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Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Dec 11, 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 feature discussion today centers on patients with acute stroke due to large vessel occlusion, and asks the question, "Does interhospital transfer prior to thrombectomy relate to delayed treatment and worse outcomes?" Well, stay tuned for more right after these summaries.

                                                Our first original paper this week tells us that cardio protection is alive, and mitochondrial cardiomyocyte calcium-activated potassium channels of the BK type may be a promising target. In this study from first author Dr. Frankenreiter, corresponding author Dr. Lukowski, from University of Tuebingen in Germany, the authors used a combination of transgenic, pharmacologic and electrophysiological approaches to show that mice with a cardiomyocyte-specific knockout of BK channels had larger infarct size after 30 minutes of coronary occlusion, and 120 minutes of reperfusion, and were less protected by ischemic pre- and post-conditioning maneuvers, such as guanylate cyclase stimulators or activators and phosphodiesterase-5 inhibitors.

                                                In a chronic infarct model, mice with cardiomyocyte-specific knockout of BK channels had more fibrosis and lower left ventricular function. Mechanistically, the activation of BK channels in the inner mitochondrial membrane by cyclic GMP and protein kinase G was identified by patch clamping, and resulted in reduced formation of reactive oxygen species and activation of cardioprotective signaling. In summary, deficiency of BK channels in cardiomyocyte mitochondria rendered the heart highly vulnerable to ischemic and reperfusion injury, whereas the beneficial effects of cardioprotective agents known to target the nitric oxide cyclic GMP pathway required these cardiomyocyte BK channels. This thus establishes these cardiomyocyte mitochondrial BK channels as a promising target for limiting acute cardiac damage and adverse long-term events following myocardial infarction.

                                                The next study suggests that integration of maximal myocardial blood flow and coronary flow reserve, termed coronary flow capacity, may be helpful in predicting cardiovascular mortality in patients with stable coronary artery disease. First author Dr. Gupta, corresponding author Dr. Di Carli, and colleagues from Brigham and Women's Hospital, quantify myocardial blood flow and coronary flow reserve in more than 4,000 consecutive patients referred for myocardial perfusion PET scans from 2006 to 2013.

                                                Maximal myocardial blood flow of less than 1.8 mLs per gram per minute, and coronary flow reserve of less than two, were considered impaired. Four patient groups were then identified based on the concordant or discordant impairment of maximal myocardial blood flow, or its coronary flow reserve. The authors found that in patients with known or suspected coronary artery disease, impaired coronary flow reserve with preserved maximal myocardial blood flow identifies patients at an increased risk of cardiovascular mortality, despite a lack of myocardial ischemia. Patients who may be targeted for initiation or intensification of lifestyle preventive therapies for cardiovascular risk reduction. Conversely, preserved coronary flow reserve, even in the absence of impaired myocardial blood flow, identifies patients at low risk, in whom the need for revascularization should be reevaluated.

                                                The next study provides insights into cardiac regeneration, particularly with regards to using resident cardiac progenitor cells expressing the tyrosine kinase receptor c-Kit, which is being tested in clinical trials. In this study from first authors Dr. Chen and Zhu, corresponding authors Dr. van Berlo from University of Minnesota and colleagues, the authors used single-cell sequencing and genetic lineage tracing to show that there was innate heterogeneity within these c-Kit positive cardiac cells, where some have either endothelial or mesenchymal identity. Cardiac pressure overload resulted in a modest increase in c-Kit derived cardiomyocytes, with significant increases in the number of endothelial cells and fibroblasts. On the other hand, doxorubicin-induced acute cardio toxicity did not increase c-Kit derived endothelial cell fates, but instead induced cardiomyocyte differentiation.

                                                Although the overall rate of cardiomyocyte formation from c-Kit positive cells was below clinically-relevant levels, the authors further showed an important role for p53 in the differentiation of c-Kit positive cells to cardiomyocytes. Thus, this paper shows that different pathologic stimuli induced different cell fates in c-Kit positive target cells. These are novel findings that could aid in the development of strategies to preferentially regenerate cardiomyocytes.

                                                Since December 2014, a series of pivotal trials have shown that endovascular thrombectomy was highly effective in acute stroke management, prompting calls for reorganization of stroke systems of care. But how have these trials influenced the frequency of endovascular thrombectomy in clinical practice? Well, the last original paper in this week's journal tells us how. First and corresponding author, Dr. Smith from University of Calgary in Alberta, Canada, and colleagues, used data from the Get With The Guidelines stroke program to determine how the frequency of endovascular thrombectomy has changed in U.S. practice. They analyzed prospectively-collected data from a cohort of more than two million ischemic stroke patients, admitted to more than 2,000 participating hospitals between 2003 and the third quarter of 2016.

                                                The authors found that the use of endovascular thrombectomy for acute ischemic stroke accelerated sharply after the publication of pivotal randomized control trials beginning in December 2014. The endovascular thrombectomy case volume doubled at hospitals providing therapy. In the third quarter of 2016, endovascular thrombectomy was provided to 3.3% of all ischemic stroke patients. This represented 15.1% of all patients who were potentially eligible for endovascular thrombectomy based on stroke duration and severity. In summary, endovascular thrombectomy use is increasing rapidly, however there are still opportunities to treat more patients. Reorganizing stroke systems to route patients to adequately resourced endovascular thrombectomy-capable hospitals might increase treatment of eligible patients, improve outcomes, and reduce disparities.

                                                Coming right up, we will be discussing even more about endovascular thrombectomy in acute stroke management. Just hang on, our feature discussion is coming right up.

                                                Endovascular treatment with mechanical thrombectomy is beneficial for acute stroke patients suffering a large vessel occlusion. And that is in the guidelines, however we also know that treatment efficacy is highly time-dependent. And so, will interhospital transfer to an endovascular-capable center help in cases of acute large vessel stroke? Well, today's feature paper really helps to present novel data to answer that question. And it is from the STRATIS study. I'm so delighted to have with us the first and corresponding author, Dr. Michael Froehler from Vanderbilt University Medical Center, who will tell us about his findings, as well as Dr. Graeme Hankey, associate editor from University of Western Australia, joining us today. Welcome, gentlemen.

Dr. Michael Froehler:     Hello Carolyn.

Dr. Graeme Hankey:       Thank you Carolyn.

Dr. Carolyn Lam:               Thanks for making the time. Mike, tell us about the STRATIS study. What inspired it, what you found.

Dr. Michael Froehler:     Well, the STRATIS study was actually a large registry of the use of the Solitaire device for large vessel occlusion. Those results, the primary results, were published separately. But what we did in this study is look at one key aspect of the system of care for stroke delivery, in terms of its effect on time to treatment and patient outcomes.

                                                And so in short, what we found is that patients that are transferred from one hospital to another for mechanical thrombectomy take longer to receive treatment, and do worse in terms of functional outcome, compared to the patients that present directly to that thrombectomy center.

Dr. Carolyn Lam:               Wow. Could you put some numbers to that?

Dr. Michael Froehler:     Well, so we looked at 984 patients, almost a thousand patients. And what we found was that the time from stroke onset to revascularization, until the time the vessel was actually opened, was 202 minutes on average, for patients that presented directly to the thrombectomy center. Compared to over 311 minutes for patients that were transferred from one hospital to another. So that's a difference, on average, of over 100 minutes.

Dr. Carolyn Lam:               And I really was impressed with this other analysis you did. So I was wondering if you could share, where you did a hypothetical bypass modeling. Could you tell us about that? Because I thought that was really practical with a feasible message as well.

Dr. Michael Froehler:     I'm excited about that, and I should also share with you that we're working on a more in-depth bypass analysis, to really understand the implications of going to one center directly versus another. But the model that is built in to this publication is really designed to answer one or two questions. And the first is, how much time would we save if we went directly to the thrombectomy-capable center, compared to what actually happened? Meaning the patient was taken to a regional hospital and then subsequently transferred to the thrombectomy-capable center. And this was basically an ideal scenario.

