, in Japan and Taiwan. There are Japanese studies showing that 15 milligrams was not only safer than warfarin, but more efficacious than warfarin in a trial like J-ROCKET. You're right, the 15 milligram dose is available in the US- it's approved for renal insufficiency, but at this time, it's not labelled for the ACS or stented patient.

But again, physicians are at liberty to look at this data, which is the first real data that we have to guide decision-making in this setting, and they're at liberty to make their own choices.

Dr Deepak Bhatt:             Yeah, I would agree with that assessment, and emphasize ... Like Mike said, it's an international audience for Circulation, so I would say, look in your own country, and in many parts of Europe, the 2.5 milligram rivaroxaban dose is available and approved for ACS, and could therefore be used for this purpose, though not strictly falling within the label indications. In the US, there's the 15.

I think, if I just answer the previous question, the results are very generalizable, and for doctors that critique that point, I'd say, "Why didn't you enroll your patients in the trial?" There's the RE-DUAL as well, that's ongoing, with dabigatran, AUGUSTUS with apixaban, and I'm missing one that's also ongoing as well, I think, but there are four different trials that are out there. The Pioneer was the first to report ...

Dr Carolyn Lam:                I think you're thinking of the Entrust AF-PCI with Edoxaban.

Dr Deepak Bhatt:             The most recent one, yes. I forgot the acronym, there. If people are really thinking that the results don't apply to their patients, well, there are trials that are ongoing. Enroll your patients. But to say, "Oh, my patients, I'm not going to enroll them in the trial," and then say, "The results aren't generalizable," I always find that an odd thing. I think the results are very generalizable. The one word of caution I would say, though, is to make sure to renally dose, as was done in the trial. That is, there was a downward adjustment in dose from the 15 milligrams to the 10. In real life, we've seen in registries with NOAC use, whether it's rivaroxaban or any of the others, a lot of times, the renal function is not carefully monitored in those patients that are on the fringe in terms of their renal function, and that's the one situation NOACs can backfire, where the dose isn't corrected for their degree of renal dysfunction. Other than that one caveat, I think the results are quite generalizable.

Dr Carolyn Lam:                Excellent comments. We should wrap up soon, but not before I want to ask Dharam. Thank you for managing this beautiful paper. What, to you, is the take-home message for clinicians out there?

Dr Dharam Kumbhani:   Yeah, it was an absolute honor and delight to manage this, and I think the paper's great. The editorial's great. It's gotten a great response. I think the take-home message is that this is a very clinically relevant question, and a very clinically relevant trial, and it shows that the needle will be moving towards using non-VKA-based agents, especially in patients such as this, who have both a-fib and PCI. I think this is very exciting space, a very important space. This trial suggests that if you use the strategy rivaroxaban low dose, with or without a DAPT, that it is safer, both in terms of mortality and bleeding, compared with what is traditionally being used with warfarin plus DAPT. I think this was a very, very exciting trial.

Dr Carolyn Lam:                Indeed, and congratulations to all three of you. Thank you so much for joining me on Circulation On The Run. Thank you, listeners, for joining us too, and don't forget to tune in next week.


Jan 16, 2017


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

                                                In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.

                                                The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.

                                                They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.

                                                On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence. 

                                                In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.

                                                The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.

                                                This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.

                                                All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.

                                                They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.

                                                In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.

                                                In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.

                                                The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.

                                                They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.

                                                Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.

                                                Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.

                                                The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.

                                                The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.

                                                These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.

                                                After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.

                                                These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.

                                                The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.

                                                As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.

                                                The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.

                                                Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.

                                                Those were your highlights. Now, for our featured discussion.

                                                On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.

                                                This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.

                                                Welcome Daniel.

Dr. Daniel Singer:             Thank you for having me.

Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana.

Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here.

Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found?

Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.

                                                There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.

                                                While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.

                                                What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper.

Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation.

Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.

                                                Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.

                                                Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.

                                                If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"

                                                We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores.

Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static.

Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.

                                                We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.

                                                One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation.

Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.

                                                Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts?

Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.

                                                A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.

                                                I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well.

Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.

                                                The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.

                                                We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.

                                                This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.

                                                I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror.

Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.

                                                As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.

                                                If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.

                                                In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that?

Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.

                                                At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.

                                                We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke.

Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.

                                                I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.

                                                One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients.

Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.

                                                Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings.

Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.

                                                The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.

                                                I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid.

Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.


Jan 9, 2017

Dr. Lam:                               Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This episode marks the six month milestone of our run together, a run that has taken us around the world from the United States to Europe, South Africa, and Asia, and one that is shared by listeners all over the world.

                                                On behalf of the editors, and from the bottom of my heart, I want to thank you for your support and request that you please subscribe to our podcast and share it with your friends and colleagues. We commit to bringing you the best of cardiovascular science in the most accurate and digestible way possible, thus suiting the busy cardiologist on the run.

Dr. Lam:                               All right, here are your highlights of this week's issue.

                                                The first paper looks at tissue plasminogen activator, or TPA treatment in ischemic stroke, addressing two aspects that are still unclear. Number one, the degree of additional benefit accrued with treatment in the first 60 minutes after onset of ischemic stroke; and number two, the shape of the time-benefit curve through 4.5 hours. First author, Dr. Kim, corresponding author Dr. Saver and colleagues from UCLA stroke center analyzed more than sixty-five thousand acute ischemic stroke patients treated with intravenous TPA within 4.5 hours of onset from the "Get With the Guidelines" Stroke U.S. National Program.

                                                They found that 878 of these over sixty-five thousand patients were treated within the first 60 minutes after onset, a ten-fold increase over previously available data. Thrombolytic treatment within the first 60 minutes was associated with the highest rates of favorable discharge outcomes. The shape of the time-benefit curve throughout the first 4.5 hours was non-linear for some outcomes. Discharge to home and discharge free of disability decayed more rapidly in the first hundred to a hundred and seventy minutes after onset than later. While independent ambulation at discharge and in-hospital mortality declined in a steady fashion through the time window.

                                                These findings reinforce the importance of quality improvement programs to accelerate door to needle time for thrombolytic therapy in acute ischemic stroke.

Dr. Lam:                               The next study sheds light on mechanisms underlying red blood cell mediated hypoxic vasodilation. A highly conserved response coupling oxygen delivery to metabolic demands of the tissues, and very clinically relevant in states of systemic hypoxemia and impairment in oxygen delivery, such as in patients suffering from cardiovascular, pulmonary, or hemolytic diseases.

                                                In this paper, Dr. Bailey and colleagues from University of British Columbia Okanagan in Canada studied ten healthy participants who were randomly assigned to a normoxic, or 21% oxygen, and hypoxic, or 10% oxygen trial with measurements performed at rest and following 30 minutes of cycling at 70% of maximal power output. Blood was sampled simultaneously from the brachial artery, internal jugular, and femoral veins with plasma and red blood cell nitric oxide metabolites measured. Cerebral and femoral venous blood flow were determined by transcranial doppler ultrasound and constant infusion thermodilution respectively.

                                                The authors found that hypoxia was associated with a mild increase in both cerebral and femoral blood flow, with further more pronounced increases observed in femoral blood flow during exercise. Plasma nitrite gradients reflecting consumption were accompanied by red blood cell iron nitrosyl hemoglobin formation at rest in normoxia, during hypoxia and especially during exercise, with the most pronounced gradients observed across the femoral circulation. In contrast, there were no gradients consistent with S-nitrosohemoglobin consumption.

                                                Collectively, these findings suggest hypoxia, and to a far greater extent exercise, independently promote arteriovenous delivery gradients of intravascular nitric oxide with deoxyhemoglobin mediated nitrite reduction, identified as the dominant mechanism underlying hypoxic vasodilation. This is as opposed to the competing hypothesis of S-nitrosohemoglobin formation.

                                                In summary, by distinguishing between the two competing mechanisms that underpinned endocrine nitric oxide vasoregulation, that is, the S-nitrosohemoglobin hypothesis versus the nitrite reductase hypothesis, these data help us to understand the dynamic interplay that takes place between nitric oxide metabolites as a function of oxygen demand in vivo, and will help to establish the most specific and sensitive prognostic markers of vascular health and therapeutic interventions that optimize tissue oxygenation.

Dr. Lam:                               The next study addresses the controversial issues of thrombus aspiration during percutaneous coronary intervention, or PCI, for the treatment of ST elevation myocardial infarction, or STEMI.

                                                Dr. Jolly and colleagues from Hamilton General Hospital in Ontario, Canada performed an individual patient meta-analysis of three eligible large randomized trials that is the TAPAS, TASTE and TOTAL trials including more than eighteen thousand patients who underwent PCI for STEMI. They found that as a routine strategy thrombus aspiration did not reduce cardiovascular mortality for STEMI patients undergoing primary PCI, and that exploratory analysis of patients with high thrombus burden suggested that thrombus aspiration may improve cardiovascular mortality but at the price of an increased risk of stroke or transient ischemic attack.

                                                In summary, these data suggest that thrombus aspiration should not be used as a routine strategy in patients with STEMI, however in patients with high thrombus burden, further large randomized trials are needed to determine if improved forms of thrombus aspiration can reduce cardiovascular mortality and to determine its safety with regards to stroke.

Dr. Lam:                               The next paper is the first study to look at coronary artery calcium imaging as a tool to personalize systolic blood pressure treatment goals.

                                                Dr. McEvoy and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland studied 3,733 participants from the multi-ethnic study of atherosclerosis with systolic blood pressure between 120 to 179 millimeters of mercury. Within subgroups categorized by both systolic blood pressure and estimated ten year atherosclerotic cardiovascular disease risk, they compared multi-variable adjusted hazards ratios for the composite outcome of incident atherosclerotic cardiovascular disease or heart failure after further stratifying by coronary artery calcium.

                                                The authors found that combining coronary artery calcium imaging and assessment of global atherosclerotic cardiovascular disease risk had potential to guide personalized systolic blood pressure goals, particularly among adults with an estimated risk between five to fifteen percent, and pre-hypertension, or mild hypertension.

                                                For example, among those with an atherosclerotic cardiovascular disease risk of less than fifteen percent and who had systolic blood pressure between 140 and 159, those with a coronary artery calcium score up to 100 were at two times the risk, while those with a coronary artery calcium score more than 100 were at 5.7 times the risk of events, all compared to a coronary artery calcium score of zero. Thus, information on coronary artery calcium burden may be considered when making personalized treatment decisions about blood pressure targets, particularly among patients with an estimated cardiovascular risk between five and fifteen percent, and who have either pre-hypertension or mild hypertension.

                                                In summary, information on coronary calcium burden may be considered when making personalized treatment decisions about blood pressure targets, for example, choosing a traditional goal of 140 or a more intensive goal of 120 millimeters of mercury. The authors ended by calling for a precision medicine clinical trial evaluating risk-based blood pressure treatment goals, preferably incorporating coronary artery calcium.

                                                Well, those were your highlights, now for your feature discussion.

Dr. Lam:                               On today's episode we are going to be discussing the very important issue of type-two myocardial infarction, very important yet usually neglected compared to type-one myocardial infarction. As a reminder to our listeners, type-two MIs are the ones where there is myocardial demand-supply mismatch whereas type one is the usual acute coronary artery plaque rupture and thrombosis. To discuss this I am really honored to have two James' on the podcast. The first is Dr. James Januzzi from Massachusetts General Hospital, the second is Dr. James de Lemos, executive editor of Circulation from UT Southwestern.

                                                Welcome to you both.

Dr. Januzzi:                         Thank you very much Carolyn, really great to be speaking with you.

Dr. de Lemos:                    Thanks Carolyn, it's great to be on.

Dr. Lam:                               Dr. Januzzi, could you please let us know what you found in this paper, it's really extraordinary. Just give us a top line of the results.

Dr. Januzzi:                         Basically we set out to examine the question of how frequent type-two myocardial infarction is in a population of patients followed longitudinally after they have taken a trip to the cath lab for one reason or another. Really with the goal to better understand the type-two MI syndrome. It was our hypothesis that type-two MI was perhaps more common than people may have recognized, and that type-two MI would be higher risk in terms of the likelihood for ischemic complications than what people had previously recognized. As you point out, type-two MI is often neglected from a management perspective.

                                                What we found, basically, was among a cohort of patients, 1,250 patients coming through the cath lab at the Massachusetts General Hospital Heart Center, in follow up over a several year follow up period with a maximum of eight years of follow up, with a mean of about 3.4, a median of 3.4 years follow up. Out of the 1,251 patients that we enrolled and followed, 152 actually had an incident type-two myocardial infarction during follow up. Additionally, type-two MI was actually quite recurrent in many patients, and in each of the cases whether individual or in most patients with recurrent type-two MI, the mortality risk was really quite striking. Patients that had a type-two MI, partially because they were more complicated medically speaking, as one might have expected, they were older and had lower blood pressure, more coronary disease, heart failure and other medical comorbidities. The likelihood for a major adverse cardiovascular event was more than doubled in patients that suffered an incident type-two MI, the risk for mortality was actually remarkably almost ten-fold higher with a cardiovascular death rate that was around nine-fold higher, heart failure was tripled.

                                                Really just illustrates the very morbid nature of the type-two myocardial infarction, and illustrates the fact that studies are urgently needed to better understand how we should manage these patients.

Dr. Lam:                               Dr. Januzzi when I manage patients I find this diagnosis of type two-MI to be a very dirty one to make, if you know what I mean. It's hard to really be sure what's happening, and what to attribute rises in troponin to, and so on. Could you tell us a little bit more about how difficult it was to adjudicate the events, and what's the risk of misclassification in your study?

Dr. Januzzi:                         It's a challenge, and that's something that came up during the peer-review process. We really wanted to make sure that we got this right, so in fact we went back and did a cross-sectional re-review of cases to make sure that our adjudication process was accurate. It's not a very straightforward thing to judge, obviously. A rise and/or fall in troponin may be from a type-one myocardial infarction. There's increasing interest in a syndrome of myocardial injury in the absence of a classical myocardial infarction. Then lastly, we recognized that troponin may rise and fall, for example, in patients with heart failure, possibly due to non-coronary mechanisms. You are correct, it may be a challenge to classify these patients solely on the basis of the presence of a rise or fall of troponin.

                                                What we did was classify them utilizing the Universal Definition of MI Task Force criteria, which includes symptoms and signs, as well as a rise and/or fall of troponin, plus evidence for loss of myocardial function on non-invasive testing. We were pretty strict, actually, in terms of how we judged them, and when we went back and re-reviewed ten percent of the cases, we actually found that all of the fifteen cases that we went back and re-reviewed met the criteria that we had articulated in the front end. We feel pretty confident that we got the diagnosis correct, but obviously it's a challenge in every day practices, as you rightfully point out.

Dr. Lam:                               It does certainly sound very rigorous, indeed. Dr. de Lemos, you managed this. He mentioned reviewers giving him a hard time, what was it like managing this paper?

Dr. de Lemos:                    It was fascinating because the Universal Definition that introduced type-two MI into the classification scheme is only a decade old. It's remarkable how little we know about the problem, and how much we struggle in clinical practice. We thought this paper was one of the first and most comprehensive evaluations to put some construct around the problem. As you pointed out, Carolyn, it is a messy diagnosis. Even when you do it in an organized, researched fashion this reflects what we all deal with in clinical practice where it's not so easy to define myocardial infarction even when given the criteria of the Universal Definition. The challenge really is that only a minority of the troponin elevations that are the classic type-one MIs that we know what to do with. The rest of them are either these troponin elevations NOS, type-two MI, or something on a continuum on this spectrum that's really hard to differentiate.

                                                This paper's important because it really highlights that these non-type-one MIs whatever they are, are common and associated with really high risk, and it's sort of a call to arm that we better start to understand and sub-classify these if we're going to be able to reduce risk in this very high risk population. That's really why we were so interested in the paper, and why we worked so closely with Jim and his team to address some of the issues that you just raised.

Dr. Lam:                               I completely agree, in fact it's beginning to remind me of the world of HFpEF when we first started realizing that people with heart failure, even though ejection fraction's normal are definitely not doing well. James Januzzi, if you don't mind, what do you think are the implications for treatment, what are the things that you think need to be examined going forward?

Dr. Januzzi:                         Carolyn I laughed when you mentioned HFpEF because at one of the recent Universal Definition of MI Task Force meetings, I actually said that type-two MI is the HFpEF of the myocardial infarction world. To answer your question, I have approached this question very much the way we do in the heart failure space relative to heart failure with preserved EF. In order to develop a strategy for treatment for type-two MI, we need considerable advances still in our understanding of just what exactly is a type-two MI, what types of patients have type-two MI, and on an individual level, the treatment strategies may follow.

                                                The problem here is if you look just at all comers who suffered a type-two MI in our study, the majority were actually taking statins, they were taking aspirin, they were more likely to be taking beta-blockers. So the patients themselves were actually on the very treatments that we might think about prescribing in those folks that have a type -wo MI, and yet they still suffered the MI, and they had worse outcomes. One might think about coronary disease and revascularization, and indeed one of the nice things about our study is we enrolled patients at the time of coronary angiography, and then followed them subsequently, so we actually had detailed coronary angiograms on every one. Those suffering an incident type-two MI certainly had more coronary disease, so one might argue revascularization might either be protective if done prior to the onset of type-two MI, or at the time of type-two MI a revascularization-driven strategy might be a logical approach.

                                                I think more fundamentally, bringing it back to heart failure and to the HFpEF analogy, I think that in order to better understand treatment we need to better understand just who these patients really are. So much like has been done in the heart failure space we're now doing cluster phenotype analyses where we're looking at the various phenotypes of patients with type-two MI using network analyses, which is one way to approach a problem when you've got a mix of various diseases that fall under the same title. So in those patients with preserved ejection fraction heart failure, there are patients that are younger obese patients, there are the patients with advanced diabetes, et cetera.

                                                Our hypothesis for our present research is to examine this question within the type-two MI diagnosis to see if we can identify specific clusters of phenotypes that might be treated in specific ways. The coronary patients might deserve revascularization, the heart failure patients might deserve a different approach for their care. That, I think, might be the way forward, exactly taking a page from the playbook that you just mentioned with respect to preserved ejection fraction heart failure.

Dr. Lam:                               Wow, how terribly exciting. Congratulations again for this paper, I really think it's a landmark and will open the door to many more important papers. I would like to switch tracks a little bit at the moment. We are coming to six months into the new Circulation editors that have been under the leadership of Joe Hill and James de Lemos, and I'd actually like to start by asking you, Dr. Januzzi, what was it like working with our new Circulation team? Then handing the mic over to Dr. de Lemos to tell us a little bit more about what the journey has been so far in the last six months.

Dr. Januzzi:                         Thanks for asking, it was an absolute pleasure. I trained with Dr. Hill and with Dr. de Lemos in one degree or another during all of our respective residency and/or fellowship training, so I've known these guys for a long long time. I think that the most important aspect in the peer review process is a collaborative and collegial process where the division between author and editor can allow for communication. In this experience with this manuscript, it was a very easy-going and collaborative process where the paper from beginning to end grew in its quality, and ultimately landed in the journal, and the way that it did was, I think, a substantial likelihood for heavy citation. That says a lot about the editors who really help us to bring it to this final product.

Dr. Lam:                               Dr. de Lemos?

Dr. de Lemos:                    We're now six months in to the new Circulation editor team's tenure, and I think all of us are having a blast. I think we've put together this team of diverse international experts that build off each other and thrive off each other, so from the team perspective, we're just having great fun, working hard, learning a great deal. We hope that those of you out there that are listening and reading, and submitting papers, and using our journal for your own research, are noticing the changes that we've made and think we're headed in the right direction. We'd love to hear from you about the things you like, and those things you don't like. We do think we've, in many ways, modestly changed the focus of the journal. There's so many new content categories that are designed to speak to the global burden of cardiovascular disease, the international aspect of cardiovascular research, and new clinically relevant problems, translating basic science so that clinicians can understand it. We hope that clinically active, as well as basic investigators are finding these changes useful in their own daily lives.

Dr. Lam:                               Thank you both so much for spending time with me on Circulation on the Run. Thank you everyone, don't forget to tune in next week.



Dec 27, 2016

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. Caroline Lam, associate editor from The National Heart Center and Duke National University of Singapore. Today we will be discussing the results of an individual level meta-analysis regarding venous thromboembolism and its risk factors, but first, here's your summary of this week's issue.

The first paper provides insights into paracrine signalling pathways that regulate epicardial adipose tissue formation. That is, referring to the adipose tissue located between the epicardium and underlying myocardium that is known to be strongly associated with coronary artery disease. In the current study from Dr. Lira of Icahn School of Medicine at Mount Sinai, New York, Dr. Pu from Boston Children's Hospital, Dr. [Chien 00:00:56] from Karolinska Institute and colleagues, the authors used a novel modified mRNA screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the heart. Using two independent lineage tracing strategies in murine models, they showed that cells originating from the WT1-positive mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue following myocardial infarction. This differentiation process required WT1 expression and was stimulated by insulin-like growth factor 1 receptor activation. Insulin-like growth factor 1 receptor inhibition significantly reduced its adipogenic differentiation and reduced WT1 lineage cell differentiation into adipocytes following myocardial infarction.

These results thus establish insulin-like growth factor 1 receptor signalling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury. And it does this by redirecting the fate of WT1-positive lineage cells. The study also demonstrates the utility of a modified RNA based paracrine library screening to dissect signalling pathways in homeostasis and disease.

The next study brings us closer to understanding the mechanisms underlying diabetes-associated heart failure. In this study by first author, Dr. Wang, corresponding authors, Dr. Abel and Xiang from University of California, Davis and colleagues. High-fat diet feeding was used to induce obesity and diabetes in wild-type mice or mice lacking the beta-2 adrenergic receptor or beta-arrestin 2. High-fat diet feeding was found to selectively increase the expression of phosphodiesterase 4D in the mouse hearts in concert with the reduced phosphokinase A phosphorylation of phospholamban which contributed to systolic and diastolic dysfunction. The expression of phosphodiesterase 4D was also elevated in human hearts with diabetes. The induction of phosphodiesterase 4D expression was mediated by an insulin receptor and substrate as well as by beta-arrestin-2 dependent activation of a beta adrenergic receptor, ERK signalling cascade.

Genetic deletion of beta-2 adrenergic receptor or beta-arrestin-2 or pharmacological inhibition of beta-2 adrenergic receptor with carvedilol or G-protein receptor kinase 2 with paroxetine all significantly attenuated insulin-induced phosphorylation of ERK and phosphodiesterase 4D induction thus preventing diabetes-related systolic dysfunction. Thus, targeting the insulin beta-2 adrenergic receptor pathway may be a novel way to prevent diabetes-associated heart failure.

The next study addresses the gap in care pertaining to implantable cardioverter-defibrillator or ICD use among Medicare patients with low ejection fraction following myocardial infarction. Dr. Pokorny and colleagues from Duke University Medical Center examined rates of post-discharge ejection fraction assessment and ICD implantation among more than 10,280 Medicare-insured patients age 65 years above with an ejection fraction 35% and below during an index myocardial infarction admission in the ACTION Registry Get With the Guidelines. They found that the cumulative incidence of ejection fraction reassessment within one year of myocardial infarction was 66.8%. Within the first year of post-myocardial infarction, 11% of patients who had an ejection fraction reassessment underwent ICD implantation which was significantly higher than patients without an ejection fraction reassessment. After multivariable adjustment, ejection fraction reassessment remained significantly associated with a higher likelihood of ICD implantation within one year in both revascularized and non-revascularized patients. Based on these findings, the authors recommend that all patients who are potential candidates for ICD therapy be scheduled for follow-up outpatient ejection fraction assessment prior to hospital discharge to bridge these currently observed gaps in care.