                                                So if they were taken to one hospital and then transferred to another, we simply calculated what the maximum driving time from the starting position to the thrombectomy-capable center would be. And that did rest on the assumption that you actually had to drive past the first hospital. We didn't take any shortcuts in terms of the driving, and probably that small amount of driving time is actually shorter than the number that we found in our calculation.

                                                So the first question was, how much time would we save with that bypass? And the second question was, what kind of impact would that have on IV-tPA? Because, as a lot of us are thinking right now, with strong evidence in support of endovascular therapy for large vessel occlusion, if necessary how should we prioritize getting to endovascular treatment versus the standard therapy that we've known for 20 years, which is IV-tPA? And if you've got a choice, which one is more important?

                                                I don't know the answer to that question, but to try and help lead up to it, we did this hypothetical bypass analysis to look at the impact of bypass, driving directly to the thrombectomy center, the impact of that on the time to delivery of IV-tPA. And so that was really the second question that we asked with this hypothetical bypass analysis.

Dr. Carolyn Lam:               Yeah. I love that analysis, because I agree with you, it's a very, very practical question, and it's the way we clinicians think, right? So, tell us, what's the bottom line?

Dr. Michael Froehler:     So, the bottom line is, you're gonna save about an hour and a half if you bypass the regional hospital and go directly to the thrombectomy-capable center. On average, you're gonna get to the ultimate treatment center 91 minutes sooner, compared to the transferred group. Contrast that 91-minute time savings with a delay of IV-tPA delivery of 12 minutes. So yes, tPA will be delivered a little bit later, but endovascular therapy will be delivered much sooner.

                                                Now, that solution is probably not going to work everywhere, depending on your geography. So one of the other things we did within the hypothetical bypass analysis was limit that analysis only to patients who were transferred within a 20-mile radius. And that doesn't seem like a long distance, but actually there's a lot of patients in that group, that are still taken to the nearest hospital and then need to be transferred to another hospital that may be less than 20 miles away.

                                                So if we looked at that group of patients, then thrombectomy is still performed an hour and a half earlier, in that analysis it was 94 minutes earlier, but IV-tPA was delayed by only seven minutes. So certainly, there is a large group of patients out there that are perhaps being taken to hospitals that are not necessary, it's not a necessary stop.

Dr. Carolyn Lam:               Wow, Mike, this is really amazing results, it's starting to make me think of the old days of acute myocardial infarction treatment, when we were thinking of intravenous thrombolytics, comparison to primary PCI, an analogy and comparison that was also mentioned in the accompanying editorial that you invited. Graeme, would you like to share some of your thoughts on the implication of all this?

Dr. Graeme Hankey:       Just to take a step back, of course this begins with a stroke occurring out in the field. And unlike acute coronary syndromes, where chest pain is the major symptom, there are many symptoms of stroke. And the first problem is trying to identify the patient who has actually had a stroke, and in particular, one of the 15% or so who's had a large vessel occlusion, who's amenable to large vessel mechanical thrombectomy. So in the field we have an issue with clinical triage, and trying to work out who's the one in six who really need endovascular therapy, and who are the five in six who perhaps don't.

                                                And we're trying to develop clinical triage scales like the RACE scale to work out in the ambulance where someone should go. But we still haven't nailed that yet. Then you have scales that are very sensitive but not very specific, and have a high sort of false-positive rate. So then the question at the ambulance is, where does it go, to the hospital, the primary stroke center nearby, and give the patient the earliest opportunity to get tPA?

                                                And that's the potential benefit of early transfer to a primary center, but tPA is not very effective in dissolving these big clots in large arteries. And so, of course the trials have shown a substantial benefit of endovascular therapy to remove the clots via thrombectomy. But those resources, they're only really limited to comprehensive stroke units, and that's what this paper was about. So the trade-off is early transfer to the primary center so you can get some tPA, versus delaying, as Michael has shown, by 1 1/2 to two hours on average, to get to a comprehensive center that can access the expertise of endovascular thrombectomy experts.

                                                And this paper is really taking us forward in emphasizing again that time is brain, and we really don't want to delay. Perhaps there's a small trade-off in driving a little bit further, another 20 miles at the most perhaps, to get to a comprehensive center directly. And there may be some who are not shown to have a large vessel occlusion at that comprehensive stroke center, but the overall benefit is probably offset, the few who might miss out on tPA. And so this is a really important study, the largest registry of large vessel occlusion patients to observe and compare the outcomes after adjusting for all the different factors. And give us some clues, that perhaps we really need to be trying to focus on building our resources in comprehensive stroke centers, and also being able to more accurately identify those who are likely to benefit and go directly there.

Dr. Michael Froehler:     I agree with everything Graeme said, and I would just amplify one thing that he said, that it does depend on distance, and those distances in turn depend on your own geography. We did an analysis of all our transferred patients and then limited it to those that were within a 20-mile radius. For Graeme in Western Australia, you know Graeme's mailbox is probably 20 miles away. And so there are huge distances in Western Australia to account for. And it may not be possible.

Dr. Carolyn Lam:               Contrast that to me in Singapore. I think if I drive any bit more, and I'll be driving out of my country already.

Dr. Michael Froehler:     I think that you make a great point though, Carolyn, that the solution that works for metro Singapore is not what's going to work for rural Western Australia. And we've seen this in New York City, for example. My colleagues at Mount Sinai are looking at different ways to deliver care across metro New York, which obviously is very different compared to myself in Nashville, Tennessee. So the right solution is not gonna be the same solution for everyone.

Dr. Graeme Hankey:       And that's right Carolyn, because in rural places like out in Western Australia, we are learning now that another important message is to try and help upscale and reorganize our primary stroke centers, or just our medical centers out in the rural and remote areas. Because as Mike's paper shows, the delays once someone comes to a primary stroke center or a rural center, is about 30 minutes for diagnosis, about 30 minutes to arrange the transport, and about 30 minutes to actually do the transport.

                                                So we need to once trying to develop comprehensive stroke units, also build up those peripheral hub and spoke centers to be more slick with their diagnosis, arrangement of transport, and transport times. And one of the important things I think is, we need our primary centers, when a stroke does come, to not just do a plain CT to exclude hemorrhage, but to do a CT angiogram at the time. And find out those who really do have an occlusion, rather than putting them all on the plane and sending them down, and quite a few of them don't actually have an occlusion by the time that they've got here. They haven't been fully investigated, it's just an extra five minutes to do the contrast CT angiogram at the time in the primary center if they're gonna go there.

Dr. Michael Froehler:     I think the one other thing I should add, and this is just to reflect back on something Graeme said a minute ago, is that one of the differences we found that really came out of that bypass analysis is the impact on tPA was smaller than we expected. Because the door-to-needle times are actually much longer at the regional hospitals that are not thrombectomy-capable, compared to the thrombectomy centers themselves, that are not only obviously delivering mechanical thrombectomy, but are actually delivering IV-tPA much sooner in terms of door-to-needle times.

Dr. Carolyn Lam:               So, room for improvement even for non-endovascular-capable centers, isn't it?

Dr. Michael Froehler:     Right, I think it's another area where there's room for improvement.

Dr. Carolyn Lam:               Please don't forget to tune in again next week.

Dec 4, 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 Center, and Duke National University of Singapore. This week's journal features important information, that will aide identification of children with latent rheumatic heart disease, who are at highest risk of unfavorable outcomes. This important discussion is coming right up after these summaries.

                                                The first original paper this week describes the largest study to date to examine payer approvals and rejections of PCSK9 inhibitor therapy, and describe the patient characteristics associated with successful prescribing. First author, Dr. Hess, corresponding author Dr. Yeh and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts, performed a retrospective descriptive cohort study utilizing nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The data set included over 220 million patients from all 50 states, and all pair types with more than 5,000 distinct health plans. PCSK9 inhibitor prescriptions were submitted for 51,422 patients in the pharmacy data set.

                                                The authors found that among patients who were prescribed a PCSK9 inhibitor, 47% were approved for coverage by the payer. Variables that were associated with approval included age above 65 years, history of atherosclerotic cardiovascular disease, prescription by a cardiologist or a non-primary care provider, statin intolerance, longer statin duration, and non-commercial payers. Interestingly, higher LDL cholesterol levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates of 24 from 4% and Medicare had the highest at 60.9%. Thus, rates of approval for PCSK9 inhibitor therapy are low, even for patients who appear to meet labeled indications. While a combination of clinical characteristics increase the likelihood of approval, payer type is the most significant factor.

                                                The next study identifies a novel mitochondrial localized protein that plays a role in cardiac dysfunction, remodeling, and heart failure. This protein is FUN14 domain-containing 1, or FUNDC1, a highly conserved outer mitochondrial membrane protein. In today's study, first author, Dr. Wu, co-corresponding authors, Dr. Xie and Zou from Georgia State University, and their colleagues, showed that in cardio myocytes, FUNDC1 bound to inositol 1, 4, 5-triphosphate type 2 receptor, to form mitochondria-associated endoplastic reticular membranes.

                                                These, in turn, modulate a calcium release from endoplasmic reticulum into mitochondria and the cytosol. FUNDC1 deletion lowered the levels of calcium in both mitochondria and the cytosol. A reduction at intracellular calcium resulted in mitochondrial fusion, mitochondrial dysfunction, cardiac dysfunction, and heart failure. In summary, this study identifies FUNDC1 as a novel mitochondrial localized protein that plays a role in maintaining mitochondrial dynamics, and cardiac function, and may therefore be a therapeutic target in heart failure.

                                                The next study takes a deep dive into the J-Curve phenomenon of systolic blood pressure by providing an experimental approach to an observational paradigm. First and corresponding author, Dr. Kalkman, from University of Amsterdam and colleagues assess the association between on-treatment systolic blood pressure levels, cardiovascular events, and all cause mortality in patients randomized to different systolic blood pressure targets in the pool database of the SPRINT-6 and ACCORD trials. For both the intensive blood pressure target of less than 120 millimeters mercury, and the conventional target of less than 140 millimeters of mercury, the authors found an identical shape of the J-curve was present with a [inaudible 00:04:44] for cardiovascular events and all cause mortality just below the systolic blood pressure target.

                                                The advantage of the intensive treatment group persisted at any level of the difference between the intended target and the achieved blood pressure targets. As discussed in an accompanying editorial by Dr. Verdecchia from Hospital of Assisi in Italy, these data suggest that if two patients achieve identical low values of blood pressure during treatment, prognosis is expected to be better in the patient actually targeted to achieve low values. Conversely, the outcome might be worse in the patient randomized to a higher blood pressure target, because low values in this case possibly reflect masked or unmasked confounders linked to a poorer outcome.

                                                Thus, physicians should not be reluctant in lowering blood pressure in their patients because of an expected detrimental effect of BP reduction on death or major cardiovascular events. Rather, they should carefully monitor the possible occurrence of other adverse effects linked to blood pressure lowering, such as syncope, renal impairment, or electrolyte disturbances. This study further suggests that the benefit or risk associated with intensive blood pressure lowering treatment can only be established via randomized clinical trials and should not be extrapolated from observational data.

                                                The final study establishes a causal link between dysregulated Tryptophan metabolism and abdominal aortic aneurysm. In a series of elegant mouse experiments from first author, Dr. Wang, two corresponding authors, Dr. Liu] and Ding from Georgia State University in Atlanta, Georgia, the authors establish that 3-Hydroxyanthranilic acid or 3-HAA, a key Tryptophan catabolite of the Angiotensin II induced abdominal aortic aneurysm in vascular smooth muscle cells was indeed responsible for Angiotensin II induced abdominal aortic aneurysm in Vivo. 3-HAA activated nuclear factor kappa-B transcription factor, promoted matrix metallopeptidase 2 expression in vascular smooth muscle cells. Human abdominal aortic aneurysm samples had stronger staining with the antibody against 3-HAA, than those in the adjacent non-aneurysmal aortic sections of these samples.

                                                The identification of 3-HAA in Angiotensin II triggered abdominal aortic aneurysm and in human patients with abdominal aortic aneurysms, suggests that Tryptophan derived metabolites may be a biomarker for abdominal aortic aneurysm diagnosis. Furthermore, agents that alter Tryptophan metabolism may have a therapeutic potential in preventing or treating abdominal aortic aneurysms. Well on that intriguing note, we're at the end of this week's summaries. Now, for our featured discussion.

                                                Today's feature paper really reminds us that rheumatic heart disease remains the most common cardiovascular disease among the world's youth. These days, echocardiographic screening provides a promising tool for early detection. However, the utility of this tool really depends on knowing the natural history of screen detected rheumatic heart disease, so-called latent rheumatic heart disease. Now, that has remained clear until today's paper. I'm so pleased to have with us the first and corresponding author, Dr. Andrea Beaton, from Children's National Medical Center in Washington D.C., as well as Dr. Bongani Mayosi, Associate Editor from University of Cape Town, South Africa. Andrea, could you start by letting us know about your study and what you found?

Dr. Andrea Beaton:         As you mentioned, over the last decade or so it's become clear that in addition to the substantial burden of clinical rheumatic heart disease that we see around the world in low and middle income countries, there's also an even larger burden of latent rheumatic heart disease or early rheumatic heart disease that we can see on echo. This brings up the question if echo screening might represent a very powerful tool for rheumatic heart disease control, but we can't move forward with that discussion until we understand the rate of progression of children who are found to have echo detected rheumatic heart disease, and if we can do something to intervene to prevent progression in that population.

                                                That something is likely penicillin, which is known to prevent progression in clinical rheumatic heart disease. To start to address that question, we followed a large cohort of children who had been diagnosed with echo detected rheumatic heart disease through school-based screening in different areas of Uganda and had collected about 227 cases of children with latent rheumatic heart disease who had been in clinical followup between two and a half and almost six years.

Dr. Carolyn Lam:               Great. Could you tell us what you found about the progression and risk factors perhaps of progression, which I think are most significant?

Dr. Andrea Beaton:         Right, so this is the largest natural history cohort of children with latent rheumatic heart disease to date and four major findings emerged from our study. The first is that we find a lot of echo detected rheumatic heart disease in low income settings that is more advanced. What we found is that children, even if this is their first time of diagnosis at echo screening, if they had moderate to severe rheumatic heart disease on screening, if they had poor outcomes even if over a very short time period. In our study, children with moderate to severe disease, only 10% of those children improved over the study period and 10% had died after only two to five years of followup.

                                                We also saw that kids with mild, but definite rheumatic heart disease, which is more criteria for rheumatic heart disease than borderline, showed worse outcomes. Although, both children with mild definite and borderline disease had substantial risk of progression. 25% progressed in the mild definite group and 10% in the borderline rheumatic heart disease group. That tells us that even with very minor changes on echo screening, there is substantial risk of progression to more severe rheumatic heart disease, because we had a larger cohort using a multi-variant model.

                                                We also found that there were features of rheumatic heart disease that put children at higher risk of progression. In our cohort, if children had aortic insufficiency at the time of screening, or some specific morphological changes, or changes in the mitral valve at time of screening, then they had higher risk of progression. While older age at time of screening showed a protective effect against progression.

Dr. Carolyn Lam:               Wow. Andrea, congratulations on this remarkable study and you've highlighted so many important public health messages just in this one study. Bongani, what do you think was the most important or significant finding?

Dr. Bongani Mayosi:        The most important finding is the reflection of the progression even in the mild and borderline cases. I think there has been an understanding that the definite cases do have a higher rate of progression and on top of that, I think showing the fact that there are some predictors that can be detected on echo is also very useful. Those with more advanced disease categories, those with younger age, as well as those with morphological valve abnormalities, I think those are very, very valuable points. Of course, the other point that is not all here is the fact that the majority of the initial progression appears to occur early and this is brought out in this study because of the serial echos that were done, which is again, another very valuable and a unique aspect of the study.