The next study is the first multi-institutional study in Asia describing current treatment strategies for total anomalous pulmonary venous connection. This retrospective study of 768 patients with total anomalous pulmonary venous connection operated on between 2005 and 2014 is from first authors Dr. Shi, Zhu, and Chen, corresponding authors, Dr. Chen and Zhuang and colleagues from the Shanghai Children's Medical Center and Guangdong General Hospital in China. While most patients underwent conventional repair, a sutureless patient was technique was employed in 10% of patients. Over a median follow-up of 23 months, there were 38 intraoperative deaths and 13 late deaths. A younger age at the time of repair, next an infracardiac total anomalous venous connections, pre-operative pulmonary venous obstruction, prolonged cardiopulmonary bypass time and longer duration of ventilation were all factors associated with increased mortality. Among these 717 survivors, recurrent pulmonary venous obstruction was found in 15% or 111 patients. Risk factors for recurrent pulmonary venous obstruction included pre-operative pulmonary venous obstruction, infracardiac total anomalous pulmonary connection, mixed venous connections and prolonged cardiopulmonary bypass time, a sutureless technique was associated with a lower restenosis rate compared to conventional repair in patients with pre-operative pulmonary venous obstruction but not in newborn patients. Thus, this study provides an important data on the outcomes following surgical correction and risk factors for poor prognosis in total anomalous pulmonary venous connection in Asia.

The final study is the first systematic review and meta-analysis on the association of genetic polymorphisms and outcome of clopidogrel-treated patients with ischemic stroke or transient ischemic attacks. In this paper from first author, Dr. Pan, corresponding author, Dr. Wang and colleagues from Beijing Tiantan Hospital, Capital Medical University in Beijing, China. Authors looked at 15 studies of 4,762 patients with stroke or transient ischemic attack treated with clopidogrel and this included 3 studies from Europe and 12 studies from East Asia. They found that carriers of the CYP2C19 loss-of-function alleles were at increased risk of stroke compared to noncarriers. Composite vascular events were also more frequent in carriers compared to noncarriers while bleeding rates were similar. There was no evidence of statistical heterogeneity among the included studies for stroke but there was for composite vascular events suggesting that publication bias cannot be ruled out. Genetic variance other than CYP2C19 were not associated with clinical outcomes. The author suggested that their findings may justify genetic testing when clopidogrel is otherwise considered the preferred treatment modality, especially in East Asian patient populations in whom the prevalence of CYP2C19 loss-of-function allele is high.

In an accompanying editorial, Dr. Simon and [inaudible 00:10:11] suggest it maybe time to consider a prospective trial of personalized medicine using CYP2C19 genotyping in acute ischemic stroke and perhaps considering alternative medications in poor or intermediate metabolizers such as in the popular ongoing genetics trial in STEMI patients undergoing PCI. That wraps it up for the summaries this week. Now for our feature discussion.

Today's feature paper talks about the association of traditional cardiovascular risk factors with venous thromboembolism. And it is the first individual level meta-analysis of prospective studies. I am so delighted to have the first and corresponding author here with us, Dr. Bhaktawar Khan Mahmoodie from San Antonio's Hospital in the Netherlands. Hi Khan, thanks for being here.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you for inviting me. Thanks a lot.

Dr. Carolyn Lam:              

And I am particularly delighted to have associate editor, Dr. Josh Beckman from Vanderbilt University joining us today as well. Welcome Josh.

Dr. Josh Beckman:          

Caroline, it is such a pleasure to be here with you. I've been listening to these podcasts and they have been incredible. I've been waiting to be able to jump in and today's paper is an awesome place to start.

Dr. Carolyn Lam:              

It certainly is. Congratulations on managing such an important paper. Khan, maybe I could start with you. Venous thromboembolism versus arterial thromboembolism. We're very familiar with the latter. We know it comprises coronary heart disease, stroke, peripheral artery disease. We're very familiar with the risk factors such as hypertension, hyperlipidemia, diabetes, smoking. But here you're asking, are these same risk factors applicable in venous thromboembolism. That would include deep venous thrombosis, pulmonary embolism, where we traditionally classify it into provoked events that is triggered by things we know well like immobilization, surgery and so on. And then there are the unprovoked events that don't have any risk factors. So could you, first of all, point out ... you were looking at venous thromboembolism. What was your hypothesis with regards to the traditional cardiovascular risk factors?

Dr. Bhaktawar Khan Mahmoodie:            

Many researchers in the last 10, 15 years, they go questions whether there is connection between venous and arterial thromboembolism. Since then, several studies published on that with controversial results. So our hypothesis for this paper was to see whether there is real associations or are we looking at some kind of associations due to confounding factors such as age and overweight which are risk factors for both.

Dr. Carolyn Lam:              

Yeah. And yours is actually the first individual level meta-analyses of prospective studies dealing with this. Tell us what you found in ... Were you surprised by your findings?

Dr. Bhaktawar Khan Mahmoodie:            

What we found that actually traditional, modifiable, cardiovascular risk factors like hypertension, diabetes and hyperlipidemia were not risk factors for venous thromboembolism. The exception was smoking, current smoking, which was particularly associated with provoked venous thromboembolism which is probably pro its association with cancer. And cancer itself is a strong risk factor for venous thromboembolism. About whether I was surprised, I was not surprised at all. We saw in several cohort studies and well-defined cohort studies that the association disappeared after adjustment for age and body mass index which are important confounders in these [inaudible 00:14:06]. That's what I expected and we found it and it is confirmed with this large individual level meta-analysis.

Dr. Carolyn Lam:              

Great. But what did you think of the association of higher systolic blood pressure not with higher but with lower risk of venous thromboembolism?

Dr. Bhaktawar Khan Mahmoodie:            

That was a bit surprising for us too but I think the best explanation we can give at the moment is probably that we have some kind of competing risk. And one suggestion that we gave in the paper as well is that maybe what we already know is that higher blood pressure is a strong risk factor for atrial fibrillation. Most of these people they receive oral anticoagulants. That is subsequently probably a protective factor for venous thromboembolism. We probably deal with some kind of competing risk from another condition like the atrial fibrillation and use of anticoagulants which we could not unfortunately adjust for in this analysis.

Dr. Carolyn Lam:              

Sure. That makes sense. Josh, can I bring you into this? I mean I remember well our multiple and long discussions at the editors meetings. This is one of those papers that is extremely important for its negative, neutral associations isn't it?

Dr. Josh Beckman:          

I think this is one of the more important papers in this field in a long time. I am one of those people who has followed this literature and believed, based on the best previous publications, that there was a link between many of the arterial thrombosis or atherothrombotic risk factors and venous thromboembolism. In fact, Circulation published one of these meta-analyses, and I'm going to say only because this little paper is so large with only 21,000 patients demonstrating a clear association. So the first question I would have, we published that back at 2008, the first question I would have is can you describe for the general readership what such a large series of patients allows you to do that was not permitted by the other meta-analyses of say twenty to thirty thousand patients that have been previously in the literature.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you Dr. Beckman and thank you also for managing this paper. This is an important question and I think what we were able to do compared to the previous analysis in 2008, we were able to adjust for confounding risk factors. In the course, we included were all with validated venous thromboembolism events and also the events are temporal character, like all the risk factors were measured and then followed-up for event. While in that paper, there were many case-controlled studies added and the results were not adjusted for age and also not adjusted for body mass index. And if we do the same with what's done there, then we have the same results like in our [inaudible 00:17:14] associations, all of these risk factors were indeed positively associated with risk for venous thromboembolism.

Dr. Carolyn Lam:              

Let me just state, I mean, there were almost 245,000 participants in your study. With 4,910 thromboembolism events, so this is really huge and gives you a lot of power to look at this thing very carefully.

Dr. Josh Beckman:          

It was a 10-fold increase from any of the major publications in this area. It was almost geometrically larger in size which is why, I think its conclusion will be accepted differently than all the previous analyses. Now, let me ask one question about what you already identified in your discussion as a possible limitation. Is this study applicable to all populations around the globe or do you think it is a bit more focused?

Dr. Bhaktawar Khan Mahmoodie:            

I think it is focused at least. We don't have Asian population in these analyses and also the proportion of African-Americans were limited which was only limited to some U.S. cohorts so I think that there is a limitation which is results are probably only applicable for Caucasian population.

Dr. Josh Beckman:          

I guess my other question is, one of the reasons that people, I think, advance the argument that there may be overlap between the two kinds thrombosis is that there was evidence that the medication, statin, may ... to a much smaller degree, reduce venous thrombosis as well as reducing arterial thrombosis. Do you think that this is evidence of some common pathophysiology? Or is it like smoking, it's truly working separately from arterial disease?

Dr. Bhaktawar Khan Mahmoodie:            

Personally, I think that this association or the finding of statins reduce the risk of thromboembolism could be due to some pleiotropic effects of statins. Like even for stroke, we know that the association of cholesterol with stroke is not so clear-cut as it is with myocardial infarction but still it reduces risk of stroke. And also for venous thromboembolism, the risk reduction of venous thrombosis in the JUPITER trial was like 50%, which is very high, even better than aspirin. But I think that may not be directly related cholesterol levels but more to another pleiotropic effects of statins. It could influence levels of various coagulation [inaudible 00:19:56] in the endothelial stabilization which may be also important risk factors for venous thrombosis.

Dr. Josh Beckman:          

One of the reasons that this paper is very important is that we begin to look for therapies and risk factors based on what the disease is caused by. And so the fact that you guys were able to establish, in my opinion, quite clearly what does and what does not contribute to venous thrombosis allows us to begin to think about the disease differently and approach it differently. I would like to provide congratulations. My one little ask of you is that one of the things that I think this podcast is great for is to explain to the readership what goes into this kind of work. Everybody thinks that someone else's research is easier to do than their own, which of course is a ridiculous thing. But can you describe for us what it's like and how long it took from the study initiation to when you completed it? How much work went into trying to get all these studies together to create this individual patient level data?

Dr. Bhaktawar Khan Mahmoodie:            

Yeah. That was a great amount of work. Actually, I did a systematic review of the only PubMed publications back in 2014 and it took almost 2 years at least. I was not always active the whole 2 years but still I had to visit several PIs of the studies to get them so far to share their data. Eventually, I had to develop a code that will make it possible without sharing the individual level data by using the same definitions and the same categorization of variables so we call it a two-stage meta-analysis similar to one-stage if the definitions are similar. And eventually, I think that the real part of the analysis and inclusion of studies took like half a year or so. There was a lot of work.

Dr. Josh Beckman:          

I think this is a tremendous amount of work and for those members of our readership who do basic research, or translational work, or practice in the clinics, it really needs to be made clear that this is a heroic effort of hundreds and hundreds of hours. And that getting together all of these studies is just an enormous undertaking. And that even though, we can read the paper in 10 minutes and gleam the most important part. It is an incredible amount of work for which you guys are to be congratulated.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you for acknowledging this. Thanks a lot.

Dr. Carolyn Lam:              

Josh, I couldn't agree with you more and I truly couldn't have said it any better. Thank you both of you for making this just one of the best discussions we've had on this podcast. I'm sure the listeners all agree what a wonderful time we've had.

You've been listening to Circulation on the Run. Please remember to tune in next week.


Dec 19, 2016

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. We have such a special issue today. You see, it's entirely focused on resuscitation and I am delighted to have with me today, Associate Editor, Dr. Mark Lane from Puffs Medical Center, who really put this issue together. Welcome, Mark.

Dr. Mark Lane:                  Thank you Carolyn.

Dr. Carolyn Lam:               Mark, maybe you could start by telling us why the focus on resuscitation? I do believe this is the first time we've done this at Circulation.

Dr. Mark Lane:                  Yes, this is the first time we've done this at Circulation. It really was a confluence of a couple things coming together. Once is that over the spring and summer, we had a very high volume of high quality resuscitation papers come to Circ. This was not something that we actually asked for but we noted that there were a number of these. Also, it's an important time in resuscitation because a number of the resuscitation counsels across the world have called for improvements in the survival rate, noting that we already have the tools that we need to increase survival and we have to better apply these tools. The HA has provided a goal of doubling resuscitation and resuscitation counsels in Europe, New Zealand and Australia have also echoed that call.

Dr. Carolyn Lam:               That's great, so this is a really important issue. I just echo your words about their being a remarkable number of original papers. We have seven and they're just such high quality. Let's chat through them, shall we? I'm going to go by pre-hospital setting to the out of hospital setting and finally end up in the in-hospital setting. Shall we do that?

Dr. Mark Lane:                  That sounds great.

Dr. Carolyn Lam:               The first paper is really about identifying patients at risk for pre-hospital sudden cardiac death at the early phase of myocardial infarction. You want to tell us a bit about that one?

Dr. Mark Lane:                  This is a study coming from the emergency medical services in the greater Paris area, where they looked at their cardiac arrest and STEMIs over the last seven or eight years. What they were specifically looking at is, can you identify STEMI patients who are at risk for having a cardiac arrest, because if you could identify those patients, you'd want to get there very quickly because if you know they're going to arrest or they're going to have a cardiac arrest, then having a defibrillator there would be very important.

                                                What they found, is that you can actually identify STEMI patients who are higher likelihood of arrest and those STEMI patients are those with younger age, they're not obese, they don't have diabetes. They have shortness of breath in addition to their chest pain and they have a very short delay from the time of chest pain to their call EMS. That is they're very concerned about their chest pain. You could use these characteristics to predict which STEMI patients, which chest pain patients were at highly likelihood of having a cardiac arrest. There was as much as a 19-fold difference between individuals without any of these factors and individuals with several of these factors.

Dr. Carolyn Lam:               What I like about this, is that simplicity of that score. Age, symptoms and kind of the absence of diabetes, absence of obesity and that short time frame. It's something that could be asked on a routine questionnaire by EMS dispatchers, for example.

Dr. Mark Lane:                  Right. It highlights the importance of the dispatch system. That simple questions, you can really stratify risk and it's not just getting an ambulance out there. Truly stratifying risk in order to get there quicker.

Dr. Carolyn Lam:               There are two papers that deal with out of hospital cardiac arrest. One of them interestingly focusing on the neuro-protective effects of Glucagon-Like Peptide-1 analog Exenatide. Thoughts about that one?

Dr. Mark Lane:                  This is a randomized study from Denmark. Notable that there are very low number of randomized trials in resuscitation so the fact that they did this is remarkable. What they did, is this glucagon-like peptide analog is a type II diabetic medicine and there is some reason to believe that that may protect the brain after resuscitation and ROSP. They had two goals in this trial. One was to see if it was feasible to administer a drug within six hours of a cardiac arrest and the other was to get any sort of outcome measure of whether this could provide some benefit. They randomly assigned 120 comatose patients and half of them got the peptide analog and the other half did not. What they showed, it is feasible to give IV administration of a drug within six hours of a cardiac arrest. Unfortunately, the drug they used did not appear to have any clinical benefit and this was both a composite end-point of death in neurologic function but also an evaluation of a brain neuron specific amylase, which was actually brain damage so they didn't see any biological or clinical neuro-protective effects of this drug.

Dr. Carolyn Lam:               I didn't realize it until you said it, it is very difficult to do a randomized control trial. This is very significant just for that. The next study about the out of hospital arrest, really talks about bystander CPR and I think seeks to answer to what degree bystander CPR remains positively associated with survival with increasing time to potential defibrillation. Important question, what do you think of that?

Dr. Mark Lane:                  It's an important question that surprisingly has not been evaluated that closely. Most either studies either look at bystander CPR or EMS arrival times but don't look at the interaction between the two. This study looks at the interaction between bystander CPR and EMS response time and that's the critical thing in this paper that's very interesting.

                                                What they did is, they split bystander CPR with or without and then EMS response times five minutes, 10 minutes and longer. If EMS responds within five minutes and you had bystander CPR, the survival rates with good neurological outcome were 14.5%, which is really a remarkable number. If there was no bystander CPR and the EMS arrived within five minutes, it dropped to 6.3%. There was 2.3-fold higher likelihood of good neurologic survival with bystander CPR with EMS within five minutes.

                                                They also looked at the 10 minute response time of EMS and if you had bystander CPR and EMS arrived within 10 minutes, the survival rate was 6.7% and without bystander CPR, it was 2.2%. With bystander CPR and EMS arrival within 10 minutes, there was a three-fold higher likelihood of survival with bystander CPR. It's interesting that by 13 minutes, there really was essentially no difference in those individuals who had bystander CPR or not, suggesting that at that point it's taken so long for EMS to arrive, it really doesn't make really much difference between whether you have bystander CPR.

                                                A really important paper showing that bystander CPR is critical, but so is EMS arrival within five minutes especially, but even 10 minutes.

Dr. Carolyn Lam:               I like that paper and I really like the way you crystallized the findings so clearly like that. What I'm also liking is the way, even though these papers weren't invited or anything, there is this nice flow because from bystander CPR we now talk about duration of resuscitation. There's one regarding adults and followed by one in pediatric population so very nice set of papers. Could we start by maybe talking about the adult one? The one looking at the association between duration of resuscitation and favorable outcomes after out of hospital cardiac arrest from North America.

Dr. Mark Lane:                  The reason that these two papers are important is really the futility issue. When is it futile to continue a CPR and that's a very important question. This adult paper is from the ROC Consortium. The ROC is a North American Seer NIH Sponsored consortium that's been going on over the last 10 or so years. What they looked at was outpatients and they had a very large number of greater than 11,000 subjects and of those 8% survived with a good outcome. That's 8% of those 11,000. If you looked at those 8% that survived, 90% of those had return of spontaneous circulation with 20 minutes. You really wanted to get their blood pressure back within 20 minutes.

                                                If you went beyond 20 minutes to the return of spontaneous circulation, you still could get good outcome. It was less likely but it was more likely if you had initial shockable rhythm, you had a witnessed cardiac arrest or you had bystander CPR. If you had some of those features, then you would argue to continue CPR for a longer time period. Actually a very nice important paper that if you had those other three features, you could still get good neurologic functioning, even with resuscitation attempts up to 40 minutes.

Dr. Carolyn Lam:               Exactly. I thought I saw 47 minutes somewhere, but it gives us a bit of a guidance when we're making these really tough decisions and talking about tough decisions and futility, I think it's even more amplified in the pediatric population, isn't it? This next paper from Japan talks about the duration of pre-hospital CPR in the pediatric population. What are your thoughts on that one?

Dr. Mark Lane:                  This was a study from Japan, using their nation-wide Japanese data base. Actually, in many ways mirrored the adult experience. The number of patients analyzed with roughly the same. This was nearly 13,000. They looked at 30 day survival both overall and 30 day survival with good neurologic function and 30 day survival overall were 9% so similar to the 8% in adults and good neurologic function were 2.5%, which wasn't quite as good as in the adults and that the duration of CPR also was very important. Once CPR went out to 42 minutes there was less than 1% chance that that individual was going to survive with any significant neurologic outcome. If you had bystander CPR you could increase that time by four to five minutes but again showing very similar numbers to the adult population that once you start hitting that 40 to 45 minute time frame, if there's no return of spontaneous circulation then the odds of survival are really quite low.

                                                The time frame may be extended a bit by CPR, maybe be extended by a bit if you had a shockable rhythm. Again, very similar features to what were found in the adult study.

Dr. Carolyn Lam:               What a nice pair of papers. You know, the pediatric paper was paired by yet another, wasn't it? This one now addresses very importantly conventional versus compression only CPR in the pediatric population. Again, from Japan. I know both the pediatric papers were of great interest because you invited an editorial on this as well. You want to comment on those?

Dr. Mark Lane:                  This issue of compression only CPR versus standard CPR, which includes compression and ventilation is a very hot one because we know that if you can do compression only CPR, the individuals willing to do that type of CPR are much greater than the individuals willing to do mouth to mouth. In the adult population, there's been a number of very good retrospective registries and also randomized trials that showed that compression only CPR may be very similar ... In fact some studies better, some studies a little worse than compression-ventilation CPR.

                                                Whether this applies to the pediatric population is not clear. There is more asphyxial arrest in the pediatric population whereas in the adult it's more cardiac so there is concern that compression only CPR will not be as good in children. This group of investigators used the same registry. A little shorter time-frame. They looked at it for two years and thus only had 2,000 patients in this registry. Of these 2,000 patients 400 received conventional CPR, 700 received compression only CPR and 1,000 did not receive any CPR. The important findings in this study was that any CPR increases survival so if you did not get any CPR, your survival was 3.7%. If you got conventional CPR your survival was 25.9% and if you got compression only CPR your survival was 9.3%.

                                                When you compared unadjusted survival with compression only versus the standard CPR, the odds ratio were 3.42 that standard CPR was better than compression only CPR. However when you did multi-variable adjustment, that big difference decreased and was no longer statistically significant between conventional CPR and compression only CPR. The same was true when you did propensity score matching which is an attempt to randomize to match groups. There was really no difference between conventional CPR and and compression only CPR.

                                                From this study, it's clear that any CPR is better than no CPR. There was a hint here that standard CPR was better than compression only CPR but because that improvement disappeared with multi-variable adjustment and propensity score matching both the authors and the editorialists have called that it's time for a randomized trial of compression CPR in kids.

Dr. Carolyn Lam:               Very nice. That brings us already, to the last original paper. Into the in-hospital setting and it talks about time to epinephrine. That's nice. We've got time to balloon and time to door and and now we've got time to epinephrine. Tell us about this one.

Dr. Mark Lane:                  This was a very nice study from the guidelines database. This is a data base that the HA is using to evaluate resuscitation in hospitals. In this database, the investigators looked at times to the epinephrine administration and then overall patient survival for the hospitals. What they found is that there was wide variability in the time to first epinephrine dose. The HA and other counsels have recommended that it be given as soon as possible or early-on in resuscitation and in this database 12.7% of patients had delays greater than five minutes to epinephrine.

                                                What importantly they showed, when you looked at the hospital's overall time to epinephrine administration and the hospital's overall resuscitation survival rates, they were inversely proportional. That is, the longer that hospitals took to give the first dose of epinephrine, the lower their survival rate. This really leads to a very important question, is it the delay in epinephrine administration that makes the difference between these good functioning hospitals and poor functioning hospitals, or is it that the delay to epinephrine administration is really a surrogate for poor CPR performance. I suspect that both of them could be true, although I suspect the second one is probably a higher likelihood.

Dr. Carolyn Lam:               Congratulations again on this amazing issue with extremely important take-home messages just from the original papers. Were there other papers you wanted to highlight in this issue?

Dr. Mark Lane:                  Yeah, there were three research letters and this is a newer type thing for SERP. These are original manuscripts but in a very succinct fashion in that they're making a single point. I actually thought these three research papers were very interesting also. One was on the mechanical CPR in the cares database and in this paper they actually showed that mechanical CPR was associated with poor outcomes in resuscitation so a paper well worth reading. In another paper from France looked at pulmonary embolism related to sudden cardiac death and what they found is that PEs were present in a significant percentage of people who had sudden cardiac arrest and again if you had a non-shockable rhythm, female, prior thromboembolism or absence of heart disease you were more likely to have a pulmonary embolism.