                                                Previous studies have only done an echo at the time of diagnosis and perhaps an echo at the end of the followup period. I think that these features really make this study a valuable one. There is one question though that I wanted to put to Andrea, the issue of auscultation is one that we realized very early was not very useful for screening patients with latent rheumatic heart disease. We missed too many. I'd like to ask you now, once we've identified patients with latent disease, do you think auscultation of those patients could in fact identify the ones with clinical disease? Presumably, the more severe aortic regurgitation, mitral regurgitation, may be audible using a stethoscope? In other words, now shifting the role of the stethoscope not so much for diagnosis, but for risk stratification. I just want to know if you looked at this issue at all in this particular cohort?

Dr. Andrea Beaton:         That's a really good question, Professor. We did not specifically look at the role of auscultation in this cohort. Although, it stands to reason that children with moderate to severe rheumatic heart disease, which by our definitions meant at least moderate to severe regurgitation at one of the valves, or presence of mitral stenosis would be audible. In that way, I think separating out children with moderate to severe disease, versus children with mild definite and borderline disease, would be quite possible and reasonable by auscultation.

                                                My worry with the use of auscultation is I don't think it would separate out well children with mild definite disease, who by definition could have no more than mild regurgitation at any one valve, from children with borderline disease. Whether that distinction is important, I think still remains to be understood, but it would not be a very sensitive way to follow children until they had progressed to the point of having much more significant disease. I think echo still remains incredibly sensitive compared to auscultation for minor progressions, which to be clear, were included here as counting as progression of disease, even minor changes on echocardiographic evaluation.

Dr. Carolyn Lam:               I have a question along the same lines Andrea, what kind of expertise was required for these echocardiographic screening procedures, both of the acquisition and then the interpretation? I do notice that you had a trained pediatric cardiologist with expertise in rheumatic heart disease who actually re-reported some of the echos. Do you think this is needed? What do you think about that?

Dr. Andrea Beaton:         This is a complicated question, but a good one. A lot of the research that we've done outside of this paper has been looking at the ability to task shift echo screening, so to have non-physicians, not experts conducting echo screening. What we found across the board, as well as other groups around the world have found, is that you can train non-experts in a relatively short period of time to both screen and diagnose, at least on a screening basis, the presence of absence of rheumatic heart disease. For the purposes of this study, we're using very precise and very detailed diagnosis. According to the World Heart Federation criteria, which do really require experts to interpret.

Dr. Bongani Mayosi:        The other issue, Andrea, which you highlight in the paper is the whole issue of the definition of progression, and regression, and the fact that there isn't consensus in the field about how we handle that, which results in papers not being comparable among each other. What do you suggest is the way of taking this forward so that we can build a consensus and a way of actually following up this patients that will be comparable between studies?

Dr. Andrea Beaton:         That's a really important question and something we struggled with while we were writing this paper. You'll note in our paper that we reported it in two different ways because we couldn't come to a consensus and we thought both had some legitimate importance. Most of the papers in this field have reported the groups as progression and as stable lumped together, versus regression or improvement of disease. We felt the most important endpoint and something we had the numbers to power, was progression by itself. How many children were getting worse over the study period? In one sense, we powered it progression, versus stable plus regression, trying to dichotomize it still.

                                                Then on the other hand, we thought that it was important if you had mild definite disease, even if you remained stable and mildly definite, and so we reported differently on the second outcomes based on if you had definite disease where we grouped progression and stable together, versus if you had borderline where we only counted true progression as a change for the worse. I don't have the perfect answer of how this should be reported. Although, I think the more granular we can be as we report these studies going forward, the more we can separate out the data that is reported to make it comparable. A lot of the previous papers, I think, lack the granularity needed to compare in different ways.

Dr. Carolyn Lam:               We're coming to the end of our time, so may I just wrap up by asking Andrea, what do you think are the next steps?

Dr. Andrea Beaton:         That's a good question and something I feel strongly about. Another part of our paper showed that the other incredibly important outstanding question is if we can find these kids, can we change what happens to them over time, and does penicillin do that? Even with our large cohort of patients, we couldn't determine the effect of penicillin on progression or trajectory of these children over this time period. It's something that now that we have large numbers of children and still can't come to a conclusive response, I think warrants a randomized control trial to look at the effect of penicillin on children with echo detected rheumatic heart disease, because that's really what's going to drive the policy on if echo screening makes sense as a public health policy to reduce the global rheumatic heart disease burden.

Dr. Carolyn Lam:               I'm sure listeners out there, you've appreciated this as much as I have. Tune in again next week.

Nov 29, 2017

Jane Ferguson:                 Hello, I'm Jane Ferguson and you are listening to Getting Personal: Omics of the Heart, the podcast from Circulation: Cardiovascular genetics, and the functional genomics and translational biology council of the AHA. This is episode ten, from November 2017.

                                                November is always a big month for AHA and the annual Scientific Sessions were held in Anaheim, California, November 11th through 15th. For those of you who were able to attend, hopefully you came away feeling refreshed and invigorated and with your desired level of Disney merchandise. For those of you who could not attend, or who didn't make it to all of the genomic sessions, this month's episode should catch you up.

                                                For the past several years, the FGTB Council has been organizing boot camps at AHA sessions to give people a chance for hands on learning in a flipped classroom model. This year was no exception and in addition to a clinical genomics boot camp focused on patient centric genomics including single gene testing, whole genome sequencing and pharmacogenomics there was also a new boot camp focused on tackling big data network systems analysis for high input data interpretation.

                                                These boot camps are always very well attended and popular, so if you're interested in attending one next year, make sure to get in early and sign up during registration. There was also a hands on session in collaboration with the AHA's Precision Medicine Institute to teach people how to use the precision medicine platform to further their research.

                                                In addition to this, there was a full day of programming related to precision medicine in the precision medicine summit, which is held on the Tuesday of Sessions. That covered topics ranging from big data, electronic health records, collaborations and the All of Us initiative to rapid fire reports from ongoing consortium, large scale analysis to disease specific approaches in cardiomyopathy.

                                                We were planning to have an in depth focus on the Institute for Precision Cardiovascular Medicine in a future podcast episode, so stay tuned for more on that coming soon. There were a number of individuals who were recognized for their contributions to science and we would like to congratulate all of these outstanding individuals.

                                                The FGTB medal of honor was awarded to Stuart Cook from the Duke National University of Singapore. The FGTB mentoring award was awarded to Robert Gerszten from Beth Israel Deaconess Medical Center. The FGTB distinguished achievement award went to Sekar Kathiresan from the Broad Institute. And the functional genomics and epidemiology mid-career research award went to Kiran Musunuru from the University of Pennsylvania. Congratulations to all of these.

                                                One of the highlights for the FGTB council at sessions is the FGTB young investigator award. This award celebrates early career investigators and recognizes outstanding research in basic science, populations science, genetic epidemiology, clinical genetics and translational biology. Four finalists presented their research on the Sunday afternoon sessions and I had the chance to chat with all four of them before and after their presentations. So listen on for a behind the scenes over view of the finalists research and the announcement of the winner.

                                                Mark Benson is a cardiology fellow at Brigham and Women's Hospital and is working on post-doctoral research at the Beth Israel Deaconess Medical Center in Boston with Dr. Robert Gerszten. His talk was entitled "The Genetic Architecture of the Cardiovascular Risk Proteum."

Mark Benson:                    My name's Mark Benson. I'm just finishing up a cardiology fellowship at Brigham and Women's Hospital and am in the middle of post doc in Robert Gerszten’s lab at Beth Israel.

Jane Ferguson:                 Great, and congratulations on being chosen as a finalist for the FGTB Young Investigator Award. We would love to hear a little bit more about what you’re working on and what you're gonna be telling us.

Mark Benson:                    Yeah, absolutely. So the goal of the project was really to integrate proteomic data with genomic data, with the idea that we may be able to use the overlap between those data sets to identify potentially novel biological pathways that underlie very early cardiovascular disease risk.

                                                And the thinking behind that was that the lab had just finished up applying DNA-aptamer-based proteomic platform to profile over 110 proteins and the Framingham-Offspring Cohort and from that work, we had identified a very specific signature of 156 proteins in plasma that were each very strongly associated with cardio-metabolic risk.

                                                The idea was while those associations were very strong, it was unclear if we were capturing cart or horse or how these associations were fitting together. We wanted to incorporate the genomic data to try to get a better handle on that, to try to connect those pathways to see how these proteins might actually associate with the end phenotype of risk.

Jane Ferguson:                 It's a sort of Mendelian randomization-esque.

Mark Benson:                    Exactly, yeah. So what we were able to find in doing this, we were able to use peripheral blood samples from participants at the Framingham-Offspring study. With a validation in participants of the Swedish Malmo Cancer and Diet Study. Then we did protein profiling using commercial DNA aptamer platform, soma scan. What we were able to find is we were able to detect very strong associations between these circulating cardio metabolic risk-proteins and genetic variance.

                                                What was fascinating was we were able to see many things. We were able to start mapping where are these associations, where are these genetic variance in relation to, for example, the gene that's coding the protein that we're measuring. That had some interesting implications because for about half of the protein that had significant associations, we could track those genetic variance back to the gene. It was coding the protein that we were measuring, which was interesting because it's validating the specificity of the proteomic platform that we're using.

Jane Ferguson:                 Right that's nice, because so often you found a gene that's nothing related to what you think it's going to be so it's nice actually the gene you expect.

Mark Benson:                    Yeah, it's very reassuring too when you're looking at rows and rows and rows of data. When the top association of the p value of 10 in the minus 300 is the actual gene you thought would be coding the protein that you're measuring. So that was very reassuring, but we also found dozens and dozens and dozens of associations that were totally unexpected and that may point to completely unexplored biological pathways in cardiovascular disease. So that was obviously very exciting.

                                                That actually led us to do two things. One was to make all these data available publicly on dbGaP because as a resource for cardiovascular research there is just way too much data for one group or a handful of groups to digest. The other thing that was fun about the project, is we were able to take one association that was particularly interesting for a number of reasons and experimentally validate it in a tissue-culture model.

Jane Ferguson:                 So how did that work?

Mark Benson:                    So this was an interesting challenge where we all of a sudden got all of these hits back, which was probably to be expected, but to try to figure out which of these dozens and dozens and dozens of new, unexpected hits, what do you do? There was one hit, one association, that was particularly strong and it was between several variance around this gene. That's a phosphatase called PPM1G. It's a transcription factor.

                                                These variants, which was interesting, were associated with several different circulating cardio metabolic risk proteins. So our idea was, isn't that interesting? Is it possible that this is mapping to some central regulator? And so it fit that that would be ... that the nearest gene to these variants was a transcription factor and could be a central regulator.

                                                What made it more interesting to us was that several variants in the GLGC had recently been described that were highly associated with circulating levels of total cholesterol and triglycerides and they were located around this PPM1G locus as well. The association between those variants and circulating cholesterol didn't have a clear biological connection.

                                                So what our work had shown is that those same variants were associated with circulating levels of apolipoprotein E. So wouldn't that be interesting if these variants mapped to PPM1G, the transcription factor, this PBM1G in turn regulated circulating apolipoprotein E and that would provide some insight into the biology behind the GLGC findings.

                                                So sure enough we were able to knock down PPM1G using SRNA and hepatocytes and then see that that led to a significant down regulation of the transcription of Apo-B and extra-cellular presumably secreted Apo-B in this model, which is kind of a nice proof of principal that this idea of integrating proteomics and genomics may lead to some novel biological pathways.

Jane Ferguson:                 Yeah, it's really interesting. So what's next. There are probably a lot more associations that you're going to have to go after?

Mark Benson:                    Yeah, I think that what this showed us is that this seems like a powerful tool. Joining these orthogonal data sets to find new pathways and so we're continuing to pursue that with an increasing number of proteins for example, so we're doing genome-wide association studies and x-gamma rays. We've gone from 156 to 1100 to 1300 and are now going beyond that and so as those numbers get higher, you start to see these central nodes come together and more interesting targets and potential pathways. It's also interesting to use these data to find new associations or new tools that you would never think to look for as ways to modulate protein levels.

                                                So you can imagine, for example, one thing that we've been exploring for the last few months is can we identify, for example, SNP associated with an interesting circulating protein. That SNP maps to an enzyme or some other druggable mechanism and very preliminary studies, it seems like the answer is probably yes, but there is still a lot of work to be done.

Jane Ferguson:                 Well that's cool. That sounds really interesting.

Mark Benson:                    Yeah, I think the key thing is that all these data will soon be out there and so it's a very rich data set and I think there are many ways that we could use the data.

Jane Ferguson:                 So is that the genomic data and all the proteomic data or it's the summary of the those associations?

Mark Benson:                    All the genomic data, all the proteomic data and the associations as well. You can do the associations yourself if you'd like to.

Jane Ferguson:                 We can find that dbGaP. Awesome, well thank you for talking to us.

Mark Benson:                    Thank you. It's been fantastic.

Jane Ferguson:                 Congratulations again.

Mark Benson:                    Thanks so much. ...

Jane Ferguson:                 Jenny Lin is an instructor at the University of Pennsylvania, working with Dr. Kiran Musunuru. Her presentation was entitled, "RNA binding protein A1CF Modulates Plasma Triglyceride Levels through Transcriptomic Regulation of Stress-Induced BLDL Secretion".

                                                Jenny, can you take a moment to introduce yourself?

Jenny Lin:                            Yes, hi. Thank you for this opportunity to participate. I'm Jenny Lin. I'm an instructor of medicine at the University of Pennsylvania, a nephrologist by clinical training, but training in cardiovascular research in Kiran Musunuru's lab.

Jane Ferguson:                 So congratulations for getting selected as a finalist for the Young Investigator Award. We'd love to hear a little bit more about what you've been presenting and what you've been working on.

Jenny Lin:                            Thank you. So basically, what I've been working on over the past year is functional follow-up of this A1CF locus, which is a novel locus for triglycerides. So say Sek Kathiresan's group recently published in Nature Genetics and x and y association study on plasma lipids involving more than 300,000 individuals.

                                                One of the key findings from that study is this strong association between a lo-frequency coding variant and elevated plasma triglycerides. So we wanted to delve more deeply into the biology for why we have that genotype/phenotype connection. One of the key things that we wanted to do was ... A1CF is not a stranger to lipo-protein metabolism, but we wanted to see what else it may be doing outside of its canonical role of facilitating the editing of Apo-B messenger RNA.

                                                It really took us on a little bit of a wild journey using different unbiased approaches to try to figure out some of the mechanisms that could be behind it.

Jane Ferguson:                 So you had to do a lot of different types of experiments to really get at this question.

Jenny Lin:                            Yeah. So again, one thing we wanted to see was: if you lose A1CF function, whether or not you would have differences in Apo-B 100-B48. We actually found that A1CF isn't even needed for that editing reaction and that our mice that we were able to create with crispr cas9 genome editing, so knocking in the mutation and knocking out the gene, actually have the phenotype even though they don't have changes in editing.

                                                But what surprised us was that we know that A1CF as an RNA binding protein binds Apo-B transcript, yet it somehow does not alter transcriptional abundance of the Apo-B messenger RNA. And it has nothing to do with Apo-B synthesis so we basically had to think, what is A1CF doing outside of Apo-B biology?

                                                We found that you have A1CF loss of function, you have increased triglycerides secretion. There is more Apo-B secretion, but that seems to be a downstream effect of other processes going on in the cell and to really try to figure out what those processes are, we had to take an unbiased approach using enhanced clipseek to figure out binding targets and also doing some transcriptional profiling with RNA sequencing and found that it's not necessarily regulating that transcriptum on a differential expression level, but there are some key alternative splicing events as well as messenger RNA binding to affect translational efficiency of some key targets that could be driving the biology.

Jane Ferguson:                 That's really interesting and you wouldn't have been able to find that by just looking at levels of protein or levels of mRNA, you really had to do these additional clipseek and some experiments to really get at this splicing.