                                                The final research letter looked at ticagrelor versus clopidogrel in comatose patients undergoing PCI, a randomized study. Succinct paper well worth reading. In addition to those three research letters, there were four frames of reference. These are more a personal perspective on resuscitation and resuscitation signs over time and interesting reading, all four of them.

Dr. Carolyn Lam:               Mark, that was a beautiful summary and I am sure you've whet the appetites of all the listeners to just grab hold of this issue. Thank you so much for joining me today. Thank you listeners for tuning in and don't forget to tune in next week.

Dec 12, 2016

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. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal.

The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms.

Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo.

In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases.

The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking.

First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders.

The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers.

Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers.

The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation.

These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways.

The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States.

Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model.

In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman.

The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction.

The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial.

Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level.

Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level?

We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims.

Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events?

Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard.

Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find?

Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25.

Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions?

Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example.

Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses?

Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here.

I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50?

One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you.

We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies.

Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred.

Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall.

As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs?

That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial.

Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help.

Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.

Dec 5, 2016

Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion is regarding the exciting results of the masked hypertension study showing that clinical blood pressure underestimates ambulatory blood pressure, but first here's your summary of this week's issue.

The first study reviews the largest clinical experience so far with pulmonary vein stenosis following ablation for atrial fibrillation. First author Dr. Fender, corresponding author Dr. Packer and colleagues from Mayo Clinic Rochester, Minnesota evaluated the presentation of 124 patients with severe pulmonary stenosis between 2000 and 2014 and examined the risk for re-stenosis after intervention utilizing either balloon angioplasty alone or balloon angioplasty with stenting. All 124 patients were identified as having severe pulmonary vein stenosis by CT in 219 veins. 82% were symptomatic at diagnosis with the most common symptoms being dyspnea, cough, fatigue and decreased exercise tolerance. 92 veins were treated with balloon angioplasty, 86 with stenting and 41 veins were not intervened on. The acute procedural success rate was 94% and did not differ by initial management. Overall, 42% of veins developed re-stenosis, including 27% of veins treated with stenting and 57% of veins treated with balloon angioplasty.

The three-year overall rate of re-stenosis was 37% with 49% of balloon angioplasty treated veins compared to 25% of stented veins developing re-stenosis. This was a difference that remained significant even after adjusting for age, CHADS2 VASC score, hypertension and time period of the study with an adjusted [inaudible 00:02:30] ratio of 2.46 for risk of re-stenosis with balloon angioplasty versus stenting. In summary, this study shows that the risk for pulmonary vein re-stenosis is significant following atrial fibrillation ablation. The diagnosis is challenging due to non-specific symptoms and while there is no difference in acute success by type of initial intervention, stenting significantly reduces the risk of subsequent pulmonary vein re-stenosis compared to balloon angioplasty.

The next paper shows that the index of microvascular resistance, which is a novel invasive mreasure of coronary microvascular function, has emerging clinical utility as a test for the efficacy of myocardial re-perfusion in invasively managed patients with acute ST elevation myocardial infarction. In this study by first author Dr. [Carrick 00:03:30], corresponding author Dr. Barry and colleagues from the University of Glasgow in Scotland, index of microvascular resistance and coronary flow reserve were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST elevation myocardial infarction. Authors found that compared with standard clinical measures of the efficacy of myocardial re-perfusion, such as ischemic time, ST segment elevation and angiographic blush grade, the index of microvascular resistance was more consistently and strongly associated with myocardial hemorrhage, microvascular obstruction, changes in left ventricular ejection fraction and left ventricular end diastolic volume at six months as well as all caused death of heart failure during the median follow up of 845 days.

In fact, compared with an index of microvascular resistance greater than 40, the combination of this index and coronary flow reserve less than two did not have incremental prognostic value. The take-home message is therefore that an index of microvascular resistance above 40 represents a prognostically validated reference test for failed myocardial re-perfusion at the end of primary percutaneous coronary intervention. This study supports further research into microvascular resistance based therapeutic strategies in these patients.

The next study provides experimental data regarding molecular mechanisms underlying calcific aortic valve disease. First author, Dr. Haji, and corresponding authors Dr. Matthew and [Bose 00:05:24] from the Quebec Heart and Lung Institute in Canada performed genomic profiling and in-depth functional assays in human aortic valves. They demonstrated for the first time that the promotor region of the long non-coding RNA H19 is hypomethylated in patients with calcific aortic valve disease. This hypomethylation in turn increases H19 expression in the valve interstitial cells where it prevents Notch 1 transcription by blocking or out-competing P53’s recruitment to the Notch 1 promotor. Thus, H19 appears to be the missing link connecting Notch 1 to idiopathic calcific aortic valve disease. It may therefore represent a novel target in calcific aortic valve disease to decrease osteogenic activity in the aortic valve.

The next paper describes the largest cohort of mycotic abdominal aortic aneurysms to date and is from Dr. [Sorelias 00:06:37] and colleagues of Uppsala University in Sweden.  These authors identified all patients treated for mycotic abdominal aortic aneurysms in Sweden between 1994 and 2014. Among the 132 patients, they noted that the preferred operative technique shifted from open repair to endovascular repair after 2001 with the proportion treated with endovascular repair increasing from 0% in 1994 to 2000 to 60% in the 2008 to 2014 period. Survival at three months was lower for open repair compared to endovascular repair at 74% versus 96% respectively with a similar trend present at one year. A propensity score adjusted analysis confirmed the early better survival associated with endovascular repair. During a median follow up of 36 months for open repair and 41 months for endovascular repair. There was no difference in long-term survival, infection-related complications or re-operation. The take-home message is that endovascular repair appears to be a durable surgical option for treatment of mycotic abdominal aortic aneurysms.

The final study provides insights into the molecular mechanisms by which aldosterone triggers inflammation and highlights the particular role of NLRP3 inflammasome, which is a pivotal immune sensor that recognizes endogenous danger signals and triggers sterile inflammation. Authors Dr. Bruden [Esimento 00:08:32], Dr. [Tostes 00:08:33] and colleagues from the University of Sao Paulo in Brazil analyzed vascular function and inflammatory profiles of wild-type NLRP3 knockout, caspase-1 knockout and interleukin-1 receptor knockout mice, all treated with vehicle or aldosterone while receiving 1% saline. They found that mice lacking the interleukin-1 beta receptor or lacking inflammasome components such as NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In-vitro, aldosterone stimulated NLRP3-dependent interleukin-1 beta secretion by bone marrow derived macrophages. Chimeric mice reconstituted with NLRP3 deficient hematopoietic cells showed that NLRP3 in immune cells mediated the aldosterone-induced vascular damage.

In addition, aldosterone increased the expressions of NLRP3, caspase-1 and mature interleukin-1 beta in human peripheral blood mononuclear cells. Finally, hypertensive patients exhibited increased activity of NLRP3 inflammasome. Together these data demonstrate that NLRP3 inflammasome via activation of interleukin-1 receptor is critically involved in the deleterious vascular effects of aldosterone, thus NLRP3 is a potential target for therapeutic interventions in conditions with high aldosterone levels.

That wraps it up for our summaries. Now for our feature discussion.

On today’s podcast we are going to be discussing the very important issue of masked hypertension. This is an issue that gets a lot less attention than I think compared to white coat hypertension. I’m so pleased to have the first and corresponding author of the masked hypertension study, Dr. Joseph Schwartz, from Stony Brook University and Columbia University in New York. Welcome to the show, Joe.

Dr. J. Schwartz:
My pleasure. I’m delighted to join you.

Dr. Carolyn Lam:
We have a regular on the show today as well, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back Wanpen.

Dr. Wanpen V.:
Thank you so much. Happy to be here.

Dr. Carolyn Lam:
Joe, I want to start by addressing the common misperception that ambulatory blood pressure is usually lower than clinical blood pressure. That seems to make a lot of sense to us clinically because, for example, I always use ambulatory blood pressure to diagnose white coat hypertension and so the assumption there is that my clinically measured blood pressure is higher than what I’m going to be finding if this patient measures the blood pressure on an ambulatory 24-hour basis. It’s also from the cutoffs that we use. For example, ambulatory blood pressure we use a 24-hour cutoff of 130/80 to make the diagnosis whereas with clinical blood pressure we use a cutoff of 140/90 so all of this kind of reinforces that ambulatory blood pressure is usually lower. Your study, though, tells us otherwise so please fill us in here.

 Dr. J. Schwartz:
You're right that in the doctor's office there are a certain set of people who probably get anxious when they're around a doctor and with that anxiety may cause a temporary increase in their blood pressure, a temporary elevation, and that's the basis of where we think white coat hypertension comes from. That's a very widespread belief among doctors and it's even been in previous guidelines, there have been statements to that effect. When I talk to people out in the general public and tell them I'm doing a study comparing blood pressure out in the real world compared to blood pressure in the doctor's office, all of them tell me, "Well, usually when I'm in a doctor's office that's a relatively calm period for me unless there's really something wrong with me and out in the everyday world I have to face a variety of stressors. I have deadlines. I have places I need to get to. Sometimes I have people yelling at me. Sometimes I'm just in a hurry."

All these things elevate your blood pressure out in the real world and so when we were trying to recruit people for the study, and we were very agnostic in recruiting them, telling them that we were interested in the differences in blood pressures between the doctor's office and the ambulatory blood pressure and they might go in either direction. When I told them about the fact that their ambulatory blood pressure or real world blood pressure might be higher than in the doctor's office, the vast majority of people nodded affirmatively and said, "It wouldn't surprise me at all."

Dr. Carolyn Lam:
Could you define masked hypertension compared to white coat hypertension and tell us a little bit about the population you studied.

Dr. J. Schwartz:
Sure. First with the definition. I'm going to say something a little bit different from something you said before. You mentioned cutoffs that we typically used for ambulatory blood pressure of 130/80 and those are the cutoffs that are used if you compute an average blood pressure over the entire 24 hours. What many people do, and what we did for this study, was compare the average blood pressure when people were awake to their blood pressure in the doctor's office because obviously in the doctor's office everybody is awake. The typical cutoffs there are 135/85, recommended by numerous guidelines in this country and with our international collaborators. The definition of masked hypertension is having a blood pressure in the clinic setting that's below 140/90 but having an ambulatory blood pressure where either the systolic blood pressure is above 135 or the diastolic is above 85 millimeters of mercury.

In terms of the sample, for years I've had a particular strategy for trying to recruit participants. I do worksite-based studies and so I identify large organizations that will allow me to recruit their employees and then what we did for this study is go to individual departments, both here at Stony Brook University, at Columbia University, at a residential veterans' home that's affiliated with Stony Brook University and then also at a local private hedge fund management company. We would go to these sites, I talk to the head of a department and tell them a little bit about masked hypertension and what the study was about and ask them if they would be willing to have their employees participate in the study. Once I had the okay from the department head then we would conduct public health screenings, blood pressure screenings. My staff and I would go into the department for multiple days and invite anybody who was interested to have their blood pressure taken on site and while we were taking those blood pressures carefully.

The proper way to take those is to take three readings and leave a minute or two interval between them and rather than just have silence then between the readings we would tell them a little bit about our study. At the end of the study if they didn't have extremely high blood pressure and were not taking blood pressure medication we would ask them if they might be interested in participating in the study that we just described. That's how we identified potential participants and about 2/3 of the people that we talked to who looked eligible indeed chose to participate.

Dr. J. Schwartz:
The one other thing I might mention that I think we mentioned, I hope we mentioned as a limitation of the study, is that everybody in the study had health insurance and at least until recently there were very large portions of the population that didn't have health insurance, everybody by virtue of their employment by the organizations that participated in the study, did have employer-based health insurance.

Dr. Carolyn Lam:
Thanks for clarifying the population so well. Could you just give us the top line of your findings. How big a difference did you find, which direction and that intriguing effect of age?

Dr. J. Schwartz:
Sure. The first thing we found is that on average the systolic blood pressure is seven millimeters mercury higher out in everyday life than it is in the clinic setting where we take our clinic readings. I should mention that unlike most studies, and all studies at the time that we began our study, we brought people in three separate times to take the clinic blood pressure. Up until that, almost all of the studies of ambulatory blood pressure monitoring only had clinic blood pressures from a single visit. I think we have a very reliable measure of the clinic blood pressure as well as reliable measure of ambulatory blood pressure. We see a seven millimeter difference in the systolic blood pressure and a 2 millimeter difference, again the ambulatory being higher for diastolic blood pressure.

What's more remarkable is if you think about what's a sizable difference. If you think if we perhaps somewhat arbitrarily say 10 millimeters of systolic blood pressure is a large difference. More than 35% of the population has an ambulatory blood pressure that is more than 10 millimeters higher than their clinic blood pressure whereas only 3% of our sample had that large a difference in the opposite direction, what many people would call a white coat effect. It's more than a 10 to 1 difference in numbers of people who have elevated ambulatory versus elevated clinic.

You asked me to mention something about the age difference. When you look at how that difference in systolic blood pressure varies by age, it's quite a bit larger for people who are younger. If you're under 30 the difference is, on average, 10 millimeters rather than seven millimeters and if you go up as you approach 60 years of age or so the difference becomes relatively small, perhaps in the neighborhood of two millimeters. We don't have enough people because it's a working population over 65 to say very much about what would happen. In fairness to prior research, which often is on older populations and particularly hypertensive populations, the studies that have historically shown that ambulatory blood pressure tends to be lower than clinic blood pressure are in these older populations and populations that have elevated blood pressure to start with.

My speculation there, and you haven't asked me to mention it but I will, is that older people and those with hypertension have a reason to be more nervous or more anxious when they go to the doctor than people who are not taking medication and probably don't even know that they have hypertension. People who are just being screened perhaps during a routine physical for the possibility of hypertension, because the doctors take a blood pressure reading every time you go in, they're doing that in order to see whether you might have hypertension, but most people who are going in for what we call a well patient visit are not nervous about their blood pressure being high.

Dr. Carolyn Lam:
I have to say, the take-home message for me when I read this was, I am not paying enough attention to masked hypertension and then another thing was, maybe I need to think about more white coat hypertension in the older and masked hypertension in the younger. Wanpen, do you think it's as simple as that? What were your take-home messages?

Dr. Wanpen V.:
I think this is a very important study that examines this in a systematic way. I'm not surprised that Joe found as much masked hypertension here. I think that he's absolutely right. We looked at this in Dallas Heart Study as well recently and we found that in the population-based sample in Dallas almost 20% of people have masked hypertension and white coat we found only like 3% and the average in the Dallas Heart Study was very close to those samples, about mid-40s. I think that's a very important finding in that the people with masked hypertension would not be suspected otherwise to have problems. Also, in the Dallas Heart Study they used home readings but Dr. Schwartz used ambulatory blood pressure monitoring. Unless extra out of office monitoring is being done we will totally miss these people who are more likely to have target organ damage from high blood pressure. I think that's absolutely important.

Dr. Carolyn Lam:
Actually, Wanpen you brought up something I was going to bring up as well. Where does home blood pressure fit in with this? Do you think it's home blood pressure versus ambulatory blood pressure?

Dr. Wanpen V.:
The US Preventive Services Task Force has issued a little bit of recommendations recently that we need to either use ambulatory blood pressure monitoring or home blood pressure monitoring to confirm diagnosis of hypertension in the office. If someone shows up with elevated blood pressure in the office either home blood pressure or ambulatory blood pressure needs to be done. If we just followed that guidelines we're still going to miss people with masked hypertension because by definition they don't have elevated blood pressure in the office. I think that from these findings and Dr. Schwartz' study I think to catch these people we really need to pay attention to people with pre-hypertension type of blood pressure because it seems like those are the group that has the most probability to have elevated ambulatory blood pressure so anyone with borderline blood pressure in the clinic, those are the ones who the doctor needs to tell the patient to monitor blood pressure at home or order ambulatory blood pressure themselves if that's available in their facility.

Dr. Carolyn Lam:
Wanpen, I fully agree. What an important message. Joe, I'd like to give you the final word but I'd love to hear how you have maybe taken this into your own practice.

Dr. J. Schwartz:
I think we mostly focused on and indeed the paper mostly focuses on the difference between clinic blood pressure and ambulatory blood pressure. When we talk about the young people, the young people have a bigger difference but those differences are for the most part all in the normal range. You might see a 10- or a 12-point difference but it might be that the ambulatory is 124 and the clinic is 112 and no doctor is going to worry about that very much. There are really always two things that we're trying to look at simultaneously: The first is what is that difference between the ambulatory and the clinic, but the second is for whom does the clinic stay under the threshold for diagnosis of hypertension but the ambulatory is over? That's the diagnosis of masked hypertension.

We haven't said it today so I'll say it: Of those people who had normal clinic blood pressures averaged across three repeated visits, 15.7% of them had elevated ambulatory blood pressure and would have been diagnosed as having hypertension based on their average daytime ambulatory blood pressure reading. That's one message.

The last message is unfortunately there is almost no research yet telling us what we should do in terms of treating people with masked hypertension. We are now at the point where we can identify these people and we're also at the point where we now know that there are a lot of such people and we don't even have any research to base guidelines on for deciding what we should do with them. The most obvious thing is to recommend lifestyle changes. If they're overweight we could suggest that they lose weight. We could suggest that they exercise more. We might think about treating some of those people, especially if their ambulatory blood pressure is well above 140/90. There are no statements out in the literature by any of the organizations, and in fact there's no research examining whether there's a benefit or not a benefit to perhaps putting some of those people on medications. I think that's a big question that future research needs to address.

Dr. Carolyn Lam:
Joe, thank you so much. I think your last statements just really emphasize how important this paper is. It increases awareness and it's going to open the door to much more needed research in this area. Thank you so much. Thank you Joe and Wanpen for being on the show today.

Thank you listeners for joining us. Don't forget to join us next week for even more news and exciting discussions.


Nov 28, 2016


Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.

The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.

Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.

The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.

However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.

In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.

The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.

A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.

The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.

Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.

Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.

Speaker 2:
Thank you very much.

Carolyn Lam:
We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.

Speaker 3:
Hi Carolyn, thanks for having me.

Carolyn Lam:
So Jonas, could you start off by telling us why you did this study and what you found?

Speaker 2:
We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.

Carolyn Lam:
Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.

Speaker 2:
It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.

Carolyn Lam:
Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?

Speaker 2:
We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.

Carolyn Lam:
Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?

Speaker 3:
I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.

But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.

Carolyn Lam:
Actually, Jonas could you let us know is there any sex differences in the performance of the score?


Speaker 2:

There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.

Carolyn Lam:
That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.

Speaker 3:
We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.

Speaker 2:
We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.

Carolyn Lam:
It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.

Speaker 3:
Yeah, no absolutely. And I think that's great.

Carolyn Lam:
Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?

Speaker 2:
We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.

Carolyn Lam:
That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.

Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.


Nov 21, 2016

Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...

In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...

The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.

The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...

The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.

They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.

The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...

The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.

They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...

The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.

In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.

Those were the highlights from this week's issues. And now for our feature paper ...

We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.

Thank you for having me.

We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.

Yes, hello Carolyn, hello Zuzana.

So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?

The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.

Could you, maybe now, clearly describe what you did in this study and what were your findings?

The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.

So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.

So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]

That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.

Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.

Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?

First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.

Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.

The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.

In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?

Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.

The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.

It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.

Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...

Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...


Nov 14, 2016

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. In today's podcast interview we will be discussing the ruling in and ruling out of myocardial infarction with the European Society of Cardiology 1-hour algorithm. Stay tuned for a discussion of new data and controversies on this hot topic. Now, here's a summary of this weeks issue.

The first paper brings us one step closer to the ultimate goal of cardiac tissue engineering. That is to replicate functional human myocardium in vitro. In this study, by first author Dr. Ruan, corresponding authors Dr. Murry and Regnier from the Institute for Stem Cell and Regenerative Medicine and University of Washington, authors recognize that human-induced pluripotant stem cells, or iPSC-derived cardiomyocytes, really provide a cell source for cardiac tissue engineering. However, their immaturity limits their potential applications. Hence, they sought to study the effect of mechanical conditioning and electrical pacing on the maturation of iPSC-derived cardiac tissues.

They found that after two weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility, tensile strength, construct alignment, cell size, and SERCA2 expression. When electrical pacing was combined with static stress conditioning the tissue showed an additional increase in force production and further increases in expression of RyR2 and SERCA2. These studies really demonstrate that electrical pacing and mechanical stimulation promote the maturation of the structural, mechanical, and force generation properties of iPSC-derived cardiac tissues and constitute a really important contribution to cardiac tissue engineering.

The next study is the first large-scale, nationwide, population-based investigation of the association between congenital heart defects and any placental measure. This study by Dr. [Matheson 00:02:27] and colleagues from Aarhus University Hospital in Denmark, included all 924,422 live-born Danish singletons from 1997 to 2011. Congenital heart defects was present in 7,569 newborns. The authors compared the mean differences in placental weight between newborns with and without congenital heart defects and found that only three specific subgroups of congenital heart defects were associated with measures of impaired placental growth. These included Tetralogy of Fallot, double outlet right ventricle, and major ventricular septal defects. In these subgroups, the mean deviations from the population mean head circumference and birth weights were reduced by up to 66%, with adjustment for placental weight. In other words, up to two thirds of the deviations in fetal growth, including fetal cerebral growth, may be related to the impaired placental growth. The present work provides an important contribution to the existing knowledge on the association between congenital heart defects and placental anomalies as well as the possible importance for fetal growth in this population.

The next study provides an up-to-date evaluation of the cost effectiveness of antibiotic prophylaxis in the prevention of infective endocarditis. In this study by first author Dr. Franklin, corresponding author Dr. Thornhill, and colleagues from the University of Sheffield, the cost effectiveness of antibiotic prophylaxis, namely single dose amoxicillin or clindamycin, in patients at risk of infective endocarditis. They did this using, firstly, recent estimates of the effect of antibiotic prophylaxis on infective endocarditis in the English population; secondly, rates of antibiotic adverse drug reactions; and thirdly, estimates of the probability of developing infective endocarditis following dental procedures derived from French data. All this as foundation for analysis of cost and health benefits.

A decision analytic cost effectiveness model was used based on the decision model by the National Institute for Health and Care Excellence, or NICE, that was used to inform the 2008 guidelines. The authors found that antibiotic prophylaxis was less costly and more effective than no antibiotic prophylaxis for all patients at risk for infective endocarditis. In fact, if antibiotic prophylaxis was reinstated in England for those at moderate or high risk of infective endocarditis, it could save 5.5 to 8.2 million pounds and result in health gains of more than 2,600 quality-adjusted life years. Antibiotic prophylaxis was even more cost effective for those at high risk of infective endocarditis, being cost effective even if only on 1.44 cases of infective endocarditis was prevented per year. In summary, these updated findings really support the cost effectiveness of guidelines recommending antibiotic prophylaxis use, particularly in high risk individuals.

The last study provides data on long term cardiac mortality among survivors of cancer diagnosed in teenagers and young adults in the largest population-based cohort to date. Furthermore, the study provided, for the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 to 39 years. For example, survivors of Hodgkin lymphoma, lung cancer, acute myeloid leukemia, non-Hodgkin lymphoma, and CNS tumors experience 1.3 to 3.8 times the population-based mortality rates. This study provides important insight into the cardiotoxicity of the treatments given in the past to teenagers and young adults with each individual type of cancer and importantly, provides an initial basis for developing evidence-based follow up guidelines.