Jenny Lin:                            Yeah, so it's been interesting. Clipseek is not as commonly performed method, so we had to collaborate with some brilliant people over at UCSD, to help us facilitate this. But again, finding that A1CF binds many more transcripts than Apo-B itself is a novel finding and the fact that it can regulate alternative splicing is also a very novel finding as well.

Jane Ferguson:                 So what was the most challenging part of this whole project?

Jenny Lin:                            I think the challenging part was that when we saw there wasn't necessarily a direct effect on Apo-B abundance and having to then cast this wide net and then figure out from all of the different unbiased data we have and integrating it find different pathways that may be relevant. In this case, it may all be relevant to ER stress, which is a field that is a little bit controversial in VLDL secretion in terms of directionality, but certainly is important in the biology.

Jane Ferguson:                 So is that something that you're going to have to start doing in the future? Are you going to start looking at ER stress or what kind of other experiments do you think you're going to keep doing to move this project forward?

Jenny Lin:                            Yeah, so actually, I think focusing in on A1CF as an RNA-binding protein and pursuing some of these additional targets will also be relevant, so I think in terms of ER stress, we could be looking at different targets, but there other processes going on in the cell that's mediated by A1CF, that could contribute maybe doing some isoform specific studies just to really prove that these alternative-splicing changes are driving some of the biology.

                                                There's a lot of work to do as I would joke to anyone on study section listening to this, perhaps four to five years of work for an RO1.

Jane Ferguson:                 Sounds very appropriate.

Jenny Lin:                            Yeah, there's a lot of exciting work to do. A1CF is actually also a locus for other cardio-metabolic relevant traits such as uric acid, gout and kidney function so there could be something very interesting going on. There could be cross talk among cellular processes that could lead to these different phenotypes.

Jane Ferguson:                 Really interesting project and a lot of really great work. Congratulations again on being selected as finalist and on this really interesting paper.

Jenny Lin:                            Thank you.

Jane Ferguson:                 Thanks.

                                                Sarah Parker is based in Cedar Sinai Medical Center in LA and her mentor is Dr. Jenny Van Eyk. The title of her presentation was "Identification of Putative Fibrous Plaque Marker Proteins by Unsupervised Deconvolution of Heterogeneous Vascular Proteomes ". And I apologize in advance for the quality of this recording. The background noise wasn't that noticeable at the time, but that recording really gives you that full immersive audio experience of a busy hotel lobby.

                                                Hey Sarah. Thank you for joining us. Could you just take a few moments to introduce yourself to the audience?

Sarah Parker:                     So I'm Sarah Parker. I'm a project scientist at Cedar Sinai Medical Center where I'm doing work to study the basic mechanisms of vascular biology of various indolent conditions.

Jane Ferguson:                 So congratulations on being selected as a finalist for the Young Investigator Award. It's a great achievement. I'd love to hear a bit more about your project, how that started and what you found.

Sarah Parker:                     The work that I did was under the overarching umbrella of a project called the Genomic and Proteomic Architecture of Atherosclerosis. So with this project, we're using tissues that we're able to obtain from individuals who are young and have passed away from traumatic and violent and so non-cardiovascular causes of death. Because of the presence of atherosclerosis in the population, we get this range of lesion, both fatty streak and fibrous-plaque lesions in these asymptomatic or non-diseased individuals and this gives us this opportunity to do some molecular profiling to really try to find protein-signatures of early stage plaque formation, that could ultimately and hopefully be used for biomarker development.

Jane Ferguson:                 That's really cool and that's such a valuable sample resource.

Sarah Parker:                     Yeah so we've essentially, in this project I was able to set up a pipeline that enabled us to do these proteomics on such a large scale, because that's actually really difficult in label free quantitative proteomics and to use other forms becomes very expensive and cost-limiting.

                                                So we were able to find a panel of proteins that we think are a putative early set of fibrous plaque markers and with this panel, we took them to see if any of these tissue derived markers would then be detectable and informative in plasma, because that's the next really big translational leap with these discovery-type data sets. Of our 58 initial candidates, we were able to detect 39 of them and about a handful 10-13 are showing informative behavior in the plasma of initial cohort of women with known coronary-artery disease.

Jane Ferguson:                 So out of the 58 that you first found, how many of them were potentially known to be involved in disease and how many were novel?

Sarah Parker:                     I would say, going through the list, it was probably about 50/50 in terms of background data that shows role as a biomarker, so there are a lot of apolipoproteins, which have all been characterized as potential biomarkers. There were a lot that could feasibly be linked through the literature to atherosclerosis. Most of them made a lot of sense, but having been proposed as potential biomarkers, some of them were more rare.

Jane Ferguson:                 Were there any of them that were sort of in different directions, let's say were elevated in tissue, but then were lower in plasma?

Sarah Parker:                     Funny you should ask. That actually has us scratching our heads a little bit right now. There were a couple of apolipoproteins that are more associated with HDL biology that we saw as being elevated in the tissue but then lower in the plasma [inaudible 00:23:34] so that's a really interesting observation so something about the role of these proteins to scavenge cholesterol and then once they're in the blood, they're cleared really quickly relative to normal, or something. So we're really trying to figure out what that biology means.

Jane Ferguson:                 Maybe if they're building up in the tissue, that's bad. But while in circulation, they're fine.

Sarah Parker:                     Yeah, maybe they're trapped in the circulation. We have a lot of exciting hypotheses to test along that front.

Jane Ferguson:                 So what's next? Are you following up some of these proteins?

Sarah Parker:                     Yep, so we have a huge discovery arm to the project where we're looking for more molecular mechanisms like why do we have these things in the tissue versus plasma and then we are working to really validate and optimize these multi-plexes in much more generalized large-scale populations to determine whether this strategy of instead of one or two biomarkers, more of a signature-style panel can be informative, especially as we try to press towards a precision medicine approach where different substratum might be informed by different protein signatures.

Jane Ferguson:                 Right, so you might have to have a specific panel based on sex or age or race or some other demographic.

Sarah Parker:                     Yes and to find those signatures, it's going to be very big numbers, with very accurate, careful quantitation.

Jane Ferguson:                 So you have a lot of work to do.

Sarah Parker:                     Yes.

Jane Ferguson:                 Alright, well thank you for talking to us and congratulations again.

                                                Louie Wang, a cardiologist and PhD student came all the way from the Victor Chang Cardiac Research Institute in Syndey, Australia. His mentor is Dr. Diane Fatkin. The title of his talk is "A novel zebrafish model of human A-band truncated titan exhibits alternated ventricular diastolic compliance in vivo and reveals enhanced susceptibility to the effects of volume overload in mutation carriers.

                                                So thank you for joining me. Could you take a few minutes to introduce yourself?

Louie Wang:                       So I'm Louie Wang. I'm a cardiologist based in Australia. I work and live in Sydney. I'm a PhD student at the Victor Chang Cardiac Research Institute and I'm an NHMRC (National Health and Medical Research Council and National Heart Foundation of Australia post-graduate scholar). I have previously been based at St. Vincent's Hospital.

Jane Ferguson:                 Great. So we'd love to hear a little bit in advance of what you're working on and what you're planning to present.

Louie Wang:                       So basically what I'm presenting is what I think is a different form of functional of genomics. What we're actually looking at is the impact of genetic changes, specific genetic change on function of the heart at an organ level. So there is a problem out there that is very common in cardiology and it's a big problem in cardiology and that is there are mutations in the sarcomere protein titan, truncating variants which actually are associated with dilated cardiomyopathy.

                                                Now they're pretty common in idiopathic dilated cardiomyopathy, present in about 15-20% of the cases depending on which cohort study you look at. But they're also widely prevalent in the general population. Somewhere between 0.3 to 1% of the general population carries this truncating variants or various forms of this truncating variant.

                                                So it's not sure whether these are disease-causing in their own right or if it's just a genetic susceptibility factor for heart failure and so what our work involves is that we actually, by chance, at St. Vincent's Hospital and at Victor Chang Cardiac Institute, two families who had the identical genetic truncation in the A-band region of his human titan gene where the individuals in the family, typically who carried the gene, typically developed systolic heart failure, which is a mild phenotype and occurred at middle age, but in two individuals, they developed severe onset accelerated disease trajectory in a very severe phenotype when exposed to conditions associated with chronic volume overload.

                                                We suspect and this was a hypothesis, not only was this genetic-truncation disease-causing, but at volume overload was disease-modifying and given that volume overload is a very common condition present in birth, a lot physiological processes like lung endurance, exercise, pregnancy as well as a lot of pathological disease states in cardiovascular disease, this was actually a very important modifiable factor.

                                                So what we did, was we created a novel zebrafish model of this human A-band truncated variant. We then studied the animals when they became adults to look at their heart structure and function and we used zebrafish echocardiography. So reversed translated all the techniques you can do in human echocardiography so they can be used in the zebrafish.

                                                What we found was, yes, this animal, or heterozygotes developed dilated cardiomyopathy but also the volume overload exacerbated this condition. So this is a phenomenon that has conserved this by four hundred million years of vertebrate evolution so this is a pretty important mechanism.

Jane Ferguson:                 So what kind of next steps do you see for this project?

Louie Wang:                       So one thing is that we obviously have shown that there is an association with volume overload in precipitous disease. The corollary of our work is that perhaps interventions that could reduce volume load in these genetic susceptible individuals or alternatively in people who can't avoid volume overload. Because a lot of volume overload conditions can be modifiable and perhaps this could be protective and that would have wide-ranging population benefits.

Jane Ferguson:                 Thank you for sharing that soundbite of your work and good luck. Congratulations again on becoming a finalist.

Louie Wang:                       Thank you. ...

Jane Ferguson:                 Each of these four finalists gave compelling presentations of their research and the judges were highly impressed of the quality of the research and level of accomplishments of these early career investigators.

                                                Just getting selected as a finalist for this award is a huge accomplishment. But there did have to be one winner. I'm delighted to announce that Jenny Lin was selected as the 2017 FGTB Young investor award winner. Congratulations, Jenny, and thanks to all four finalists for agreeing to appear on this podcast.

                                                And that's all for this month. We'll be back at the end of December with a new episode. Subscribe to the podcast through iTunes or your favorite podcast app. to get new episodes delivered automatically and thank you for listening.

 

Nov 27, 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 Center and Duke National University of Singapore.

                                                Our journal this week features novel data informing the choice between conscious sedation and general anesthesia for transcatheter aortic valve replacement. A very relevant discussion for those of us who see these patients. Stay tuned, that's coming right up after these summaries.

                                                Subclinical hyperthyroidism is known to be associated with an increased risk of atrial fibrillation, but the association with thyroid function in the normal range or subclinical hypothyroidism is unclear. That is, until today's study, which shows us that variation in thyroid function within the normal range is associated with atrial fibrillation.

                                                First author, Dr. Baumgartner, corresponding author, Dr. Rodondi and colleagues from University of Bern in Switzerland, conducted a systematic review and obtained individual participant data in more than 30,000 participants from 11 prospective cohort studies that measured thyroid function at baseline and assessed incident atrial fibrillation, which occurred in 8.6% of individuals.

                                                They found that in youth thyroid individuals, there was a significant increase in the risk of atrial fibrillation with increasing free T4 levels within the reference range. Risks did not differ significantly by age and sex.

                                                Conversely, there was no association between TSH levels within the reference range, or subclinical hypothyroidism and the risk of atrial fibrillation. Thus, free thyroxin levels might add to further assessment of atrial fibrillation risks. Further studies are needed to investigate whether these findings apply to thyroxine treated patients.

                                                The next study provides insight into how exercise promotes metabolic remodeling in the heart. First author, Dr. Gibb, corresponding author, Dr. Hill and colleagues from University of Louisville, use radiometric, immunologic, metabolomic and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise.

                                                They found that in the heart, glucose utilization via glycolysis was reduced during exercise and in the early recovery period after exercise. Low rates of myocardial glycolysis were sufficient to activate gene programs that instigate physiologic cardiac growth. Metabolic inflexibility of the heart, such as occurs in heart failure and diabetes, was sufficient to diminish mitochondrial function.

                                                Phosphofructokinase mediated changes in metabolism appeared to regulate genes involved in processes critical for metabolic remodeling, transcription, cell division, differentiation, cell proliferation and contraction. Thus, this study provides important preclinical evidence, showing how exercise-induced changes in glucose metabolism may promote physiologic cardiac growth.

                                                The next study addresses the question of whether antiarrhythmic drugs are safe and effective when non-shockable rhythms evolved to shockable rhythms during resuscitation for out of hospital cardiac arrests. In this study from first and corresponding author, Dr. Kudenchuk of University of Washington and his colleagues, patients who initially presented with non-shockable out of hospital cardiac arrests were randomized upon subsequently developing shock refractory VF or VT to receive amiodarone, lidocaine or placebo by paramedics.

                                                The primary outcome was survival to hospital discharge, with secondary outcomes, including discharge functional status and adverse drug-related effects. The authors found that outcome from non-shockable turned shockable out of hospital cardiac arrest was poor, but not invariably fatal. Though not statistically significant, point estimates for survival showed a trend to greater survival after amiodarone or lidocaine than placebo without increased risk of adverse effects or disability. Together, these findings may signal a clinical benefit that invites further investigation.

                                                The final study provides experimental data supporting the importance of a novel Cardiokine governing the local environment in infarcted hearts and determining the fate of implanted cells. This novel Cardiokine is C1q/tumor necrosis factor-related protein-9, or CTRP9, which is a novel pro survival Cardiokine that is significantly down regulated after myocardial infarction.

                                                In today's study by co-first authors, Drs. Yan and Guo and co-corresponding authors Drs. Ma and Wang from Thomas Jefferson University in Philadelphia, mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells, CTRP9 or their combination. The authors found that administration of adipose-derived mesenchymal stem cells alone failed to exert significant cardio protection.

                                                However, administration of these cells in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9, suggesting a synergistic effect. CTRP9 promoted adipose-derived mesenchymal stem cell proliferation, survival, migration and attenuated cardio myocyte cell death by signaling mechanisms that included binding with N-cadherin, activation of ERK, MMP9, and ERK-Nrf2 signaling and upregulation or secretion of antioxidative proteins.

                                                In summary, these results suggest that CTRP9 is a Cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue. Well, that wraps it up for your summaries, now for our feature discussion.

                                                Conscious sedation is very frequently used during transcatheter aortic valve replacement, or TAVR, but with limited evidence as to the safety and efficacy of this practice. Well, that is until this week's journal and this feature paper. We're so lucky to have with us the corresponding author, Dr. Jay Giri from Hospital of University of Pennsylvania, to discuss his novel findings, as well as Dr. Dharam Kumbhani, Associate Editor from UT Southwestern.

                                                Jay, tell us your study findings and how this really helps us to characterize anesthesia choice and clinical outcomes of at least U.S. patients undergoing TAVR.

Dr. Jay Giri :                        We looked at 11,000 patients treated over a 15-month period in 2014 and 2015 with percutaneous transfemoral TAVR. Notably, this was a time period that was identified as the start of the era of conscious sedation for TAVR in the United States.

                                                Also, this five quarter period that we looked at represented a time of relative technological stability where only two valve types, the Sapien XT and original Medtronic CoreValve were being used in America.

                                                Looking at that 15-month period when conscious sedation was first being used in TAVR, we elected to compare those patients to a propensity matched group of patients who underwent TAVR by, what at that time was, the more traditional approach of general anesthesia.

                                                Our primary outcome within hospital mortality, because we had complete followup for this outcome. We also looked at 30-day outcomes for which we had about 90% followup. What we discovered was actually an associated reduction in mortality, an absolute reduction of about 1% in the patients who were treated with conscious sedation.

                                                We also noted that they had modest decreases in the hospital length of stay, as well as significant decreases in the rates of ICU length of stay and the rates of pressor or inotrope use during the procedure. Obviously, the most provocative of the findings was the fact that we seemed to discover, after propensity matching a slight improvement in in-hospital mortality that held true at 30 days, as well.