Those were you summaries. Now for our feature interview.

Our feature paper today discusses the hot and controversial topic of ruling in and ruling out myocardial infarction with the European Society of Cardiology 1-hour algorithm. I'm so excited to have with us the corresponding author of the paper that really represents the first multi-center external validation of these ESC guidelines for MI and the first multi-centered direct comparison of the performance of the algorithm with high-sensitivity troponin I and high-sensitivity troponin T assays. This would be Dr. Martin Than from Christ Church Hospital in New Zealand. Welcome Martin.

Thank you very much. It's a great pleasure for me to be able to join everybody and talk here.

It's great to have you. We also have with us the editorialist on this paper, Dr. Allan Jaffe from Mayo Clinic, Rochester, Minnesota. Allen, it's so good to hear your voice again.

Good to talk to you again too, Carolyn.

Finally, we have Dr. Deborah Diercks, Associate Editor from UT Southwestern. Welcome Deb.

Oh, it's good to be here and I'm looking forward to the conversation and what we're going to learn from these two gentlemen.

Absolutely. You know what? I'm going to start with Martin. I love the way to set up your paper. You very correctly pointed out that there's a tension in that ED physicians require really high sensitivity to confidently rule out MI and send patients home, whereas cardiologists do not want high proportion of false positives because we don't want false high risk to lead to invasive testing. I just love, if you could start by telling us how the ESC 1-hour algorithm fits into all this and what you were trying to do in your study.

I heard Deb Diercks on the phone as well, who's a very respected emergency physician in this area, and I think we would both say that we have a certain bias in our perspective on this, which is of course we are the people at the end of the day that have to send people home when they present with chest pain and possible myocardial infarction. We are also, of course, the people that take the fall if there are any mistakes made. Historically, people have not been very kind to emergency physicians who miss such a diagnosis. It's an extremely high source of medical legal action in the United States and, in fact, worldwide. So we're somewhat paranoid as a speciality about missing cases of myocardial infarction because at the end of the day, the worst thing that can possibly happen is for you to send someone home who comes to harm from the very clinical complaint for which they came to you for help. We want to avoid that at all costs and that was the basis behind us trying to put together this paper.

Soon after the ESC guidelines come back and I returned from London, where they were announced at the conference, to New Zealand, I received quite a lot of phone calls and correspondence saying, "Okay, we see these new ESC guidelines are out. When are we going to start introducing them?". I immediately wanted to say, "Well, the key thing is to understand how they would work, how they would be implemented, and whether they'd work in my own setting" because if we want to implement them in New Zealand or Australasia, we would want to double-check on that first. That's the basis and the philosophy behind the manuscript.

Tell us what you found.

As Allan will be the first to point out, I think there are a number of flaws in the data we had available to us that allowed us to do this analysis, but based on the concept that when we've surveyed emergency medicine physicians, the sensitivity that was wanted was at least 99% if not higher. We found that neither of the algorithms produced that level of sensitivity, although the algorithm based on hsTnI was very close. I think it's 98.8%, so that was very good. Reasonably wide confidence intervals on that. The hsTnT algorithm performed slightly less well with a sensitivity around 97%. I guess, if I was to start with an a priori question, which is did we reach a standard of 99%, then our answer to this was, in one case, not quite, and the other case, no, we probably didn't. We said that if you wanted to use a metric of negative predictive value, which I know a lot of people do, then there was actually very good negative predictive value in the high 99 percentage range for both pathways.

Do you mind if I stretch you a little bit and ask you to describe exactly what you did in the cohorts? You were saying that there were some imperfections. Maybe you'd like to tell us a little bit about that.

Absolutely. As always, when you're writing a paper, you look back and you always feel there are far too many imperfections, but I guess the principle one I would say that's been noted is that we had samples done on arrival and the algorithm itself specifies a [inaudible 00:11:43] one-hour second sample. We didn't have those specimens, so we had to base our data analysis on samples done either at 90 minutes afterwards or two hours afterward. It's clearly not being tested exactly as it was written, although one could argue that that slightly delayed sampling is potentially reflective of real life, where it's very hard to hit a one hour mark in a busy emergency department, and two, where the slight delay in getting the samples would actually allow more time for a troponin to rise and therefore give a chance of providing a better sensitivity.

I think the other I guess key flaw is that of course, the people present to emergency departments at different time frames following the onset of their symptoms. There's been some valid concern raised that algorithms may not necessarily perform as well in very early presenters. In fact, that is something that's being emphasized now in the ESC guidelines.

Right. Allan, I loved your editorial. You did mention a couple of these points. Would you like to maybe clarify your view of this?

I think that there are two or three terribly important issues. We all would like to have very facile algorithms. Particularly given removing the high sensitivity, the idea would be gee, wouldn't it be nice to have something really simple that works perfectly? If you look at the validation and the way the algorithm has been put together, immediately there are some concerns that people ought to have and that at least we tried to point out, that were important. One of them Martin has already discussed a little bit, which is one looks at most of the validation studies. There are very few patients who are evaluated very early after the onset of their symptoms. That's a potential problem because the overlap, since they use very low values or very small change, that there could be, with people who have real disease, is in those very early presenters. The initial algorithm from the ESC used both a very low level troponin and a set of change criteria. Actually when they published those criteria, they changed that and eliminated, at least for the first three hours, the very low values. If one looks at Martin's study, it was again, the very early patients who potentially may have been missed. I think we need more data before we go ahead and acknowledge that this will be working for those early presenters.

There are two other problems with the population that we need to be careful about. It's been well known that when you have a negative troponin at six hours all the way back to [Chrisann's 00:14:26] original article in the '90s, that you're pretty safe. The population that you'd like to look at really are the patients who, after two hours in Martin's study, since he took a little bit longer given the logistics that were there in New Zealand and Australia, is the patient who came in at four hours because by six, they're actually meeting that six-hour criteria. When you have a large number of other such patients, you simply add noise and it makes you sensitivity look better, but it's not necessarily the case that that give you that same degree of reassurance that ED physicians would like.

The third population-related issue is that you'd like to do this in all-comers. The protocol was developed for chest pain patients, but there are a variety of patients in whom we evaluate myocardial infarction in, who may not qualify for that. The patients who are critically ill, for example, who may have Type 2 infarctions. The individuals who may come in who are very elderly, who often don't have chest pain so we don't identify them necessarily as a rule out. Interestingly, if you start thinking about those groups, they tend to have much higher troponin, so they may well skew the cut-offs that are used and change the algorithm.

In truth, we don't want more than one way of defining myocardial infarction. We only want one algorithm for ruling in and ruling out. Having an all-comers study, in my way of thinking, would be important. In that same regard, let me point out that you can rule out myocardial infarction because you don't have an acutely changing pattern of troponin elevations, but what we really rule in myocardial infarction? You rule in acute cardiac injury. Could be myocarditis, could a apical ballooning. There are a whole variety of other types of disease entities that could be involved and the arbitrary value of 52 that was put in the algorithm really, I think, is much too low for two reasons. One reason, because it didn't include all-comers. A second reason is because of the way in which the comparison between troponin T and I were done. I'll talk about that in just a moment. I would point out that using a different assay, the troponin I assay, in another set of studies, another group from Hamburg has suggested that very different metrics would be much better.

The final thing to say about extrapolation between the assays, and then I have some suggestions about what would make this better if you want to go there now or we can wait, is the comparison and the way in which the metrics for troponin I were developed really weren't by using troponin I as a gold standard. It was by taking and using troponin T as the gold standard for the diagnosis, then thawing samples many years later, running troponin I, and then extrapolating from the gold standard of troponin T to troponin I. Well, there's several problems with that. Number one is that appropriate comparisons should be fresh samples. Fresh samples. In addition, we believe, from the way in which we think about high sensitivity, which may not be correct, that the troponin I assay should be more sensitive and in [inaudible 00:18:05] fact, in the papers that were done validating this approach or attempting to describe the approach, troponin T was wildly more sensitive than was troponin T. We're extrapolating some data that doesn't sort of fit the way in which the information we have, it would mean all of the troponin I validation studies are incorrect.

That's where those numbers came from and even more problematic are the change numbers, which are very low. For the troponin T assay, they're three in five between ruling in and ruling out, which if you look at the assay imprecision, is something the assay can't do. Now you're extrapolating them in a very, very loose manor to troponin I and making them even lower. Those are not doable sorts of things. There's a real problem with the way in which the metrics for troponin I, even though it performed well in this circumstance, ended up being developed. I think all of those things need to be taken into account when we look at the results of the study. The results that Martin and his group got are very similar to the other validation studies that have been done because they've all done it pretty much that same way. There's not a surprise that their validation is similar, but I think unfortunately, we didn't have an opportunity to unmask, in a data-driven way, the problems that I just described.

Thank you Allan. Deborah, if you could share your thoughts on this.

Martin raises some valid issues. That if something goes out as an algorithm, people want to use it. That use needs to be predicated on does it work in their patient population and is it feasible in the time frame and can it be adopted safely and what the indications are. In the emergency department, the value really is the negative predictive value because we want to be able to safely send people home. That's where rapidity of an evaluation is very important.

The other issue raised was exactly what Dr. Jaffe talked about. Does the algorithm itself reflect what we really need? Can you validate something that was created by the scientific way, but really a combination of a lot of information? Are the thresholds really valid themselves? That's the challenge with it. I think what you heard here are kind of two issues we struggle with it. We have a very respectable organization putting out an algorithm that is scientifically based and we want to adopt early, but there are questions on both sides of the issue on whether it can be adapted into real-world clinical practice on a global nature where prevalence of disease is different and the patients it'll be applied to vary, whether it's been on time of presentation or overall demographics.

Also on the scientific side, on the assays itself, are we using the right cutoff? Especially when we're looking at deltas and looking at such a rapid change. It's very nice to hear both of those points so eloquently described today during the discussion.

Thanks Deb. I fully agree. Hence, again, the importance of this paper. Martin, I'd love to hear your responses to Allan's comments and then also share with us, what's the take-home message for you as a clinician? How are you applying what you just found?

The guidelines are good on the right line, it's just as I said, they may not necessarily translate to all other environments. I guess that's my take-home message to myself, which was if I were to look at my own data from my own center, in Christ Church, and the way it's applied here, if I had applied the ESC guidelines and it had met the metrics which I was satisfied with, which I guess would be a very high sensitivity for me in terms of rule out, then I would actually seriously consider implementing it in my own center. It didn't reach that threshold so now I want to try and refine or explore further how I could allow the guidelines to do that. For example, one way that, and this is in the guidelines, but not necessarily in the flow chart, is the importance of applying clinical judgment and clinical findings with the results of the algorithm. I think that's a very important step in it. For example, if I was going to apply this in my own center, I'd want to be setting out clearly for the doctors concerned, how one would incorporate clinical judgment rather than it being a very subjective thing, which might vary significantly between a junior doctor or a far more experienced one.

I guess the take home message for me is this. The ESC guidelines are a very important piece of work. They've been robustly developed. For people who want to implement them, I'm no saying don't use them at all. I'm just saying that, you know, just think about carefully how you would use them and check whether you think they're appropriate for your setting.

That's great. Allan, what about you? What are your thoughts on how this may be applied in clinical practice and what more needs to be done?

I think we need to have a real trial where patients are managed based on the results of these approaches rather than more observational studies. I would argue that those management trials that involve an all-comers sort of population, so we are comprehensive, and should also interrogate whether or not the protocol itself is adequate or whether or not it requires follow-up to meet the metrics that have been proposed. I would point out that in the past, in the studies from the group from New Zealand and Martin Than particularly, have had very, very good follow-up. One at least needs to ask the question whether or not the algorithms that are proposed work perfectly without any follow-up or whether or not follow-up is an important component. We don't know that yet.

Thanks Allan. I'd love to give the final words to Deb. Take home messages?

You know, I think that we need to look at this as a positive in that we're looking at time frames that provide a rapid evaluation and the discussion is around safety. As long as we keep focused on appropriate evaluations for the patients and applying the right algorithm to the right patient, we're going to benefit the care of those we're really concerned about. I appreciate the work that both Martin and Allan both have done on really pointing out how we can do that in a great manor.

Thank you, all of you, for joining us today. I mean, it's been such an enlightening conversation. I'm sure the listeners have enjoyed it and thank you listeners for tuning in. Don't forget to tune in again next week.


Nov 7, 2016


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 for the National heart center and Duke National University of Singapore. Our podcast is really going around the world, and today's feature interview comes to you live from China. Where we will be discussing the prediction of ten year risks of cardiovascular disease in the Chinese population. So now to all our Chinese colleagues out there: Chinese dialect

First here's your summary of this week's journal. The first study challenges the assumption that all patients with vascular disease are at high risk of recurrent vascular events. First author Dr. Kasenbrud corresponding author Dr. Viceren and colleagues form the University Medical center Utric in the Netherlands, provide new data on the estimation of ten year risk of recurrent vascular events and a secondary prevention population. In other words, in patients with established cardiovascular disease they applied the second manifestations of arterial disease or 'smart' score for the ten year risk prediction of myocardial infarction, stoke or vascular death in more than six thousand-nine hundred Dutch patients with vascular diseases ranging for coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm and poly-vascular disease. Predictors included in the SMART risk score included age, sex, current smoking, diabetes, systolic blood pressure, total cholesterol, HGL cholesterol, presence of coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm, estimated glomariaol fruition rate, high sensitivity CRP and years since the first manifestation of vascular disease. They further externally validated the risk score in more than eighteen thousand four hundred patients with various types of vascular disease fro the TNT ideals Sparkle and Capri trials.

The overall findings was that the external performance of the SMART risk score was reasonable apart from over-estimation of risk in patients which a ten year risk of more than forty percent. What was striking was the substantial variation in the estimated ten year risk. The median ten year risk of a reoccurring major vascular event was 17 percent but this varied for less than 10 percent in 18 percent to more than 30 percent in 22 percent of patients.

The authors further estimated residual risk at guideline recommend targets by applying the relative risk reductions form meta-analysis to estimated risks for targets for systolic pressure, LDL, smoking, physical activity and use of anti-thrombotic agents. They found that if all modifiable risk factors were at guideline recommend targets only half of the patients would have ten year risk of less than 10 percent. Even with optimal treatment many patients with vascular disease appear to remain at more than a 20 percent or even more than 30 percent of a ten year risk.

The take home message is that a single secondary prevention strategy for all patients with vascular disease may not be appropriate. Instead novel risk stratification approaches may be helpful to individualize secondary prevention by identifying high risk patient which may derive the greatest benefit from novel interventions.










The next study provides experimental evidence that an indigenous-gastro transmitter hydrogen sulfide may potentially be a therapeutic target in diabetic patients with cardiovascular diseases. In this paper by first author Dr. Chen, corresponding author Dr.Kisher and Colleagues from the Louis Cat's school of medicine Temple University in Philadelphia. Authors aim to evaluate the role of hydrogen sulfide deficiency in diabetes induced bone marrow cell dysfunction and to examine the therapeutic effects of restoring hydrogen sulfide production in diabetic bone marrow cells on ischemic high limb injury in diabetic DBDB mice. They further specifically investigated the effects of hydrogen sulfide deficiency on the nitric oxide pathways under conditions of high glucose. They found that bone marrow cells for diabetic DBDB mice had decreased hydrogen sulfide production and lower levels cystathonine gamma lyaze which is the primary enzyme that produces hydrogen sulfide in the cardiovascular system. Administration of a stable hydrogen sulfide donor and over expression of cystathonine gamma lyaze in diabetic bone marrow cells restore their functional and restorative properties. Further more they demonstrated that the therapeutic actions of hydrogen sulfide were mediated by nitric oxide pathway involving endothelial nitric oxide synthase PT495.

In summary these results support the hypothesis that hydrogen sulfide deficiency plays critical role in diabetes induced bone marrow cell dysfunction and suggests that modulating hydrogen sulfide production in diabetic bone marrow cells may have transformational value in treating critical limbs ischemia.

The next study reinforces the importance of hypertension as a critical risk factor for inter-cerebral hemorrhage, and suggests that Blacks and Hispanics may be a particularly high risk. In this study by DR. Walsh and colleagues for the University of Cincinnati, authors conducted the largest case controlled study to date on treated and untreated hypertension as a risk factor for inter-cerebral hemorrhage. They also investigated whether there was variation by ethnicity. The ethnic racial variations of inter-cerebral hemorrhage or eriche study is a prospective multi-center case controlled study of inter-cerebral hemorrhage among Whites, Blacks and Hispanics. Cases were enrolled from 42 recruitment cites, controls were matched cases one to one by age, sex, ethnicity and metropolitan area. A total of 958 white, 880 black and 766 Hispanic cases of inter-cerebral hemorrhage were enrolled. Untreated hypertension was more highly prevalent in Blacks at almost 44 percent and Hispanics at almost 47 percent compared to whites at 33 percent. Treated hypertension was a significant independent risk factor and untreated hypertension was substantially greater risk factor for all three ethnic groups and across all locations. There was a striking interaction between ethnicity and risk of inter-cerebral hemorrhage, such that untreated hypertension conferred a greater risk of inter-cerebral hemorrhage in Blacks and Hispanics relative to Whites.











The nest study provides the first prospective multi-centered data on mortality and morbidity in rheumatic heart disease from low and middle income countries. First author Dr. Zulky, corresponding author Dr. Mayoci and authors from Gertrude hospital and University of Cape Town in South Africa present the results of two year follow up of the global rheumatic heart disease registry or remedy study in 3343 children and adults with rheumatic heart disease from 14 low and middle income countries. They found that although patients were young with a median age of only 28 years the 2 year case fatality rate was high at almost 17 percent. The median age at death was 28.7 years. Mortality was higher in low income and low middle income regions compared to upper middle income countries. Independent predictors of death was severe valve disease, more advanced functional class, atrial fibrillation and older age. Where as post primary education and female sex were associated with a lower risk of death. The authors carefully noted that apart from age and gender the independent risk factors for mortality such as severity of valve disease heart failure, atrial fibrillation and low education were all modifiable and thus they called for programs focused on the early detection and treatment on clinical rheumatic heart disease.

Well that's it for the summaries, now lets go over to China

For our feature interview today we are going all the way to Beijing at the great Wall meeting where we will be meeting authors as well as editors. So here we have first and corresponding author Professor {Dong Fen Gu} and co-author Professor {Sherliang} both from {Fu Y} hospital Chinese academy of medical sciences in Beijing. Welcome

Welcome we are so delighted to be interviewed by you

Dr. Carolyn Lam:

Thank you so much we are so excited to be talking about your paper predicting the ten year risks of cardiovascular disease in the Chinese population. And here we have as well editor in chief Dr. Joe Hill as well as Dr. Amid Kira digital strategies editor and associate editor. Gentlemen how is it in Beijing? And I hear that you have a Chinese greeting for everyone as well.

Joe Hill:
{Ni how} and {nuchme and senchmen}

Amid Kira:
I can't top that but I agree with what Joe said

Dr. Carolyn Lam:
Dr. Gu, could you please tell us what is it that is so different about cardiovascular disease in China compared to what we heard about in the western world.

Okay cardiovascular disease is both leading cause of death in China and in United States as well in European countries. However the patterns for components of cardiovascular disease including coronary arteries and stroke are still quite different in the Chinese populations compared united states. For example there are coronary arteries mortality rate in the united states is along the 100 thousand per year and this is the first leading cause of death in the united states. And for stroke the annual mortality rate is along 36 per 100 thousand in the united states populations. However in china the stroke mortality rate among Chinese populations is around the 160 per 100 thousand, so that almost 3.5 to 4 as high as in untied states. Obviously for our lifestyle in including battery behavior quite different you can easily identify one kind of difference in the united states and the Europe restaurants from Chinese restaurants and some western style restaurants you can figure it out.





And another example, smoking rate is major component for risk of cardiovascular disease it is very high in Chinese adult men. It over 50 percent right now but in the united states in the past 50 years it declined immensely. And around maybe less than around 20 percent and from the previous experiment from studies by Dr. Liu Chin from and my colleague Dr.WU they used the questions for predictions of coronary arteries compared to equations and also use the similar prediction model compares that its chemical cardiovascular disease from the united states population and the Chinese population. That to over estimation if we use the united states produced this kind of equation. So based on this kind of scenario we based on Chinese long term larger scales cohort to precede and study our own prediction model.

Dr. Carolyn Lam:
Wow that is really fascinating Dr. Gu and I really could not agree with you more because I sort of trained in the united states for quite some time and then I moved back to Singapore and saw for myself in Asia the tremendously high rates of stroke. I was also very struck by the relative youth of the patients suffering cardiovascular disease and the differences in risk factors, the smoking but not just that, obesity is almost defined on a different scale in our relatively sized smaller Chinese population compared to that in the western. Congratulations to you and your team for a successful amazing effort. Could you or Dr. Yang now just let us know what are your main findings.

Dr. Yang:





Well I think there are 2 major finding for our work. First we developed a new prediction risk model you know after analysis is for high risk score or equations released by AJ and ACC and is some other risk scores. We included 6 conditional risk factors in combination with our previous knowledge that included age, treated or untreated ISBP, total classical, HDLC current smoking and diabetes. So this traditional risk factors were set up as a base model and then we use the predefined statistical to include new additional variables they were Chinese special elements. Finally in our model there were rates as constraints and geographic region which means northern part versus the southern part in China and also organization is rural or urban area. And finally the forth one is family history as a CVD so this for additional variables in our model suggest that we maybe as a Chinese prediction and equations has something special. For example we feel more attention for central obesity in primary prevention in Chinese populations and also you know the norther part and the southern part there are large differences in the risk profiles. And so maybe according to our risk prediction model we pay more attentions for the residence living in northern part in China.

And then for the second points I think we found that PCE equation which shows for equations was not appropriate to predict ten year risk of in Chinese populations. For example in our revelation cohort we found that our model just slightly over predicts severity risk by 17 percent in Chinese man but when we use the PCE models released form AHA the over-estimation come to 50 percent so maybe equations from western populations are not appropriate to Chinese populations.

Dr. Carolyn Lam:
Thank you so much Dr. Yang I mean those are just such important findings applicable to a huge population in china, like you said. And just as important as the second point that the pooled equations derived from western populations may not be the most appropriate for certain other ethnic populations. I think that a very important message and that why we are so proud to be publishing this in Circulation. Could I ask then are you applying these new equations in your personal clinical practice?


Risk assessment is a fundamental components for prevention of ASSVD. In Chinese we question {turn the PA on} provide a valuable to identify high risk individuals in Chinese populations. And not with just complicated [inaudible 00:18:02] for further analysis. And propose three levels of groups of risk stratification could be identified by cut off 5 percent and 10 percent. So lower risk individuals with predicted activity risk of less than 5 percent should be offered lifestyle wise to maintain the lower risk status. While the moderate risk individual is predicted risk of 5 to 10 percentage for intensive therapeutic lifestyle change wit drug therapy if necessary. For the high individual risk high or large 10 percent teheraph of clinical aliment taken account for physicians recommendation should be required with therapy for the lifestyle modification. Then annually clinic up, including an echocardiographic information for carotid artery back and even for outer [inaudible 00:19:09] CT examinations for coronary artery are recommended. Also blood pressure, lipids, glucose measurement if necessary are suggest according to Chinese guideline. While cardiovascular disease prevention as well as for the epidemic of this kind a lines. For ACVD patients those are different kinds of risk assessment we could know whether their risk profile had been improved or be progressed so that appropriate clinical elements should be taken in clinical practice.

Dr. Carolyn Lam:
Thank you very much Dr. Gu so that just show that these findings are immediately clinically applicable and I trust that means you're suing it in your clinics too, and once again were so happy to be publishing this in Circulation so in the rest of the time in going to now direct questions at Joe and Amid.

How's China been? How are your chopstick skills and any word on how Circulation is being received there?

Joe Hill:
Well Carolyn its a delight to be here this is a bustling media that get better and better every year. In about 2 hours we have our first ever Circulation session, we brought several editors here to discuss the types of content that we are looking to publish, the type of work across prevention and population and electrophysiology of heart failure. This is an extraordinary media that is now internationally acclaimed and as we've heard here, the face of cardiovascular disease in Asia is changing. And as you pointed out 60percent of the human race lives in Asia and we want to do everything we can to be here on the ground, in Asia trying to address this curve that is already present and is worsening by the day.

Dr. Carolyn Lam:
Amid, you know you've seen the latest statistic on our podcasts and you highlighted that we have quite a number of listeners over there as well. Would you like to tell me how this is all blending it to the digital strategies and anything else you might want to highlight?

Amid Kira:
Sure its been an incredible meeting and we get to meet great colleagues like our colleagues today on this podcast and learning so much from this meeting. Our podcast as you pointed out quite a sizable and growing cadre of people in Asia and Japan and China who are listening and we truly want to enhance that as Joe mentioned with the large splurge of cardiovascular disease and the great science that is going on here. Want to make sure that we are able to be apart of that conversation and interact with researcher and clinitions here. In addition to podcast, we are exploring some other options involving social media, specifically in China so stayed tuned in how those develop but we certainly appreciate the importance of being her and interacting where so much of cardiovascular disease and cardiovascular science is occurring.

Dr. Carolyn Lam:
That's so great. Joe or Amid now there's a specific we would like to highlight to our listeners the doodle, either of you want to pick that up a bit about blipping the doodle?

Amid Kira:
So there is as you know Circulation now has this doodle where we change it periodically and its sort of a fun themed thing. Right now I think it Halloween and we've had several other ones that people have designed to sort of keep thing fresh and light and interesting. There's a new app called blippar which you can download from iTunes or android stores and you can essentially scroll that over with your phone with the doodle and that will take you to new content either table of contents of videos, different kinds of content that it can navigate you to. So I hope people will not only enjoy the doodle kind of anticipate what's next in terms of seasons but will take the time t blip the doodle when they get a chance.

Dr. Carolyn Lam:
That great and that blippar- B l I P P A R. You really c should check it out, anyone who is listening to this really check it out you'll be floored. Joe could I just turn the mic to you for any last words about the global outreach of Circulation, I mean its just so amazing that you're there in China

Joe Hill:
Well heart disease Carolyn knows no boundaries nor does Circulation. There was a day when cardiovascular disease was largely an issue in the developed world that is long since gone and that's why the study that we are talking about today with these authors is so important because the face of cardiovascular disease is different than in the west, the ways in which it is  evolving id different here than in the west and I like many others foresee an increase a significant increase in the types and prevalence of heart disease here in Asia. for all the reasons that we have been talking about, hypertension, obesity, type two diabetes, smoking the environment all of these challenges I fear are going to lead to a substantial increase in the prevalence of heart disease in Asia and that why we're here on the ground with Circulation in Asia that's why we have one of our major leaders Chong Shong Ma who is here in Beijing. Circulation is in China everyday, it’s in Beijing everyday to try and address this problem.

Dr. Carolyn Lam:
And you heard it from our editor and chief, so thank you everyone for listening to this episode of Circulation on run. Tune in next week.



Oct 31, 2016


Dr. Carolyn Lam:
Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Our interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:

The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.

In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].

These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.

In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.

The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.

During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.

In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.

The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.

They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.

The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.

Well, those were your summaries! Now, let's on to Rome.

Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]

Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.

Dr. Eric M. :
Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.

What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.

With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.

Dr. Carolyn Lam:
That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.

Dr. Mark P:
Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.

When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.

What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.

We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.

Dr. Carolyn Lam:
OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?

Dr. Mark P:
Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.

Dr. Carolyn Lam:
With bypass compared to medical, yes.

Dr. Mark P:

Dr. Eric M. :
I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.

Dr. Carolyn Lam:
That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?

Dr. Eric M. :
I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.

Dr. Mark P:
Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.

Dr. Carolyn Lam:
You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.

Dr. Mark P:
I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for  for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.

Dr. Carolyn Lam:
Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.

Dr. Nancy S.:
So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.

I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.

Dr. Carolyn Lam:
Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?

Dr. Mark P:
So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".

Dr. Carolyn Lam:
Kudos to you, Nancy! And from your point of view, was it fun?

Dr. Nancy S.:
It actually was fun.

Dr. Carolyn Lam:

Dr. Nancy S.:
You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.

Dr. Carolyn Lam:
[inaudible 00:21:34] how long?

Dr. Nancy S.:
We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.

Dr. Eric M. :
First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.

A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.

Dr. Carolyn Lam:
You've been listening to Circulation on the Run. Tune in next week for more.


Oct 24, 2016


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. We have such a special podcast for you today. The entire podcast is going to be a conversation with two very special guests, Dr. Marc Ruel from The University of Ottawa Heart Institute, the guest editor of the surgery themed issue this week. Hi Marc.

Hello Carolyn. How are you?

Very good. Especially because we also have Dr. Timothy Gardner, Surgeon, Associate Editor from Christiana Care Health System. Welcome back again, Tim.

Thank you, Carolyn. Glad to be here.

Marc, could you first give us an overview of the surgery themed issue from your perspective.

This year as we have had on previous years, we are having a surgery themed issue which comprises what I would argue which is some of the very best cardiac surgical science can offer to the wide readership in the cardiovascular community that served by circulation. This year, we will have a total of ten articles that would be published in circulation, as a section of one of our regular issues and out of those ten, there are five original papers. There's one research letter which is an original research article but in a shorter format and we'll also have one invited perspective paper namely about coronary artery bypass grafting and its future with respect to multi-arterial grafts and the themed issue will be completed by three state of the art papers that deal in a very in depth comprehensive way with some important problems that the cardiovascular community faces from a clinical point of view.

Thanks Marc. That was a beautiful summary of the issue. I couldn't help but notice that there was a theme of coronary artery bypass surgery covering at least four of the papers and I really like your thoughts on that. You covered everything from medical therapy, CABG versus PCI, on versus off-pump, emergency surgery in the setting of shock. Could you go through each of these four papers a little and tell us what was your take home message from each?

As you said, there are three original research articles and one invited perspective that relate to coronary artery bypass grafting surgery and these encompass the number of clinical problems that are still controversial and certainly I believe they contribute a very, very significant [inaudible 00:02:31] with the wealth of knowledge that the cardiovascular community is looking for at this point. If I may go one by one, just with a very high level overview, if you will. The first one is a paper from the Leipzig Heart Center with first author, [Pieroz Adewalla 00:02:45], which looked at surgery for acute myocardial infarction but accompanied with cardiogenic shock. As you know, many patients undergo surgery in an acute MI context, but surgery for cardiogenic shock is often a very gruesome difficult decision.

Leipzig Heart Center looked at over 3,000 patients who had an acute MI prior to cardiac surgery for bypass surgery and of these, there were 508 patients who actually had cardiogenic shock due to [valve 00:03:15] failure with myocardial dysfunction and to give you an idea, these patients were quite sick. There's about 40% of the patients who were ventilated prior to surgery or very close to 40%. The timing was quite urgent, those patients were on inotrophes and on vasopressors to support their blood pressure prior to operation. Essentially, what they found is that first the outcomes got better over the last number of years, this is a series that dates back to about the 2000's, so the early 2000's.

They also favor an approach where they tried to avoid a cardioplegic arrest of the heart. Their favored overall approach is to do what we call on-pump beating heart type of surgery which would be a surgery where the cardioplegia would not be administered to stop the heart but the hemodynamics would be supported for the cardio coronary bypass. They also have over the years since the beginning of this year, is in 2000 ranging up to 2014 of increasing the use of the off-pump bypass surgery and certainly the outcomes have been better and the mortality although high has decreased significantly. It was as high as 40% in the early parts of the cohort if you will and in the latest third of the experience, therefore from 2010 to 2014, the mortality has been down to about 25%.

Again, these are patients who present with cardiogenic shock. What's also interesting to note is that patients who survive out of hospital still have a significant mortality burden and about 50% of them survive long term. What was interesting is the  Leipzig group is looking at some predictors of bad outcomes in those patients and they found that the serum lactate over four minimal per liter was actually a very robust and multi-variative predictor of a poor outcome after surgery.

That was a great summary of that first paper. You mentioned beating heart surgery and so on. Would you like to comment on next paper that I think was the largest single institution European study comparing on versus off-pump bypass surgery?

You're absolutely right. This is a paper from England, [inaudible 00:05:25] from Liverpool, where the patients were gathered from and with some contribution from Oxford as well from a statistical and methodological point of view and it's a retrospective cohort study of all isolated CABG patients in Liverpool between 2001 and 2015. These are bypass surgery patients and in total, there were over 13,000 patients who had CABG. About 6,000 patients had off CAB which is off-pump bypass surgery and more than 7,000 had bypass with cardiopulmonary bypass. The median follow up was 6.2 years. What's interesting in this paper is that they essentially found equivalent long term outcomes. As you know, there has been some debate regarding the completions of myocardial revascularization and the long term graft patency with off-pump surgery versus on-pump surgery. Also named conventional CABG.

What's interesting here is that the benefits of off-pump CABG appear to be seen early on with regards to antiemetic release as stroke rates, etc. Which does correspond to some of what has seen in the randomized controlled studies. However, the long term data is interesting. There's a a nice editorial about this paper written from a group from the Cleveland Clinic with Dr. Joe Sabik as the senior author and essentially it raised a number of good points, although this is an important series, it also shows that the surgeons who are very good at off-pump bypass surgery may overall be slightly technically more skilled at doing bypass surgery in itself and for instance, use more often arterial grafts and have more advanced techniques in their completion of bypass surgeries for their patients.

Right. I'm so glad you mentioned the editorial. I was about to bring that up as well. Switching gears to you very kindly included a paper that talked about medications and the impact of here is the medical therapy on the comparative outcomes between CABG and PCI. Would you like to discuss that paper?

This is a paper from the Care Registry which has generated some interesting publications in the past. The lead author is Dr. Paul Polinski and there's co-authors, Dr. Herbert Prince and Michael Mack from Dallas as well. This was presented at the science sessions in Orlando last November and it's an interesting paper. Essentially they have looked at large databases, again the Care Registry which comprises eight community hospitals and they look at six month period of performance of CABG and those eight community hospitals. They ended up with over 2,700 patients who were then systematically followed on a regular basis up to 2009 at which time the database was locked.

They look at various outcomes but also medication use in great detail over that period of time and the interesting perspective that this paper brings is that first, most patients at least in that period were not on optimal medical therapy. The authors used their own predefined definitions of what constitutes optimal medical therapy and this is with regards to adherence to aspirin use, lipid lowering agents, beta blockers and indicates of PCI, dual anti-platelet therapy. As expected but nicely documented in this paper, the outcomes of patients who were not on optimal medical therapy were much worse than those who were and CABG proved to be more robust in patients who were not on optimal medical therapy compared to PCI.

The differences between CABG and PCI in patients who were on optimal medical therapy tended to vanish. However, a number of caveats here is that only 25% of patients in fact in this cohort were on optimal medical therapy. The vast majority of patients were not considered to be on optimal medical therapy. Therefore, there are considerations of definitions that one has to be aware of and also considerations of statistical power because the group that was on optimal medical therapy was much smaller than the other group. Therefore, the effects, the superiority of CABG over PCI could only be firmly demonstrated in the group was not on optimal therapy, again comprising 75% of patients in this cohort.

I love your summaries and they really show that these are true significant original contributions to that knowledge gaps in coronary artery bypass surgery. To round it all up, you also invited a perspective on novel concepts. Would you like to comment on that paper?

This is an invited perspective in the view classifications that circulation has which is entitled, "The evolution of coronary bypass surgery will determine relevance as a standard of care for the treatment of multi-vessel CABG." It is authored by three leaders in the field, Dr. Gener, Dr. Gudino, and Dr. Grouw. Dr. Gener has been leading several of what I would call the advanced multi-vessel coronary re-vascularization trials looking for instance at multi-arterial grafts doing numerous anastomosis with two ventral mammary arteries in a wide fashion. He's been a leader of this movement certainly. Dr. Gudino recently published [inaudible 00:10:43] the 20 years of outcome of the radial artery graft and certainly has been one of the pioneers which use of this arterial graft for coronary artery bypass surgery. What the authors provide here is a very nice summary of what the trials have shown so far and they also report as many know that their rate of multi-arterial grafts use in SYNTAX, FREEDOM and I think we will soon see in EXCEL and NOBLE that will be presented this fall, has not been as high as it should have been.

In the US, it is estimated right now that the rate of use of more than one mammary artery is less than 10% across the nation, and other countries have not performed better than this either. This perspective is a call to improving the quality of multi-vessel coronary artery bypass mainly through the use of multiple arterial re-vascularization. There is also considerations around the hybrid coronary re-vascularization and as well as the use of off-pump versus on-pump surgery.

I am really proud and privileged to have helped to manage one of the papers as associate editors in this issue as well and that is the paper from the group with corresponding author, Dr. Veselik, from Boston Children's Hospital and it centers around patients with congenitally corrected transposition of the great arteries but a management problem that is really increasingly encountered and really needs to be reviewed properly and that is the management of systemic right ventricular failure in these patients. Tim, you were so helpful in looking at this paper as well. Could you share some of your thoughts?

Well, this is a somewhat unique situation where a patient with this condition, congenitally corrected transposition of the great arteries may go through early life, in fact may end up as a young adult before this particular condition is identified because if there is no shunting or no cause for cyanosis and heart murmurs and so on early on, the circulations seem to work pretty well until the poorly prepared right ventricle which is the systemic ventricle, starts to fail after years of work carrying the systemic circulation and that is really the focus of the paper. There's been a lot of work and publications and attention to transposition syndromes but this particular one is a condition that may be first encountered by adult heart failure cardiologist who have not had this kind of exposure to congenital heart disease. It's a particularly apt paper to bring this condition to our attention and to demonstrate that really it's the adult heart failure cardiologist who may be managing these patients in their late 20's or 30's, when that systemic right ventricle fails because of a lack of formation to manage the systemic circulation.

Exactly. Written by a group that has one of the most robust experiences in this field, so that also brings to mind another state of the art article in the issue that refers to the hypoplastic left heart syndrome and though it's entitled that and people may think it's rare, I think it's increasingly being seen in the adult cardiology world as well. You want to comment on that one?

That actually is one of the main points of this paper that this very, very difficult condition of hypoplastic left heart syndrome that requires staged operations beginning in the neonatal period has now reached the state of surgical accomplishment in medical management where many of these young children are surviving into young adulthood. Albeit, with having had two, or three, or four operations. In a community like ours here in Delaware, where pediatric patients transition to adult services and adult cardiologist sometime around their 20's, it's really important for the entire cardiology community to be aware of what has happened in terms of the successful staged treatment of children with hypoplastic left heart syndrome and that is brought out very nicely by the three authors who look at various accomplishments and different techniques for managing these staged repairs. It is very amazing to someone who has been observing this field for sometime as I have, that many of these children are in fact surviving into young adulthood and will require comprehensive cardiovascular treatment, not just by neonatal specialist but by specialist in adult congenital heart disease.

Exactly, which is why such a timely state of the art articles both of them for this issue. There is another state of the art article that you were handling, Tim, "The Surgical Management of Infective Endocarditis Complicated by Embolic Stroke", now that's an important topic.

Absolutely, as we know up to a half or more of patients with infective endocarditis primarily on their left sided heart valves will have cerebral embolic problems and it has really been a dilemma for many of us in terms of optimal timing for the cardiac surgery with respect to the existence of cerebral injury from the embolism, from hemorrhage that may occur, from hemorrhage that may be exacerbated by placing the patient on the heart-lung machine, etc, and this paper really takes an extremely comprehensive, careful and judicious look at all of the evidence that has emerged and it has been a confusing field of evidence as to how to best optimally manage these patients with cerebral involvement from infective endocarditis.

I think this paper is going to have a big impact. It appears that there are a couple of messages that I took away from this paper. Number one, we really need to use the full panoply of diagnostic opportunities or diagnostic test for characterizing the nature and the extent of the cerebral involvement in these patients and then perhaps even more important, we need to convene what the authors called the infective endocarditis team and that has to include not just the surgeon, the cardiologist and the infectious disease specialist but also the neurologist, the neuro-interventional specialist, the neurosurgeon and so on because all of these specialist need to contribute to the assessment and choosing the optimal timing for these patients.

That is the central message of the paper. The authors also suggest that we may be getting to the point where we need to update and make sure that the guidelines that we're using are in fact current. Current in the sense that the experience now with advance imaging and with more aggressive management of the neurological or cerebral issues really need to be factored into how best to handle these patients, but I think this paper is going to have a big impact, it's very well written and very thorough.

I agree. In fact all the content we just discussed is just so rich. Congratulations on such a beautiful issue. Marc, do you have any last highlights you'd like our audience to hear about?

I'd like to also mention two other original research papers that will be featured in the surgery themed issue. One, in keeping with the congenital theme that we had talked about is about the modified [Straun's 00:19:08] procedure for palliation of severe Ebstein's anomaly and this is a series actually from Professor [Straun 00:19:16] himself mostly originating from Children's Hospital Los Angeles and essentially, the series here is that of 27 patients about equal in gender distribution who were operated at seven days of life, between 1989 and 2015.

It's very interesting that patients did well, the survival at ten years is 76% and most of them have undergone successful Fontan completion. I think this is a very important paper not only because it is an extremely vexing and difficult problem to deal with Esbtein's anomaly but it comes from the innovator of the operation himself with his team and it provides much needed data regarding the long term outcomes of these children with this very difficult solution. I think this will be of great interest and also as we commented before veering into the world of adult cardiology as well, because fortunately most of these patients survive into adulthood.

The other paper I wanted to touch upon which is also an original research paper that will be in this themed issue, is a paper from the CTSN Group looking at the impact of left ventricular to mitral valve are being mismatched on recurrent ischemic MR after ring annuloplasty and this paper used the free innovative and interesting methods. As some of you may know, there were two large files recently that were conducted by the CTSN looking at either moderate MR at the time of coronary artery bypass grafting or at severe ischemic mitral regurgitation. The randomizations were different when the moderate MR was CABG lone versus CABG post mitral valve repair and the severe MR was mitral valve repair versus mitral valve replacement.

These studies have led to interesting conclusions that several will know about but what's been interesting in the current study is that they have gathered all patients who underwent mitral valve repair from both studies, original randomized trials and they ended up with about 214 patients who underwent mitral valve repair. The others had moderate or severe MR and basically the point of this study is to look at predictors of failure of mitral valve repair and this is an extremely relevant problem, not only for the cardiac surgical community I would venture, but also for heart failure community and for JV General cardiology community. What the others found is that the most important predictor of recurrent mitral regurgitation after mitral valve repair was something called the left ventricular and systolic diameter to ring size ratio and they provide an algorithm which will have to be tested clinically with regards to whether it is applicable and indeed changes outcome, but this is a very important discovery in the field of ischemic MR and enabling us to hopefully better understand and improve outcomes for patients with this very difficult problem.

I agree. Thank you so much, Marc and Tim for this most insightful discussion. Thank you very much and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next next week for more highlights and features.


Oct 17, 2016

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 Centre and Duke National University of Singapore. Have you ever wondered what the clinical implications of very brief episodes of device-detected atrial tachyarrhythmias are? Well, we will be discussing this with novel data from the RATE registry in just a moment. First, here's your summary of this week's journal.

The first study provides the first evaluation of the Sweden nationwide abdominal aortic aneurysm screening program. Of almost 303,000 men invited for screening, 84% attended. The prevalence of screening detected abdominal aortic aneurysm was 1.5%. After a mean of 4.5 years, 29% of patients with aneurysms had been operated upon with a 30-day mortality rate of 0.9%. The introduction of screening was associated with a significant reduction in aneurysm-specific mortality. The number needed to screen to prevent 1 premature death was 667, while the number needed to operate on to prevent 1 premature death was 1.5.

Furthermore, the authors showed that their screening program was highly cost-effective in the contemporary setting in Sweden. These findings confirm results from earlier randomized controlled trials in a large population-based setting, and may be important for future healthcare decision-making. This and the diverse requirements for efficient population screening for abdominal aortic aneurysm, from program management to maintaining skills in open repair are discussed in an excellent accompanying editorial by Dr. Cole from Imperial College London.

The next study looks at thoracic epidural anesthesia and suggests that caution may be needed in patients with or at risk for right ventricular dysfunction. You see, thoracic epidural anesthesia involves blockade of cardiac sympathetic fibers, which may affect right ventricular function and interfere with the coupling between the right ventricle and right ventricular afterload. Dr. Wink and colleagues from the Leiden University Medical Center therefore used combined pressure volume conductance catheters to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular pulmonary artery coupling in 10 patients scheduled for lung resection.

Thoracic epidural anesthesia resulted in a significant reduction in right ventricular contractility, stroke work, dP/dt max and ejection fraction. This was accompanied by a reduction in effective arterial elastance such that ventricular pulmonary coupling remain unchanged. Clamping of the pulmonary artery increased right ventricular contractility but decreased ventricular pulmonary coupling. These effects of increased afterload were the same before and after thoracic epidural anesthesia. In conclusion, therefore, thoracic epidural anesthesia impaired right ventricular contractility but did not inhibit the native positive ionotropic response of the right ventricle to increase afterload. These findings are clinically relevant for daily practice in cardiothoracic surgery because pulmonary hypertension is frequently encountered, and right ventricular function is an important determinant of early and late outcomes.

The next study suggests that the use of point of care hemostatic testing may have a place in the management of patients undergoing cardiac surgery. Dr. Karkouti and colleagues of the Toronto General Hospital hypothesized that point of care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery, thereby reducing blood transfusion. They therefore conducted a pragmatic multi-center stepped-wedge cluster randomized controlled trial of a point of care based transfusion algorithm in 7,402 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They found that the trial intervention reduced rate of red cell transfusion with an adjusted relative risk of 0.91 and a number needed to treat of 24.7.

The intervention also reduced rates of platelet transfusion and major bleeding but had no effect on other blood product transfusions or major complications. These findings that point of care testing improved management of coagulopathy in cardiac surgery support the consideration of their broader adoption in clinical practice.

The next study provides experimental evidence that brings us one step closer to therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis. In this study from first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein and colleagues from LMU Munich, authors focus on cathepsin G, which is stored in neutrophil and azurophil granules and discharged upon neutrophil activation. They studied site-specific myeloid cell behavior after high-fat diet feeding or TNF stimulation in the carotid artery, the jugular vein, and cremasteric arterioles and venules in APOE E and Cathepsin G-deficient mice.

Their studies revealed a crucial role for Cathepsin G in arterial leukocyte adhesion, an effect that was specific for the arteries and not found during venular adhesion. Consequently, Cathepsin G deficiency attenuated atherosclerosis but not acute lung inflammation. Mechanistically, Cathepsin G was immobilized on arterial endothelium, where it activated leukocytes to firmly adhere, engaging endocrine clustering, a process of crucial importance to achieve effective adherence under high-sheer flow.

Therapeutic neutralization of Cathepsin G specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of Cathepsin G-neutralizing antibodies really allowed the inhibition of atherogenesis in the mice. Taken together, these findings presented evidence of an arterial-specific recruitment pattern centered on Cathepsin G adhesion, thus representing a potential novel strategy and target for the treatment of arterial inflammation. Well, that wraps it up for the summary of this week's journal. Now, for our featured discussion.

Our feature paper for today discusses the clinical implications of brief device-detected atrial tachycardias and really novel findings from the RATE registry. I'm so happy to be here with the first and corresponding author, Dr. Steven Swiryn from Feinberg School of Medicine, Northwestern University. Hi, Steven.

Good morning.

We also have with us Dr. Mark Link, associate editor from UT Southwestern. We all know that prolonged episodes of atrial tachycardia or atrial fibrillation are associated with increased risk and that if we anticoagulate those with a high CHA2DS2–VASc score, we can lower the risk of stroke. Now, the European Society of Cardiology guidelines also say that recent data reinforced the assumption that even brief episodes of silent atrial fibrillation may convey an increased risk of stroke. We also know that prior studies have looked at device-detected atrial fibrillation. Steven, I'd really love if you could start by telling us what makes your study different. What was the main thing you were trying to look at?

Well, one reason it's attractive to use the device population, patients with pacemakers or defibrillators, to look at these issues is because devices have a very high likelihood of detecting episodes of atrial fibrillation whereas symptoms or single 12 EKGs miss a lot of atrial fibrillation, so the sensitivity is much higher, although not perfect. The problem is that very brief episodes of atrial fibrillation are very poorly detected by devices. The specificity of automatic detection is very low, such that all previous studies until the RATE registry have excluded any episode of atrial fibrillation detected by a device less than 5 minutes in duration because they're unreliable. A lot of them turn out to be false positive detections. Our study was designed to evaluate whether even very brief episodes of an atrial tachyarrhythmia might also be associated with risk of clinical events and might or might not warrant anti-coagulation.

Ah, that's interesting, so you really helped to answer how brief is "brief" when we need to talk about device-detected atrial fibrillation. Could you expand on how you actually defined "short episodes" here?

Right. A short episode for the purpose of the RATE registry was defined as an episode where the electrogram that we scrutinized had both the onset and the offset of the episode within the same electrogram tracing, so although we can't put a specific time duration on it because that wasn't part of the criterion, it's typically less than 20 seconds or so, although not always, whereas a long episode was defined as an electrogram where either the onset and/or the offset was not captured by the device memory and therefore we don't know the duration. Some of those may not have been very long, and some of those may have been extremely prolonged episodes. That allows us to actually scrutinize the electrogram. We looked at 37,530 individual electrograms using 8 teams of adjudicators, each with a physician and a field clinical engineer from the device company so that we could actually say definitively, "Yes, this was atrial fibrillation," or, "No, it wasn't."

This is the first study to really look under that 5-minute limit of atrial tachycardias. What did you find?

Well, we found that in contrast to prolonged episodes, short episodes of atrial tachyarrhythmias were not associated with an increased risk compared to those without atrial fibrillation of pre-defined clinical events, including death from any cause, heart failure, stroke, hospitalization for atrial fibrillation, and a few other smaller events.

This was over a 2-year follow-up period, is that right?

The median follow-up was slightly less than 2 years, that's right.

What I really was struck with was also the second finding, the propensity to develop longer episodes. Could you expand on that?

We reasoned that in the clinic, one might be faced with a short episode was we defined them, and then you don't know what's going to happen for the next 2 years to bring to bear the results of our study. We looked at if your first episode was short, what was your likelihood over the full follow-up of the study of progressing to longer episodes. About 50% of patients who had their first episode as only a short episode progressed to a longer episode over the full follow-up and therefore were in the long category for the rest of the results. Half of them never got a longer episode.

It was, as one might imagine, if you had your first short episode very early in the study and had a longer follow-up, you were more likely to end up in the long category, and if you had very frequent short episodes, you were also more likely to end up in the long category by the time the full follow-up was over with. Having an initial short episode is not a guarantee that you're never going to get a long episode and that you'll never acquire a consideration of anti-coagulation.

That was a very important message to me as well because it meant that although I can be secure or reassured by these data for very short episodes, I needed to look out for the development of longer episodes, at least that's what your registry showed over 2 years of follow-up. I'm curious, Mark, what were your take-home messages because that leaves us with a bit of a conundrum. What do we do about anti-coagulation in these patients?

I think this study is a big help to the practicing electrophysiologist and practicing cardiologists. It's a very ledger number of patients with a lot of episodes of afib. It's reassuring to me that the shorter episodes of afib as defined by the study, the individuals did not have a higher incidence of stroke compared to those with no episodes, so it's reassuring and very important clinically as I go through my practice.

I do look forward to more analyses and more data from this study because although now we know that episodes less than 20 seconds are in all likelihood not going to need anti-coagulation, we still don't know about those from 20 seconds to 5 minutes. Hopefully with more analysis of this study we'll get that answer also.

Steven, do you agree with that?

We would love to have that. At first glance, you would think that devices would give you all of the data you needed because after all, they're monitoring the patient 100% of the time, but there are difficulties with that because device memory is limited, and you don't get electrograms that go on until the termination of atrial fibrillation even if the device were accurate in determining when that termination was because depending on how the device was programmed and depending on whether it was a more modern device later in the trial or earlier and had more or less memory, it cuts off after a limited amount of time, and you don't see necessarily how long the duration is.

Now, you can use device-based data. The device gives you its estimate of how long the episode is, but those are not as reliable as adjudicating the electrograms and actually looking at them. Those data would be a little softer than the main results if we get there.

That was the data that was used for all of the other studies, was [transassert 00:14:51]. It would be comparable to those other studies. I still think it would be very important data that I'd love to see.

Okay, well, I agree. I think it would be very interesting to look at that and a number of other things. We have a number of other things we could do with this database. There are a number of substudies that are in progress. For example, one interesting one is there were some instances we found, because we actually looked at these electrograms, there's something that we termed "competitive atrial pacing," where the device will pace at times when we as clinicians would not want to pace. For example, pacemaker-mediated tachycardia would be an instance of that, but then you can pace in the atrium inappropriately. There's a rhythm called repetitive non-reentrant ventricular atrial systole, which, although it's exotic to all of us, actually turned out to be fairly common where there's pacing in the atrium that occurs for various reasons when we want it to.

We actually saw instances where the device itself induced atrial fibrillation. It wasn't that common, but we did see it. We have a substudy that we're working on about the subjective competitive atrial pacing to see how much of that there was and of what, if any, consequence that was. That's one of the things that's been done. Because we scrutinized these so carefully, we tracked morphology and atrial rate at least as a crude estimate, and we have those data, so we could actually evaluate whether if something looks very, very rapid and disorganized as opposed to more organized electrograms at a slower rate, did that make any difference. We don't have any results for those analyses yet. I agree with Mark that the intermediate durations would be interesting to look at.

I agree too, and I'm really grateful for you sharing those thoughts. Very grateful for both of you for your time today. I just have to congratulate you. I completely agree this paper fills an important knowledge gap, and congratulations once again.

Thank you very much.

Thank you.

Thank you for listening. You've been listening to Circulation on the Run. Please tune in next week.



Oct 10, 2016


Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Today's featured discussion deals with the perspective piece entitled, What I Wish Clinicians Knew About Industry and Vice Versa. Intriguing, isn't it? I can tell you it is one of the best papers I have ever read, so stay tuned. First, here's your summary of this week's journal.

The first study takes a step towards understanding atrial fibrillation on a more fundamental level by demonstrating that some patients have altered left ventricular myocardial energetics even in the absence of other comorbid diseases. First author, Dr. [Veejay Surendra 00:00:50], corresponding author, Dr. [Cassidy 00:00:53] and colleagues from the University of Oxford studied 53 patients with lone atrial fibrillation undergoing catheter ablation and compared them to 25 matched controls without atrial fibrillation. They did this using sequential studies of cardiac function with magnetic resonance imaging as well as energetics with phosphorus-31 magnetic resonance spectroscopy.

At baseline, there was subtle but significant left ventricular dysfunction and abnormalities in ventricular energetics in patients relative to controls. Following ablation of atrial fibrillation, left ventricular function measured by ejection fraction and peak systolic circumferential strain improved rapidly with a switch to sinus rhythm but remained at normal at 6 to 9 months. Although pulmonary vein isolation effectively eliminated atrial fibrillation in all the patients in the study, the hearts continued to express an energetic profile consistent with a myopathic phenotype meaning that the ratio of phosphocreatine to adenosine triphosphate was lower in the atrial fibrillation compared to controls irrespective of recovery of sinus rhythm and freedom from recurring atrial fibrillation.

The clinical implications of these findings are that apparently lone atrial fibrillation may actually be a consequence rather than a cause of an occult cardiomyopathy and that this cardiomyopathy is unaffected by ablation. Of course, future studies are needed to prove this and to examine whether therapeutic strategies that target the adverse cardiometabolic phenotype could reduce atrial fibrillation recurrence. These important issues are discussed in an accompanying editorial by Doctors Hyman and Callans.

The next study provides experimental evidence that suggests we may finally have an answer to heart failure preserved ejection fraction or HFpEF, and that is the modification of titin. Titin is a sarcomeric protein that functions as a molecular spring and contributes greatly to left ventricular passive stiffness. The spring properties can be tuned through post-transcriptional and post-translational processes and their derangement has been shown to contribute to diastolic dysfunction in patients with HFpEF. The current paper by first author, Dr. Methawasin, corresponding author, Dr. Granzier and colleagues from University of Arizona provide important proof of principal investigation of the effects of manipulation of titin isoforms as a treatment for a transverse aortic constriction murine model of progressive left ventricular hypertrophy leading to HFpEF.

Conditional expression of a transgene with deletion of the RNA recognition motif for one of the splicing factor, RBM20 alleles, resulted in reduced splicing and a substantial increase in larger more compliant titins that were named super compliant titin. The result was normalization of passive stiffness of isolated muscle strips as well as normalization of left ventricular diastolic function and chamber stiffness as assessed by echocardiography and pressure volume analyses. There were no effects on extracellular matrix stiffness. The authors also showed that other spliced targets of RBM20 did not contribute to the results and thus, the beneficial effects were almost certainly entirely related to the changes in titin isoforms.

Furthermore, treadmill exercise was used to show that treated animals displayed improved exercise tolerance. In summary, the study showed that increasing titin compliance in this murine model resulted in marked improvement in multiple measures of diastolic function and performance, thus suggesting that titin holds promise as a therapeutic target in HFpEF. This is the discussed in an excellent accompanying editorial by Dr. LeWinter and Dr. Zile.

The next study adds importantly to evidence that heavy physical exertion and anger or emotional upset may act as triggers of first myocardial infarction. In this paper by first author, Dr. Smith, corresponding author, Dr. Yusuf, and colleagues from the Population Health Research Institute Hamilton Health Sciences and Master University, authors explored the triggering association of acute physical activity, anger, and emotional upset with acute myocardial infarction. They did this in the inter-heart study which was a case control study of first acute myocardial infarction in 52 countries. In the current analysis, the authors used a case crossover approach to estimate odds ratios for acute myocardial infarction occurring within 1 hour of triggers.

Of 12,461 cases, 13.6% engaged in physical activity and 14.4% were angry or emotionally upset in the case period referring to the 1 hour before symptom onset. Physical activity in the case period was associated with an increased odds of acute myocardial infarction with an odds ratio of 2.3 and a population attributable risk of 7.7%. Anger or emotional upset in the case period was associated with an increased odds of acute myocardial infarction of more than 2.4 odds ratio and a population attributable risk of 8.5%. Importantly, there was no effect modification by geographic region, prior cardiovascular disease, cardiovascular risk factor burden, prevention medications, time of day, or day of onset of acute myocardial infarction.

Interestingly, the authors did find an interaction between heavy physical exertion and anger or emotional upset with an additive association in participants with exposure to both in the 1 hour prior to the acute myocardial infarction. The take home message, these findings suggest that clinicians should advice patients to minimize exposure to extremes of anger or emotional upset due to the potential risk of triggering an acute myocardial infarction. While heavy or vigorous physical exertion may also be a trigger, this did not refer to just any physical activity and the authors cautioned that this must be balanced against the known well-established benefits of regular physical activity over the long term and clinicians should continue to advice patients about the life-long benefits of exercise.

The last study provides insights in the molecular mechanism in pulmonary hypertension. First author, Dr. Lee, corresponding author, Dr. Stenmark, and colleagues from the Pediatric Critical Care Meds and CVP Research University of Colorado Denver hypothesized that metabolic reprogramming to aerobic glycolysis may be a critical adaptation of fibroblast in the hypertensive vessel wall, an adaptation that drives proliferative and pro-inflammatory activation through a mechanism specifically involving increased activity of the NADH sensitive transcriptional corepressor, C-terminal-binding protein 1.

The authors assessed glycolytic reprogramming and measured NADH to NAD+ ratio in bovine and human adventitial fibroblast as well as mouse lung tissues. They found that expression of the C-terminal-binding protein 1 was increased in fibroblast within the primary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with pulmonary hypertension. Furthermore, treatment of fibroblast from the pulmonary hypertensive vessels of hypoxic mice with a pharmacological inhibitor of C-terminal-binding protein 1 led to a normalization of proliferation inflammation and the aberrant metabolic signaling.

In summary, these result showed that C-terminal-binding protein 1, a transcription factor that is activated by increased free NADH acts as a molecular linker to drive the proliferative and pro-inflammatory phenotype of adventitial fibroblast within the hypertensive vessel wall. Thus, this metabolic sensor may be a more specific target for treating metabolic abnormalities in pulmonary hypertension. Those were your summaries. Now for our feature paper. Our feature today is special on so many levels, and because it's so special, I actually have Dr. Joe Hill, editor-in-chief of circulation from UT Southwestern here today with me. Hi Joe.

Sure. As always, it's a pleasure to be here with you. This is a new type of content where we solicit thought leaders from a variety of vantage points around the cardiovascular space to provide their perspective on the future of cardiovascular Science in medicine. Rob Califf, the FDA Commissioner, provided his perspective on the regulatory role interfacing with cardiovascular medicine and Science. Victor Dzau who presides over the National Academy of Medicine in the United States did the same, provided a very insightful perspective from his vantage point now, formerly in academia, but now overseeing this advisory board to the policy makers in Congress. Today, we're going to talk about a perspective that emerges from industry, from someone who also has a strong and long history in academia.

That is a perfect lead up. The title of the paper; What I Wish Clinicians Knew About Industry and Vice Versa. Here is the amazing guest that we have today, it's Dr. Ken Stein, Chief Medical Office of Rhythm Management at Boston Scientific. Hi Ken. It is a very, very intriguing title and I'd like you to first describe to us what makes you the person who can talk about being a clinician and going over to the dark side of industry and vice versa?

Thanks Carolyn and Joe. I think right now just get over my embarrassment at being called a thought leader and being mentioned in the same as Rob Califf and Victor Dzau. I met both of them but I don't think I've ever been mentioned in the same sentence as either them and probably never will be again. Why me to do this? Again very gracious of Joe to invite the submission. My history, I've been in industry now at Boston Scientific for 7 years, and prior to that was an unreformed academic faculty at Cornell. Ever since I did my training, eventually becoming co-director of the EP Lab there for many years. Then 7 years ago, the opportunity came up to leave the cloistered ivory towers of academia and to join industry. It's been a very interesting and I think very productive ride ever since.

I have to tell you that your article is just one of the most well-written pieces I have ever read and I mean that sincerely. You began with the story that everybody asked you this question. Why did you do it? What did you learn? I'm going to ask that of you today. Tell us.

In the 7 years, I get 2 questions all the time. One is, do you miss practice? The answer is, there are things about practice that I miss very deeply and that is really the engagement that you get with patients and families. I think we always have to remember as caregivers, we're privileged to be able to do what we do. On the other hand is, but I do get an opportunity to participate in decisions now that rather than affect one patient at a time, for better or for worse, affect hundreds of thousands of patients at a time.

The other question is, what surprised you? What have you learned? What didn't you know about industry? As I thought about it, it's 2 things. It's one that I think in retrospect I was and I think many of us are way too cynical about the motivations of industry, how industry operates. The other shock, if you will, was that it goes 2 ways and there's a lot of cynicism in industry about physician motivations and how physicians operate on a day to day basis.

Really? Do you have any examples of that?

I'll give you a couple of examples. First, from the point of view of how does industry work and what are the motivations in industry. One of the first decisions that I had to make 7 years ago after joining the company was to issue a recall on one of our products. It actually was a recall that had not yet failed in the field but we had some bench testing that suggested that there was a particular risk to some patients and novel to the industry and the whole thing. This is not go over well with the CEO, but in fact, really the only question people ask is, is this the right decision for patients? That was a really gratifying piece of education to me.

The flip side of the coin, we did introduce a new battery technology in our fibrillators and CRT devices just before I joined the company that basically doubled the amount of battery capacity that we have in the devices. It's one of the funny things. There are still editorials being written in journals other than circulation, I'll say, that still say that industry will never increase battery longevity of their devices but cost us money because we lose money on device replacements. We've done it and a lot of our competitors are in the process of doing it.

When I got to the company, what I found is there was a tremendous amount of angst within the leadership of the company. Do doctors do this or are they afraid in a fee-for-service environment to give up what they get doing battery replacements on short-lived devices. Of course that cynicism is unfounded. That doctors have embraced longer, better battery life technology.

Ken, to hear you say this is interesting and frankly inspiring. You can't pick up a copy of the New York Times right now and not read about some issue around drug pricing and some of the companies that have done the wrong thing with. They've increased prices hundreds of percentage, 400%, even more. To know from your perspective that those are perhaps the exceptional circumstances and that there are many, many companies who of course have to keep a business running but at the same time they truly have the patient at heart. You have said and you said in your piece that as the Chief Medical Officer, you're the voice of the patient at your organization.

I aim to be. That was the lesson I learned from Don Baim who really ... Don passed away very shortly after I joined the company, who's really a giant in cardiology. I wish that I had been able to spend more time with him as a mentor but that was very important statement he made. Say he's right, there are bad actors, there are bad actors in industry, there are bad actors among physicians, there are bad actors among academics, but that's not generally true. I also want to be careful not to be misconstrued. Skepticism and doubt are important. Cogito ergo sum, it's not just I think, therefore I am, it's probably better understood that I doubt, therefore I think, therefore I am. Skepticism is fundamental to scientific process, but there's this border that you cross over where constructive skepticism turns into destructive cynicism. I'm afraid gets in the way of our ability to work together to better the outcomes, better welfare of patients.

Do you think we've swung from the United States maybe you could give me your opinion to the wrong end of that balance between constructive skepticism and destructive cynicism? Joe, what do you think?

As someone who has not worked in my own research closely with industry, sometimes I think that we have. I mean, there are certainly many examples. We all know where people have crossed the line and that is profoundly unacceptable, but at the same time, I worry that we've thrown the baby out with the bathwater and some of the things that are uniquely done in academia and some of the things that are uniquely done in industry, a synergy between them across the divide is essential to move this field forward. I think sometimes the boundaries and the bright lines separating them are so distinct and defined that it prevents those source of synergies.

Thank you for that paper that really provides that balanced perspective. The beautiful thing, it's just so personal almost. It feels like we're sitting with you, having a conversation when we're reading that paper. Like now, it's just been an amazing experience having you on this podcast. Do you have any last messages?

My last words. I again just want to thank you and thank Joe. Has the pendulum swung too far? Thing about pendulums are that they oscillate and I think what's needed is a willingness to watch out that it doesn't swing too far. Is there cynicism? I'll admit, I was flabbergasted and I still flabbergasted that you allowed me to write this piece but I think the fact that you welcomed the piece from someone in industry within the intent of bringing this out, that is the pendulum not going too far. As long as there are voices, editors, journals who are willing to help us articulate points like this, I think that's at least what keeps us in a reasonable balance.

As Carolyn said, you brought a uniquely human conversational element to this piece. Not everybody would publish a piece in circulation and acknowledge that you are intimated and embarrassed walking into Don Baim's office. That brought us right into your living room and that was powerful.

Honestly, I wasn't looking for the job. I was more interviewing them to find out what I can about the company, but I did not want to make an ass of myself in front of them. I felt like I was [pieing 00:19:53] for fellowship. I walked in the door and honestly I'm still standing with my hand on the doorknob and he looks up at me and I have to remember his voice, he had that deep sort of growly voice. He said, "Stein, you have no idea what Chief Medical Officer does, do you?" I'm just thinking, do I try to BS my way out of this or do I just give him the God honest truth and turn around and go back to work. I said, "No, Dr. Baim." I couldn't call him [inaudible 00:20:22] and to the end, I told him, "Dr. Baim," I said, "I had no idea." That's when he said, "Your job is to be the voice of the patient within Boston Scientific." He said after that, "You don't need to know anything about business. We know you don't know anything about business. We've got a lot of MBAs and hopefully they do."

Thank you once again for the paper, for this discussion. Thank you both for being here. For all of you who are listening, thank you for joining us again on Circulation on the Run.


Oct 3, 2016

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.

Today, we will be discussing an interesting Danish nationwide cohort study on the return to the workforce following first hospitalization for heart failure, but first here's your summary of this week's journal.

The first paper addresses a common question asked by patients who have survived an aortic dissection. Will this happen to me again? First author, Dr. Isselbacher, and corresponding author, Dr. Lindsay, and investigators of the International Registry of Aortic Dissection investigated this in the largest systematic analysis to date of patients presenting to hospital with a recurrent aortic dissection.

In this large registry, the authors identified 204 patients with recurrent aortic dissection and compared these to 3624 patients in the registry with an initial aortic dissection. They found that patients with recurrent dissection were more likely to have Marfan syndrome, but not bicuspid aortic valve. Descending aortic dimensions were greater in those with recurrent dissections than those with only an initial dissection, and this was independent of the sentinel dissection type. In multivariable analysis, the diagnosis of Marfan syndrome was independently predictive of a recurrent aortic dissection with a hazards ratio of 8.6.

Furthermore, they found that the patient's age at the time of first dissection correlated with the anatomic pattern of aortic involvement. In younger patients, dissection of the proximal aorta tended to be followed by dissection of the distal aorta, whereas the reverse was true among older patients suggesting divergent mechanisms of disease.

In summary, therefore, this study shows that recurrent aortic dissection while in common does occur and in fact affected 5% of those in this registry. The data really illustrate the importance of syndromic forms of aortic dissection and suggest that occurrence of a recurrent dissection should raise suspicion of a genetic etiology of aortic disease.

The next study provides pre-clinical data suggesting that counteracting increased hepcidin may be a therapeutic target for treatment of intracerebral hemorrhage. In this study from first author, Dr. Xiong, corresponding author, Dr. Yang, and colleagues from Xinqiao Hospital, the Third Military Medical University in China, parabiosis and intracerebral hemorrhage mouse models were combined with in vitro and in vivo experiments to investigate the roles of hepcidin in brain iron metabolism after intracerebral hemorrhage. Hepcidin in an important iron regulatory peptide hormone that controls cellular iron efflux.

The authors found that increased hepcidin-25 was found in the serum and astrocytes after intracerebral hemorrhage. In hepcidin-deficient mice with intracerebral hemorrhage, there was improvement in brain iron efflux and protection from oxydative brain injury and cognitive impairment, whereas, the administration of human hepcidin-25 peptide in these mice aggravated the brain injury and cognitive impairment.

In vitro studies showed that increased hepcidin inhibited intracellular iron efflux in  brain microvascular endothelial cells, but this phenomenon was rescued by a hepcidin antagonist. Additionally, toll-like receptor 4 signally pathway increased hepcidin expression, whereas, a toll-like receptor 4 antagonist decrease brain iron levels and improve cognition following intracerebral hemorrhage.

In summary, the study showed that increased hepcidin expression caused by inflammation prevented brain iron efflux and aggravated oxidative brain injury and cognitive impairment, thus, counteracting increased hepcidin maybe a mechanistic target to promote brain iron efflux and attenuate oxidative brain injury following intracerebral hemorrhage.

The next basic science paper provides fascinating insights into the similarities between advanced atherosclerotic lesions and tuberculous granulomas, both of which are characterized by a necrotic lipid core and a fibrous cap. First author Dr. Clement, corresponding author Dr. Mallat, and colleagues from the University of Cambridge Addenbrooke's Hospital in United Kingdom looked at the C-type lectin receptor 4E which has been implicated in the events leading to granuloma formation in tuberculosis.

The authors hypothesized that the same C-type lectin receptor 4E may be involved in the formation of atherosclerotic lesions as well. They addressed this hypothesis by examining the impact of receptor activation on macrophage functions in vitro and on the development of atherosclerosis in mice. They showed that C-type lectin receptor 4E was expressed within human and mouse atherosclerotic lesions and was activated by necrotic lesion extracts. The receptor signaling in macrophages inhibited cholesterol efflux and induced endoplasmic reticulum stress responses leading to the induction of proinflammatory mediators and growth factors.

Furthermore, repopulation of LDL receptor-deficient mice with C-type lectin 4E receptor-deficient bone marrow reduced lipid accumulation, endoplasmic reticulum stress, macrophage inflammation, and proliferation within developing arterial lesions that's significantly limiting atherosclerosis.

In summary, this paper shows that C-type lectin receptor 4E orchestrates major pathophysiologic events during pluck development and progression, and thus, provides a mechanistic explanation for the close association between necrotic lipid core formation and the development of inflammatory advanced atherosclerotic lesions.

The last paper examined the impact of optimal medical therapy in the dual antiplatelet therapy or DAPT study. In this paper from first author, Dr. Resor, corresponding author, Dr. Mauri, from the Brigham and Women's Hospital in Boston and colleagues, authors sought to assess the impact of optimal medical therapy use on long term patient outcomes and on the treatment benefit and risk of continued dual antiplatelet therapy, and they did this using data from the DAPT study which was a randomized placebo control trial comparing 30 versus 12 months of final prudent therapy on the background of aspirin after coronary stenting.

Optimal medical therapy was defined as a combination of statin, beta blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker used in patients with an ACC/AHA class 1 indication for each medication. Endpoints included myocardial infarction, major adverse cardiovascular and cerebral vascular events or MACE, and GUSTO moderate or severe bleeding events.

Of 11,643 randomized patients with complete medication data, 63% were on optimal medical therapy. Between 12 and 30 months, continued final prudent therapy reduced myocardial infarction compared to placebo in both groups and had consistent effects on the reduction in MACE, and an increased bleeding regardless of the optimal medical therapy status. In other words, the P for interaction was nonsignificant for these comparisons.

Importantly, patients on optimal medical therapy had lower rates of myocardial infarction, MACE, and bleeding compared to patients not on optimal medical therapy. Rates of stent thrombosis in death did not differ. The take home message is therefore, that more emphasis on the use of optimal medical therapy after coronary stenting is needed, but the decision to continue dual antiplatelet therapy beyond 12 months should be made irrespective of the optical medical therapy status.

Those were your summaries. Now, for our feature paper.

Our feature paper today discusses a really important, but frankly, often neglected outcome in heart failure, and that is return to the workforce following first hospitalization for heart failure, and I'm really pleased to have the first and last author of this really special Danish paper, Dr. Rasmus Rorth and Dr. Soren Kristensen, both from the University of Copenhagen, here to join me today. Hello, gentlemen.

Hello and thank you for having us, Carolyn.


As a very special third guest, we actually have editorialist, Dr. Martin Cowie from Imperial College London as well. Hi, Martin.

Hi, Carolyn. Nice to be part of the conversation.

This is going to be so fun. Let's get straight into this. Rasmus, maybe you could start by telling us. This return to work concept is hardly addressed in guidelines, it's so important, and yet, you are one of the first if not the first to take a look at it. What inspired you to do this?

First of all, we are very inspired to work with heart failure because heart failure is a common costly, disabling, and deadly disease, and furthermore, information on young patients with heart failure is vast.  We know that they have a high hospitalization rate and a low mortality rate compared to all the patients. We also know from some of the big trials that young heart failure patients report low quality of life. Therefore, we wanted in this study to examine return to work for a number of reasons.

First of all, it gives off some information of the patient's performance basis and we get some information of their quality of life and mental status, and one more reason that is not that common for us as clinicians to think about is also for society, the economic burden these patients play in the society, and all of these reasons inspired us to get into this exciting field.

I really appreciated that you did this because the patients that I see here in Asia are on average 10 years younger than the heart failure patients that have been seen in other European registries and so on, so it is a very, very important aspect because my heart failure patients are often the sole breadwinners of families here. Could you, maybe, Soren, share with us what are those unique resources that you manage to look at this in such detail in the Danish registries?

The unique quality in Denmark is that you have the unique identifying numbers for all the citizens of Denmark and these numbers are not only used in the health systems. They're also used for administrative registries for tax paying and for state funds and pensions. We were able to link information from the hospital discharge registries with information on tax paying and whether or not people are getting pensions. In that way, we could follow all patients who stayed in Denmark at least to see whether or not they were receiving any funds, any pension, or sick leave money, or things like this from the state, or whether they upheld a position. That's what makes the Danish system a bit unique, that we have this ability to track the patients across all the fields of society and also that we have a public health system which all patients are included in, and the private sector is negligible in Denmark.

Wow. Listening to that is making all epidemiologist everywhere really drool. That is such a precious system to look at this. What were your main findings, Rasmus?

Maybe I should explain a bit about the setting. This is a nationwide-based study starting where we identify the patient with the first heart failure hospitalization, 18 to 60 years in the period from 1997 to 2012, and we followed them onwards. In our primary analysis, we only included patients in the workforce, that means either employed or available for the labor market at time hospitalization. That is the setting of the study.

Could you share your main findings and your take home messages?

Our primary outcome of this study is that after one year, 25% of the patients did not return to the workforce and we had a low mortality, only 7% died.

Twenty-five percent didn't return to the workforce?

Yeah, and keeping in mind, Carolyn, these are patients in the workforce at their first hospitalization and also young patients. Our take home patient from this paper is that patient in the workforce at heart failure hospitalization had a low mortality for the high risk of [inaudible 00:13:41] from the workforce at one year of followup. Furthermore, we look at some association effect associated with returning to work, and we found that young age, male sex, and high level of education were associated with high likelihood of returning to work.

Martin, you wrote just a beautiful editorial. I have to say I was chuckling and enjoying it as I read it. I could hear your voice in it. What do you make of these results in the interpretation?

I was really pleased to see something published by this really important topic that is largely ignored, and as you said in your introduction, the guidelines, if you read them you'll think that nobody of working age ever develops heart failure. There's no mention at all about return to work. There's no mention of the kind of urgent need to be able to provide people with the counseling about the heart failure and how it might impact their work, and also, no interaction, no mention of interaction with employers to tell them, "Yes, this person have this condition, but actually, could do their job or stay in the same job," or "How we can help support them?"

I think this article which is so good to see graded publish in Circulation and I think we have to see it in the context of other occupational rehabilitation work which shows that if you don't get people back to work quite quickly after a major event in their lives, then you'll never get them back, and that's got huge consequences for them in their mental health, their economic, social, family, and never mind the healthcare system. It's really nice to see this work and I hope many people read it and quote it.

Martin, you've been to Asia. You know that our patients are strikingly young, but I wonder, do you think these results are extrapolatable outside of Denmark?

I think this comment and not an editorial, Denmark, of course, is a relatively small country. It's wealthy. It's different from the states, but it's very different from Asia as you say, so lots of heart failure patients in Asia are young, of working age, and quite often, their families depend on them.

I think the tactics may have to be different to different countries, but the general principles are the same that we, as a heart failure team, as heart failure doctors, have to think about the person not just in terms of the left atrium and left ventricle, or even of the whole body function, but actually, what is their role in their family, what are they trying to achieve in life, how can we support them about way, because otherwise, we're really failing our patient.

I think, in Asia even more than in some wealthy, rich countries where there's a lot of safety nets, it's really important. I'd be interested in your comment, Carolyn, on what you think we can do to improve right across the world in terms of occupational rehab.

First, I think it begins with awareness and that's why I just wanted to tell Soren and Rasmus how much I enjoyed this paper and I will be citing it because I think it's so important especially in the younger heart for the community, but can I ask you, Soren or Rasmus, have these findings changed your practice in any way or to be even more provocative, do you think that maybe return to work should be a benchmark to evaluate heart failure programs?

Martin also points out that, first of all, we need to shed light on this hidden fact of heart failure, and afterwards, I think it's also a very good policy metrics to use in the future to see how our patients do.

Are there efforts in Denmark to improve this as a yardstick?

I'm quite sure that, by large, it's not really registered who is working, who is not working there. There's not much attention to it. We're all focusing very much on the performance of the patient of the NYHA class and so on, so I think we should put more emphasis on this issue and we should, as Martin also added, that we should discuss with the patients if they could change their job or their positions in some ways to better cope if they lost some of their performance, because we're both think and we both agree with Martin that it's a huge quality of life to be able to maintain your job in one way or the other, and we should definitely put more focus on that, but I'm afraid to say that I don't think we put much focus on it in Denmark at this time, but hopefully, we will.

I think you're right, the attitude have to change across the world, don't they, and they start with the heart failure team and the patients because I think most doctors and nurses and patients assume diagnosis of heart failure, that means really nothing can be the same again, but we really should be trying to return people to their optimal function, and I'm sure we can do a lot more, but perhaps, we need to upscale the workforce and knowing about the key things about occupational counseling, and maybe also [inaudible 00:18:30] interact with employers a little bit more without patient's permission to give them the confidence to have this person re-enter the workforce in a supported way because I'm sure the employers value many of these people and would be pleased to see them still in the workforce.

Exactly. I even think that could be like a fair way of trying to help the patient by relieving them from their job, which is actually will be a big mistake for some patients [inaudible 00:18:54] as a physician to help them with making sure they don't have to return to their job and fill out the statements and everything, but this may not be the best for the patient.


Gentlemen, I have enjoyed this conversation so much. Thank you for taking the time to discuss this very important paper.

You've been listening to Circulation on the Run. Tune in next week for more.


Sep 26, 2016


Dr. 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 in Duke National University of Singapore.

Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal.

The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School.

These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes.

Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock.

They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis.

The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal.

The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis.

Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients.

The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California.

These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique.

The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo.

These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality.

The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes.

The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction.

These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras.

This brings us to the end of our summaries. Now for our feature paper.

Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick.

Dr. Calvert:
It's a great pleasure to be here, thank you for inviting me.

Dr. Lam:
Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi.

Dr. Kumbhani:
Hi Carolyn, thanks for having me.

Dr. Lam:
Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks?

Dr. Calvert:
You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation.

Dr. Lam:
Could you tell us what makes your series special?

Dr. Calvert:
Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different.

I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work.

Dr. Lam:
Which types of perivalvular leak are you talking about here?

Dr. Calvert:
We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves.

Dr. Lam:
Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper?

Dr. Kumbhani:
I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round.

Dr. Lam:
As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings.

Dr. Calvert:
Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups.

Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis.

Dr. Lam:
Very important clinically. Take home message from your point?

Dr. Kumbhani:
I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that?

Dr. Calvert:
When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis.

Dr. Kumbhani:

Dr. Calvert:
We all have had personal experiences of that happening.

Dr. Kumbhani:

Dr. Calvert:
The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis.

Dr. Kumbhani:
After the closure?

Dr. Calvert:
After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately.

Dr. Kumbhani:
One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct?

Dr. Calvert:
That's approximately correct, yes.

Dr. Kumbhani:
You had 20 centers that were doing this?

Dr. Calvert:

Dr. Kumbhani:
1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone?

The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this?

Dr. Calvert:
I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in.

One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great.

I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices.

I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices.

Dr. Kumbhani:
It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis?

Dr. Calvert:
We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers.

Dr. Kumbhani:
I see.

Dr. Calvert:
I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space.

Dr. Kumbhani:
That's good.

Dr. Lam:
That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation.

Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.


Sep 20, 2016


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

In just a moment, we are going to be discussing the feature paper on results of the RE-LY trial in patients with valvular heart disease. Yes, you heard me right, this means dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. You need to listen to this discussion with first author Dr. Michael Ezekowitz, but first here is a summary of this week's issue.

In the first study, Dr. Norby and colleagues from the School of Public Heath University of Minnesota assessed trajectories of cardiovascular risk factors and the incidence of atrial fibrillation over 25 years in the ARIC study or the Atherosclerosis Risk in Communities Study. They first assessed the trajectories of cardiovascular risk factors in more than 2,400 individuals with incident atrial fibrillation and more than 6,400 matched controls. Next, they determined the association of those risk factor trajectories with the incidence of new atrial fibrillation among more than 10,500 individuals free of atrial fibrillation at baseline.

The main finding was that stroke, myocardial infarction and heart failure risk increase steeply during the time close to diagnosis of atrial fibrillation. All cardiovascular risk factors were elevated in atrial fibrillation cases compared to controls more than 15 years prior to the diagnosis. A trajectory analysis showed not only the presence of the risk factors such hypertension and obesity, but also their duration which was more informative in determining the risk of atrial fibrillation compared to a one time clinical measurement.

Finally, they identified diverse and distinct trajectories for the risk factors findings that carry implications for the different roles of different risk factors in the pathogenesis of atrial fibrillation. The findings of this very significant study also highlight the need to establish preventive strategies that address risk factors decades before atrial fibrillation diagnosis.

The next study is by first author Dr. van der Valk and corresponding author Dr. Strauss from the Academic Medical Center in Amsterdam. These authors aimed to better understand the underlying mechanisms responsible for atherogenicity of lipoprotein a or LPa. The authors achieved this aim by a combination of three approaches. First, in vivo magnetic resonance imaging using 18F-FDG PET/CT and SPECT to measure atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Secondly, ex vivo analysis of monocytes using facts analysis, inflammatory stimulation assays and trans endothelial migration assays. Third, in vitro studies on monocytes using an in vitro model for trained immunity.

Their main findings were that, firstly, individuals with elevated LPa had increased arterial wall inflammation in vivo. Secondly, that monocytes from these individual remain in a long lasting activated state ex vivo, and finally, that LPa elicited a pro-inflammatory response in healthy monocytes in vitro, an effect that was markedly attenuated by removing or inactivating oxidized phospholipids on LPa.

In summary, this study nicely shows that LPa induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its oxidized phospholipid content. The clinical implications are therefore, that oxidation's specific epitope targeted therapy using for example specific antibodies as single gene antibodies may bear clinical potential to modulate the arthrogenic impact of LPa.

The final study is from first author Dr. Mazen, and corresponding author Dr. Ouzounian from Toronto General Hospital and University of Toronto in Ontario, Canada. These authors sought to compare the long term outcomes of patients undergoing the Ross procedure compared to mechanical aortic valve replacement in a propensity match cohort study of 208 pairs followed for a mean of 14 years.

They found long term survival and freedom from re-intervention were comparable between the Ross procedure and mechanical aortic valve replacement. Of note however, the Ross procedure was associated with improved freedom from cardiac and valve related mortality, as well as a significant reduction in the incidence of stroke and major bleeding. This paper provides important evidence that supports continued used of the Ross procedure in properly selected young adult patients in specialized centers.

What this means is having experienced surgical teams dedicated to mastering the technique and committed to carefully following up the patients for possible late complications. This and more is discussed in a provocative editorial by Dr. Schaff from Mayo Clinic Rochester, Minnesota who provocatively entitled his editorial 'The Ross Procedure: Is it the Preferred Procedure or Double, Double Toil and Trouble?'

Those were all summaries, now for our featured paper.

I am so excited to be joined from all over the world to discuss the featured paper today, and that is on the comparison of dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. To discuss this first we have, first and corresponding author, Dr. Michael Ezekowitz from the Sidney Kimmel Medical College at Thomas Jefferson University and Lankenau Medical Center in Philadelphia, as well as from the Cardiovascular Research Foundation in New York. Welcome Michael.

Thank you very much.

Michael, you're calling from South Africa aren't you?

I am indeed.

That's wonderful. We're very honored to have Dr. Shinya Goto Sensei, Associate Editor of Circulation from Tokai University Japan. Hello Shinya.

Hello Carolyn, thank you very much for your invitation to such an excited podcast. I enjoy podcast every week.

I love this and it is extremely exciting and the most global discussion that we have had so far, with calling in Japan and Singapore and South Africa. Indeed it's because we're discussing a very important problem globally. Michael first, when we talk about the RE-LY trial and the NOAC trials, we're always associating them with non-valvular atrial fibrillation, and yet your topic is discussing valvular heart disease from RE-LY. Can you please start by clarifying that?

I think the reason we wrote this paper is that there is a misunderstanding of the patient populations that was studied in all the NOAC trials because they were characterized as having non-valvular atrial fibrillation. That's only partially true because in all the trials, patients with mechanical heart valve and hemodynamically significant mitral stenosis were excluded, and yet there were many patients with valvular disease that were included. In the RE-LY trial which is the focus of this particular paper, 25% of the patients had some form of valvular disease that were recruited into the study. So the term non-valvular is misleading.

That is such an important clarification, and it's an issue that I see a lot in Singapore. Frankly, lots of patients with atrial fibrillation have some valve disease even if you exclude prosthetic valves, significant mitral stenosis or valvular heart disease requiring intervention. We're very clear not that this is the patient population you're referring to. Shinya, I want to bring you into this. I see lots of these patients, how about you?

The same. Majority of patients have valvular heart disease, small mitral regurgitation is very common. We are excluding only clinically overt mitral stenosis and basically mechanical heart valve in all the newest trials. As Michael pointed out, it is very important to correct misunderstanding. Non-valvular atrial fibrillation, we used in the clinical trial is all atrial fibrillation except clinical overt mitral stenosis and prosthetic for mechanical heart valve.

Exactly. A great foundation for us to get our understand right before we discuss the findings. Michael, could you please give us the top line result and tell us what do the results mean for your own clinical practice?

Basically, it means that the patients with valvular heart disease that were included in the trial, and these included patients with mitral regurgitation with was the most common lesion, mixed aortic valve disease, tricuspid regurgitation, and also it turned out that there were 192 patients that had mild mitral stenosis. Those with mitral stenosis were presumed to be rheumatic in ideology, and they did have a profile of having rheumatic heart disease, that there were more females, they were younger, there was a high incidence of heart failure and a high incidence of TIA and stroke.

The bottom line here is whether the patients had mild mitral stenosis or the other forms of valvular disease that I just mentioned, that they benefited in an identical fashion from the 150 milligram BID dose of dabigatran and the one 110 milligram BID dose of dabigatran as those patients without any valvular disease. The bottom line is that clinicians can use dabigatran with equal confidence in these patients with valvular disease as in patients without valvular disease.

Thank you Michael, that was very reassuring and something that is very clinically important. Shinya, I'm going to ask a different question. First, maybe your take on the findings, and secondly, what was it like handling this paper across the globe as the Associate Editor Managing this?

That is a very important point. The past as Michael pointed out, this paper is very important to remind the clinician of non-valvular atrial fibrillation is not really non-valvular atrial fibrillation, and there is no difference between valvular atrial fibrillation except mitral stenosis and prosthetic valve. The result is similar to non-valvular atrial fibrillation in regard to the effect of dabigatran or by warfarin. That is the one point I have to assure. As a part, it is very important. We are now including many patients not limited in that North America, Europe. We are participating a huge number of patients from Asia. The results is applicable to the global level. We are now leading in that global evidence-based world and RE-LY is one of the good example for the global trial testing the hypothesis with [inaudible 00:13:58] over warfarin.

Michael made a very good summary of that, not only limited to RE-LY, he talked about as our trial like ARISTOTLE and the ROCKET trial. All of the NOAC trial include patient who is valvular heard disease, and the exclusion criteria is a little bit different. Michael beautifully summarized that difference in the table, in his paper.  There is a strong intention to publish this paper integration from all the editorial of old member. This is a very nice paper.

He's been very kind, that's very nice. That's true. In fact, the results in RE-LY were compared in an indirect fashion with the other trials, ROCKET and ARISTOTLE, through have published similar papers on patients with and without valvular heart disease. Just in summary, the bottom line is that this finding in RE-LY is highly reproducible in the other two trials so this is an important finding that is reproducible and true of the three novel agents that had looked at this in detail.

The other point that was raised is that there were differences in the exclusion criteria in these trials, but at the end of the day, the Europeans and the Americans in terms of guidelines, had fairly similar recommendation. For instance in the United States, it was felt that all patients with valvular disease could be anti-coagulated with the novel agent unless they had rheumatic mitral stenosis, mechanical or bioprosthetic heart valves, or patients that had undergone a prior mitral valve repair. The emphasis was that all other patients could be included.

The Europeans differed slightly and that they agreed that mechanical prosthetic valve and moderate to severe mitral stenosis should be excluded, but they were somewhat more global in recommending inclusions of all other valvular conditions. There is a slight difference then between the European and the American recommendations and guidelines.

On that note of looking across the world at the guidelines and what these results mean, it really leaves me to congratulate you Michael on such an excellent paper, and Shinya for just managing this paper so well.

Thank you.

Thank you very much for your invitation. Bye-bye.

You've been listening to Circulation on the Run. Thank you for joining us today.


Sep 20, 2016


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. Have you wondered which anti-platelet agent you should use in your patients with diabetes and coronary artery disease? Well, our feature paper deals with just this topic, so stay tuned, I'll be write back with it's author and associate editor. First, here's your summary of this week's journal: The first paper unravels novel peptides involved in atrial extracellular matrix remodelling in atrial fibrillation. This is work from first author Dr. Barallobre-Barreiro, corresponding author Dr Mayr from King's College London, and colleagues. They used novel mass spectrometry methods to analyze extracellular matrix in human atrial appendages from patients undergoing coronary artery bypass surgery.

Now, previous proteomic studies have examined the cellular proteome, but this is the first study to comprehensively characterize extracellular matrix proteins in human cardiac tissues, including the identification of glycosylation sites. They found extensive cleavage in the protein core of decorin which is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis and a variety of other extracellular matrix cell signalling molecules. Decorin processing differed between human ventricles and atria and was altered in disease. It's C-terminus which is important for the interaction with connective tissue growth factor was predominantly detected in ventricles compared to atria. In contrast, atrial tissues from patients in persistent atrial fibrillation had higher levels of full length decorin, but also harbored a unique cleavage site that was not found in atrial appendages from patients in sinus rhythm. This unique cleavage site preceded the M-terminal domain of decorin and altered the binding capacity for myostatin, this altering muscle growth.

The cleaved decorin peptide antagonized myostatin, such that myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and in hearts of decorin-null mice. Furthermore, a synthetic peptide corresponding to this decorin region, those dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. This is clinically important because mystatin inhibition has been implicated as a substrate for atrial fibrillation. This study therefore provides first evidence that peptides generated from the cleavage of extracellular matric proteins such as decorin, constitutes a local regulatory mechanism for growth factors in human cardiac tissue.

The next study looked at therapeutic hypothermia in patients with out of hospital cardiac arrest, and questioned if it may be most effective when induced early during cardiopulmonary resuscitation or CPR, in contrast to prior trials that looked at therapeutic hypothermia induced only after return of spontaneous circulation and hospital admission. This is the RINSE trial from Professor Bernard and colleagues from Ambulance Victoria Australia, which was a multi center randomized controlled trial which assigned adults with out of hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to two liters of cold saline, or standard care. The primary outcome measure was survival at hospital discharge. Secondary end points included return of spontaneous circulation.

The trial was unfortunately closed early at forty-eight percent of the recruitment target, due to changes in temperature management protocols at the major receiving hospitals. Still, a total of one thousand, one hundred and ninety-eight patients were randomized. Six hundred and eighteen to therapeutic hypothermia during CPR, and five hundred and eighty to standard pre-hospital care. Overall there was no difference in outcomes at discharge. In patients with an initial shockable cardiac rhythm there was lower rate of return of spontaneous circulation in patients who received cold saline compared with standard care. Thus, although this trial was stopped early, the data suggests that induction of mild therapeutic hypothermia using a rapid infusion of large volume intravenous cold saline during CPR did not affect outcomes at hospital discharge and may in fact cause harm in the subset of out of hospital cardiac arrest patients who present with shockable rhythm.

The last study provides the first generalizable risk score for sudden cardiac death among American adults from the general population without a history of cardiovascular disease. This large study from Dr. Deo of University of Pennsylvania, and colleagues, derived a sudden cardiac death prediction model using the Atherosclerosis Risk in Communities or ARIC cohort, and validated it in the Cardiovascular Health Study or CHS cohort. They found that the twelve independent risk factors in the ARIC study included age, male sex, African American race, current smoking, systolic blood pressure, use of [anti-hypotensive 00:06:00] medication, diabetes, serum potassium, serum albumin, HDO, estimated GFR, and QTC interval. Over a ten year follow up period this model combining these risk factors showed good to excellent discrimination for sudden cardiac death risk. In fact the model slightly outperformed that of the 2013 ACC AHA pooled cohort risk equations.

Finally, they also showed in the echocardiographic sub-cohort that a left ventricular ejection fraction less than fifty percent was present in only 1.1 percent of these participants and did not enhance sudden cardiac death prediction. This study importantly contributes to the distinguishing of sudden cardiac death risk across the general population, and the results can help target future strategies aimed at sudden cardiac death prevention for the highest risk subgroups in the American general population. That does it for the summaries. Now for our feature paper.

For our feature paper today we are discussing the super important issue of anti-platelet therapy in type 2 diabetes with coronary artery disease. Joining me today are the corresponding author, Dr. Dominick Angiolillo from the University of Florida College of Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate Editor from Paris, France. Welcome gentlemen.

Thanks for having us.


Dominick, I'd really like to start with you. Your paper entitled the OPTIMUS-4 Study, is really a study of the pharmacodynamic comparison of Prasugrel versus Ticagrelor in these patients with type 2 diabetes and coronary artery disease. The whole question is, what was the rationale to look at the pharmacodynamics?

As the title of the study says, OPTIMUS-4, it means that there was an OPTIMUS-1, 2 and 3 in the past, which means that there's a lot of thought that went into this and a lot of background information. The rationale for this specific study was that we're all well aware of the fact that patients with diabetes have high platelet reactivity, which may be one of the reasons why they have a higher risk of recurrent atherothrombotic events. Therefore, the need to define ways to optimize their anti-platelet effects, their levels of platelet inhibition. In this specific study we took an approach of looking at the novel, although we cannot call them novel nowadays, but the newer P2Y12 receptor inhibitors Prasugrel and Ticagrelor. Looking at them in a head to head comparison from a pharmacodynamic standpoint to see if one drug would be superior than the other, again, in terms of a platelet inhibitory effect.

This is the rationale, and just to expand a little bit on this, there's been a perception, again I want to underscore a 'perception' that based on subgroup analysis of the larger clinical trials, that Prasugrel is a superior drug for patients with diabetes. We do know that there's a benefit also with Ticagrelor compared with Clopidogrel, although the absolute risk reductions in the studies led to a perception that Prasugrel would be a better drug. We said to ourselves, "Well, we're never going to have a large scale head to head clinical comparison, why don't we do a head to head pharmacodynamic comparison to see if there are any differences?" This was the overall rationale for conducting this specific study.

That really sets a background perfectly. Tell us about the main findings.

The main finding was as follows, we conducted a very detailed pharmacodynamic study, this was a prospective randomized double-blind double-dummy crossover study, with all patients on the background of aspirin therapy. We looked at platelet reactivity, using a variety of assays, I like to say it in every possible salsa that you can imagine. The primary end point which is platelet reactivity at one week into two drugs, using an [ADP 00:10:00] specific assay, actually showed that Ticagrelor was superior to Prasugrel in terms of platelet inhibitory effects. That was the only time point where it was shown, but the study was actually designed to show the opposite, so it was a very interesting finding, while with all the other time points there were no differences between the platelet inhibitory effects between the two drugs.

The other thing that we did look at, which gives a little bit of a novelty to this study is, we went beyond just looking at ADP induced effects, which is the target for these two drugs, we looked at other signalling pathways which one would not believe to be necessarily affected by P2Y12 inhibitors, and we found these also to be reduced by both drugs to a similar extent.

Fascinating. I'm going to get to your second point a bit later. First, that first finding that surprisingly Ticagrelor appeared to perform better using one of the specific assays and so on, I'd really like Gabriel's opinion there. What do you think is the overall clinical implications or what was the message that the editorial board was hoping to get across to the audience? Because I noticed you invited an editorial as well, a beautiful one written by Dr. [Star-ee-an 11:36] Parker. What was the thinking behind that?

I think this is really a very important paper and I'm delighted that Dominick Angiolillo and his team submitted it to Circulation, in fact to be frank, we invited that paper after seeing his presentation at the ACC earlier this year. The reason that paper caught everybody's attention in the editorial board was that it's addressing a frequent and deadly disease, diabetes, that kills really patients with cardiovascular disease. There's a critical issue in the treatment because of the limitations of Clopidogrel because of the increased platelet reactivity in diabetics, and there's tremendous interest in the novel P2Y12 inhibitors Prasugrel and Ticagrelor, and of course any hint of differences between these agents has major clinical implications. In addition, I think I can state that Dominick's team is really one of the premiere international teams looking at this exact issue, platelet reactivity in diabetics. What they did was really state of the art rigorous clinical investigation by a highly skilled team, looking rigorously at a double blind crossover designed four different assays looking at platelet function and platelet response, looking both at the effect of a loading dose and the maintenance dose.

To me, the message is not a minute difference between the treatments, in fact I think that even though it's the primary outcome and it does show a slightly greater response with Ticagrelor than with Prasugrel, the overall most of the other assays at the other time points show a consistent good response with both agents. To us, and to me, the message is that the novel agents are clearly superior to Clopidogrel as we've seen in the clinical trials, but they are fairly consistent in their benefit, and it's reassuring to see this not in healthy volunteers but in actual patients with stable coronary artery disease. I think it was really important to show that. Certainly platelet reactivity doesn't summarize entirely the effects of any drug, and there might be platelet independent effects of Ticagrelor mostly and possibly Prasugrel, but I think on the platelet side, I think that this paper really nails it.

I read that editorial and really agree that that puts everything in perspective really well. I particularly like the figure that accompanied the editorial. In case any of our listeners out there don't really remember all the different pathways and how Prasugrel and Ticagrelor and Clopidogrel are metabolized differently, I'd really refer everyone to that figure as well. Just want to pick up on one of the points that both of you mentioned, and that is the non ADP induced platelet reactivity that Prasugrel and Ticagrelor both seem to have an affect on and so on, and if they're so effective, Dominick, is there still a role for aspirin co-administration with these new anti-platelet agents?

The study clearly puts a little bit more beef, let's put it this way, to some of the ongoing clinical studies looking at whether we need aspirin in the patients treated with one of these newer P2Y12 receptor inhibitors. There are a series of ongoing studies out there. There's a laundry list, so I'm not going to go into the details. It does highlight that maybe when you have ultimate P2Y12 blockade, which is a key signalling pathway and blocks other responses by virtue of the fact that there's an interplay between this pathway and others, maybe you do not need this additional anti-platelet agent such as aspirin, which we know there's associated with potential bleeding particularly gastrointestinal side effects.

Having said that, this is not something that I'm advocating at time, but what I am saying is that we'll need to look into the results of the clinical trials. I believe that this study is an additional piece of evidence from an ex vivo standpoint to prior in vitro studies showing that aspirin is not associated with additional platelet inhibitory effects, at least not substantial platelet inhibitory effects. One can say that you may get away with just one of these newer agents. Again, this is based on pharmacodynamic findings, let's just wait for the clinical trial results.

I think that's so fairly put, and I learnt so much just listening to this conversation. Thank you so much for joining me today. Any last words from Gabriel?

Yeah, I'd like to make a couple of points as an Associate editor for Circulation. The first one is, this paper was picked up when we saw Dominick's team's presentation at the ACC, and I think it exemplifies that we really want to pick up the best science from the meetings, either before the meetings and publish it simultaneously as much as possible, but sometimes also at the meetings, so expect to see Circulation Editors at your presentations and maybe you'll seduce them enough with your science that we'll get good science submitted to the journal. The other aspect to it is also that I think with the new editorial board there's really a focus on trying to make the journal very international in it's approach, and I think it's fitting that I am Associate Editor from Europe and I think there's no more international a scientist than Dominick Angiolillo who's not only a good friend but also has been trained in Italy, has practiced in Spain, and now works in the US. I think he embodies how science transcends boundaries and borders. I think there's a definite international outlook to Circulation, and we're looking for great science from anywhere in the world, not solely the US.

Thank you so much Gabriel. Thank you so much Dominick. Thank you listeners for listening today, you've been listening to Circulation on the Run. Don't forget to join us next week for more summaries and highlights.


Sep 19, 2016


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. Today we will be diving deep into issues of resistant hypertension, adherence to anti-hypertensive medication, and renal denervation. All this by looking closely at new data from the Renal Denervation for Hypertension trial. First, here are your summaries of this week's journal.

The first paper sought to answer these questions: How can we better re-stratify patients with long QT syndrome type 3? You will remember that as the type caused by a gain of function mutation in the SCN5A sodium channel, and the type that has a more lethal course than types 1 and 2. Another question is, are we sure that beta blockers are effective in type 3 long QT syndrome? Well the current study is by co-first-authors, Dr. Wilde of Academic Medical Center, Amsterdam, and Dr. Moss from University of Rochester School of Medicine and Dentistry, which is the largest multi-center long QT type 3 syndrome cohort described to date.

This study was designed to identify the risk and therapeutic factors associated with cardiac events in patients. The risk factors evaluated included clinical features such as age, gender, ECG measurements, the mutation type, and the therapeutic effects of beta blockers, other medications, and ICD. In almost four hundred patients with type 3 long QT syndrome, 30% experienced at least one cardiac event; that is syncope, aborted cardiac arrest, or sudden death. The risk of a first cardiac event was directly related to the degree of QT prolongation. Each 10 millisecond increase in QTC up to 500 milliseconds was associated with a 19% increase in cardiac events. Prior syncope doubled the risk of life threatening events. Beta blocker therapy was associated with an 83% percent reduction in cardiac events in females, however the efficacy in males could not be conclusively determined due to low number of events. The take-home message is, in your patients with long QT syndrome type 3, recognize the very high risk sub-population with prolonged QTC and a history of syncope.

The next paper is a basic science paper that reveals a novel way in which mitochondrial dysfunction may be targeted in heart failure. This paper is from first author Dr. Li, corresponding author Dr. Tian, and colleagues from the Mitochondria and Metabolism Center at University of Washington. These authors previously found that elevation in the NADH to NAD ratio induces mitochondrial protein hyperacetylation, and renders hearts highly susceptible to stresses, and they showed this in a mouse model of primary mitochondrial dysfunction caused by genetic defects. In the current study they defined the molecular intermediaries linking specific NAD sensitive hyperacetylation targets to the development of heart failure, and further demonstrated the relevance of these mechanisms in human heart failure. Specifically, they identified that hyperacetylation of the regulators of mitochondrial permeability transition poor and malate-aspartate shuttle, mediates the increased susceptibility to cardiac stresses. Further, expanding the cardiac NAD pool via pharmacological or genetic approaches normalized the NADH to NAD ratio, and thereby normalized protein acetylation in hypertrophied and failing hearts. Importantly, these measures improved cardiac function and reduced pathological hypertrophy in mice. Thus, the clinical implication is that restoring the NADH to NAD ratio may be an effective and translatable strategy to treat mitochondrial dysfunction in heart failure.

The next study broadens our considerations of the benefits versus risks of intensive anti-platelet therapy in patients with a prior myocardial infarction, and really suggests that more intensive anti-platelet therapy should be considered, not only to reduce the risks of coronary events, but also to reduce the risk of stroke. This is a paper from Dr. Bonaca and colleagues of the TIMI study group from Brigham and Women's Hospital in Boston, Massachusetts, who investigated the efficacy of ticagrelor, 60 milligrams twice a day, for reducing stroke in patients with a prior myocardial infarction from the Pegasus-TIMI 54 trial.

You will remember that in the Pegasus-TIMI 54 trial, ticagrelor was already shown to reduce the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior MI. Of more than 14,000 patients randomized to placebo or Ticagrelor, 213 experienced a stroke, 85% of which were ischemic. 18% of strokes were fatal, and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke, with a hazards ratio of 0.75, and this was driven by a reduction in ischemic stroke. Hemorrhagic stroke occurred in nine patients on placebo and eight patients on ticagrelor. Furthermore, a meta-analysis of four placebo-controlled trials of more intensive antiplatelet therapy in more than 44,800 patients with coronary disease confirmed a marked reduction in ischemic stroke, with a combined hazards ratio of 0.66. Thus this study really broadens our considerations of benefits versus risks of intensive antiplatelet regimens for the long-term secondary prevention in patients with patients with prior myocardial infarction. It really highlights the broader benefits in reducing ischemic stroke, and not just coronary events. In summary, overall, for 1,000 patients initiated on ticagrelor 60 milligrams twice daily for three years, 13 primary endpoint events would be prevented, including approximately five ischemic strokes. This benefit would come at a cost of nine TIMI major bleeds, but no hemorrhagic strokes or fatal bleeds.

That wraps it up for our summaries! Now for our feature paper. Our feature paper today discusses a really important issue that we face everywhere around the world, and that is the management of resistant hypertension. We're taking a very interesting look at the Renal Denervation for Hypertension trial, because we're actually looking at the adherence to anti-hypertensive therapy, and what we've learned in this trial. I'm so excited because I am sitting right here with first and corresponding author Dr. Michel Azizi, from Georges Pompidou hospital in Paris, France. Hello Michel, thank you!

Hello, Carolyn. Thank you also for the invitation to discuss about the paper.

We're also so lucky to have the associate editor who handled the paper, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome, Wanpen.

Hi, Carolyn.

Hi, Wanpen.

This whole issue of resistant hypertension, I'll tell you, to me that means someone who's adequately treated, and despite all the treatment that we can throw at them, they still have a blood pressure that is above a certain level, right?


But your study seems to tell us that that assumption, that everyone's receiving treatment and still having high blood pressure, may need to be questioned, so please tell us a little bit more about what you found.

This is a clinical trial where we compared the effect of renal denervation to medical treatment, optimal medical treatment. We standardized the anti-hypertensive treatment in the cohort of patients with resistant hypertension, and then we followed them on a monthly basis with home blood pressure monitoring. We also increased the intensity of the treatment every month after randomization between renal denervation against nothing, because this is a probe trial, it is not a double blind trial. We gave them the same treatment in both arms. At the end of the many study we demonstrated that there was 6 millimeter of difference, in terms of ABPM, in favor of renal denervation, against the same medical treatment alone.

However, because this trial was an open trial, it was open to a Hawthorne effect, and the possibility that patients or doctors behave differently in each arm of the study. Those having renal denervation may be more adherent to the treatment, and those not being given the new therapy, not being really adherent to treatment. This was an issue, so we specified analysis. We also measured drug levels in urine after six months of followup, and also assessed the exposure to each individual using a peptide in urine, which is N-acetyl-serylaspartyl-lysyl-proline (AcSDKP)/creatinine.

What we found after six months of followup in patients who really participated to this trial, they were willing to participate to the study, they signed an informed consent where it was written that, indeed, we will monitor drug levels. They knew that we would do this. They also knew that we will follow them very carefully every month, et cetera, that we'll provide them home blood pressure monitor for free. They had access to the same doctor, same nurse, same everything. They could arrive at the time they wanted in the morning for being investigated. After six months of followup we found that more than half of these patients did not take correctly their treatment, and even 15% of them, in reality, took zero medication over seven medications. This was a major, major surprise for us in this trial.

I think that's one of the most significant findings, even in a trial setting, that is such a lot of non-adherents, anti-habitants, of therapy. It really makes us question when we say someone has resistant hypertension, is it really that, or do we have just a very non-compliant patient?


Because it can only be worse in the real-world setting, isn't it? Congratulations, that was a very striking message to me as well. What was the other main finding that you wanted to ... ?

The other finding was that the rate of non-adherence was similar in both arms. That there was absolutely no influence of being randomized to the renal denervation group or the medical treatment group only. This means that the patients were not influenced, and other physicians behaved similarly in both arms. Because at the end you have exactly the same rate of non-adherence to treatment. This is also very important.

Yes, indeed. Wanpen, I was wondering what your thoughts were, and take-home messages from this paper. We definitely thought it was significant in the editorial board because you even commissioned a wonderful editorial by Dr. David Calhoun on this. What are your thoughts?

In the United States, using the same technique, we found as much non-adherence. I think there is a lot that we need to do and to understand what caused non-adherence. The patient should not be the only party that's to blame. I think that the doctor's as much of a culprit here to try to tease out what's the barrier to the treatment. Also, as pointed out by Dr. Calhoun, is that although the trials show improvement in blood pressure in both groups, at the end number of medications of patients in resistant hypertension, they require to take four to five drugs to get the blood pressure under control. I think this is going to be a lifelong continuing medication treatment that the physicians have to face, and to deal with the adherence problem as well. Just lastly, I think that although people believe that doing drug levels is only for research purpose, but many people don't realize that actually many drug levels for anti-hypertensive drugs actually is clinical available and can be ordered. It takes a little bit more effort to order it, but it can be done, and actually our center has been doing that already anyway.

Wow. I cannot say that my center has been doing that in Asia, but I really have to admit that this paper made me think about it. Especially the editorial when he highlights it, the very unique information that is provided by actually measuring the blood levels. Michel, you were nodding your head vigorously when Wanpen was saying that we should not just blame the patient. Tell me, what are your thoughts, and how does this affect your clinical practice?

I fully agree with Wanpen. We have to now integrate the fact that it's accessible, you can measure drug levels through technology, with mass spectrometry, et cetera. This is very important to integrate and to change our paradigm that we have to put in our brain. We have to monitor drug levels. Using this technology we have to establish a partnership with the patient.

I think the truth, also, is somewhere, as Wanpen said, we are also culprits. If patients do not take their treatment, okay, there may be some benefit and e have to look why they are not taking pill treatment, but also we are culprits because we don't listen to them, we don't take enough time, et cetera, et cetera. But I think patients should not be only blamed, so it opens a new possibility to discuss with the patient about the fact that we didn't find the drug in levels in their urine, et cetera.

However, taking into account that there will be this toothbrush effect, that is, "Patient, brush your teeth when you go to see the dentist," you'll take the pills when you go to see the doctor so you can be treated. This is one of the difficulties. However I think it's a new possibility to discuss with the patient of his or her difficulties in taking the pills. It gives us the opportunity to discuss, to take time with our patients.

It's really fascinating, you're talking from a system based in Europe. You're based in Paris.


Wanpen just said that she's doing it, and she's based in the US. Do you now routinely, maybe, monitor these medication levels?

Yes, yes, yes.


In the hospital we have these mass spectrometer platforms, so we have access to this, and we are working with the house authority to have the reimbursement. Because I think it's important, because if it's not reimbursed there is also a problem.

Of course.

We are working to see how it could be reimbursed for labs doing these measurements.

But this is for maybe selected resistant hypertensive patients that are difficult to ... ?

Yes, absolutely. Those very difficult to manage. I think, as a rule of thumb, that after four or five drugs given to the patient, if the patient-

Yeah, we should start questioning, are they taking it.

If the patients do not have secondary hypertension, we should really start questioning ourself whether they are taking or not the treatment, even if they are looking right in your eyes and telling you, "Yes, doctor, I'm taking all the pills."

Wanpen, how about the reimbursement issues and things like that in the United States? How are you getting it done in your institution?

Actually the coding for doing drug levels, it's actually generic. It's the same coding for Digoxin or Cyclosporine. They actually don't care about what the name of the drug. Strangely, they're coded by the technique, so that's how we go with it, but we have to put in miscellaneous "other" for, we wanted to test for this. That's how we get around it.

Do you do that again routinely, or in selected patients that are difficult to manage hypertensive?

Obviously we have to be selective, so we select from people who we would suspect are non-adherent, but they say they're taking it. But if they already came in and made that they're not taking the drug, there's no point doing that for the clinical purpose. We're doing it for people who we suspect it, and we use it the way ... Actually we shall describe very well, not only just to find what drug they're not taking, because when they're not taking, only about 30% are not taking everything, about 20% not taking one or two drugs. When we drill down to that drug they say, "I have side effects to beta blocker and I don't want to tell my physician that I have problems taking it, but I just not take it." I think that's what led us to pinpoint the problem a little bit better with this technique.

What a lot of practical advice, and congratulations once again for very, very meaningful findings. I learned a lot this time. I don't do this, and so I'm definitely going to think about this much more because of your work. Thank you very much Wanpen, Michel.

And thank you, listeners, for tuning in this time. Remember, you're listening to circulation on the run. Listen in again next week. Thanks.


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