Dr. Carolyn Lam:               Thank you, Jay. What important findings ... I mean, mainly because, we really didn't have much data, did we? About conscious sedation and TAVR before this. Now, it's observational data, and I suppose the question always becomes what about bias by indication? More well patients get selected for conscious sedation versus general anesthesia, perhaps? Or even the other way around. Could you elaborate a little bit on how you think that may have impacted results and the measures you took to look at that?

Dr. Jay Giri :                        I think it was something that we were highly aware of and I also have to give credit to Dr. Kumbhani and the editorial staff at circulation for pushing us on that issue of selection bias for the two procedures. The obvious concern here, when you saw that there was a potential mortality reduction with conscious sedation patients, was that perhaps the conscious sedation patients actually represented a healthier cohort to start with, or they were perhaps treated at centers that were more highly experienced and by operators that were more highly experienced with TAVR in general.

                                                We tried to account for this in a number of different fashions. The first, as we mentioned, was with an inverse probability treatment weighted analysis that accounted for 51 co-variants that were balanced between the groups. Additionally, we did adjust for site characteristics and utilized a hierarchical method technique to take into account both the experience of sites and operators.

                                                Finally and most importantly, we performed what's called a falsification end point analysis in a postdoc fashion to verify that it looked like other outcomes outside of things, like mortality, length of stay, things we would expect to be influenced by sedation type, ended up being equal between the two groups. Falsification end point analysis represents, essentially, a negative control. You're supposed to theorize for potential outcomes that you would think would not be influenced by your intervention. In this case, those outcomes we theorized were vascular complications, major bleeding and pacemaker implantation, which we theorized would not be influenced by sedation type. In fact, we discovered that those outcomes were similar after adjustment, even though they had some differences before adjustment.

Dr. Dharam Kumbhani:  Jay, I want to congratulate you and your team on this paper. You guys really picked a very important topic to look at and then you jump ... as you outlined, you jumped through a lot of statistical hoops and try to really provide evidence for a field in which a randomized controlled trial is probably going to be just logistically probably hard to conduct, just given the sample size requirements, which also you've provided in your discussion.

                                                I think all the metrics that you looked at as far as utilization of therapies and length of stay, things like that, I think many people believe that and you were the first one to systematically evaluate and show that.

                                                As you alluded to, I think that mortality, and Carolyn mentioned that, as well. I think the mortality findings are very interesting. Again, it's always hard when you have observational data to really put a lot of stock into that and you guys, as you outline, looked at so many different ways of doing that.

                                                Again, I guess, observational data are always inherently going to have that limitation, no matter what statistical rigor we put them through. They were definitely very thought-provoking and, as you outlined, it's definitely come at the right time as the field is exploding and more and more centers are getting facile at it.

                                                The other thing that you mentioned, but which I want to make sure that people fully understand is that you also provided a very elegant analysis looking at site volumes, because traditionally the sites that are doing conscious sedation have done a number of TAVR's before and there is a very clear cumulative volume outcomes association, for TAVR.

                                                By accounting for the totality of experience, so you adjusted for the cumulative volume that sites have been doing this, so these are not just the high volume, high throughput centers, which have a lot of experience doing 150, 200 TAVR's a year, that thereby have really good outcomes by virtue of being expert, both as operators and as sites, but rather potentially something that is related to conscious sedation aspect itself. You guys really stepped up and provided a very elegant analysis to try to dissociate the two issues here.

Dr. Carolyn Lam:               Dharam, and you just provided a very elegant explanation of the thought processes that were going on with our editors about this paper. I join you in congratulating Jay. Just a question. This is the best available evidence now, what are we going to do about it? I mean, Dharam, you're an inventionist, what now?

Dr. Dharam Kumbhani:  The issues were not so much related to efficacy, initially. The initial concerns were related to safety, and Jay's paper clearly addresses that. Then, in addition to that, it says, "Well, it's not just that it's a safe procedure, but it's also effective with potential patient level and hospital level benefits from having a robust conscious sedation program."

                                                I guess the one question that I have about conscious sedation and, Jay, I would love to hear your thoughts on this, as well, is it is possible but it is usually not done, TEE's or transesophageal echos are typically not done when you're doing conscious sedation. It is possible, as I said. As you move towards lower risk patients, on the one hand, these would be ideal patients for conscious sedation because then it's almost like a day procedure, in some ways for them.

                                                But on the other hand, the fidelity of being able to look for even small paravalvular leaks, things like that, may be harder with a transthoracic echo. I don't know, as we expand towards the oldest populations, whether we'll see a greater adoption of conscious sedation, or whether there'll be some scaling back.

Dr. Jay Giri :                        Two points on that. The first is, I totally agree that it's relatively unusual for a transesophageal echo to be performed in the setting of conscious sedation. There's no question, secondly that transesophageal echo allows for the most rigorous evaluation of paravalvular leaks.

                                                It is striking, though, that the rates of paravalvular leaks, due to technological improvements to the valves, are significantly improving. Even since the time of our study two years ago, a new generation of valves is consistently coming out with leak rates in pretty well-conducted analyses that are in the low, single digit percentages for moderate leak or more.

                                                Part of I think the move towards conscious sedation, even initially and especially as we go forward, is predicated on the fact of continuing technological improvements that essentially almost solve the leak problem.

                                                I think it's true that there's always going to be a very small minority of patients that are stuck with concerns about paravalvular leak at the end of their TAVR procedure. For those who have moderate or greater leak, I think that the threshold for escalating care, even to intubation and TEE to evaluate that leak, I think should be relatively low in a lower risk population.

                                                However, I think the point that you bring up about the potential harm of trace or trivial leaks, or mild leaks, which may not be perfectly interpreted with transthoracic echo and aortograms and [inaudible 00:16:41] assessments at the time of the valve placement. It's something we're going to have to keep a close eye on.

                                                From a practical standpoint, I believe this train has left the station. Totally unscientific, but around the time they released the paper online. I just shot out a poll on Twitter and got about a couple of hundred responses from folks, what they're doing now.

                                                Now, Twitter certainly, probably doesn't represent the average transcatheter valve operator in the world, but I was surprised to see that over 70% of the respondents favored a conscious sedation approach at this point in time, which obviously is much higher than what we saw in our paper from two years ago.

Dr. Carolyn Lam:               Well, audience, I'm sure you enjoyed that. Thank you for joining us today. Don't forget to tune in again next week.

Nov 20, 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 Center and Duke National University of Singapore. This week's journal features novel results from the NCDR IMPACT Registry that informs us on risk prediction in patients with congenital heart disease undergoing cardiac catheterization. We'll be taking a deep dive into this right after these summaries.

                                                The first original paper provides pre-clinical data showing that delayed repolarization may underlie ventricular arrhythmias in heart failure with preserved ejection fraction or HFpEF. First author Dr. Cho, co-corresponding authors Dr. Marban, and Cingolani from Cedars-Sinai Heart Institute and their colleagues, induced HFpEF in Dahl salt-sensitive rats by feeding them a high-salt diet from seven weeks of age. They showed that susceptibility to ventricular arrhythmias was markedly increased in rats with HFpEF.

                                                Underlying abnormalities included QTc prolongation, delayed repolarization from down-regulation of potassium currents, and multiple re-entry circuits during ventricular arrhythmias. These findings are consistent with the hypothesis that potassium current down-regulation may lead to abnormal repolarization in HFpEF, which in turn predisposes to ventricular arrhythmias and sudden cardiac death.

                                                The next paper shows that genetic testing can help to identify patients with pulmonary veno-occlusive disease who were misclassified as pulmonary arterial hypertension. Now, heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II or BMPR2 are the commonest genetic cause of pulmonary arterial hypertension. Whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene or EIF2AK4 gene are described in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

                                                In the current study, first author Dr. Hadinnapola, corresponding author Dr. Morrell, and colleagues from University of Cambridge performed whole genome sequencing on the DNA from 864 patients with pulmonary arterial hypertension, as well as 16 patients with pulmonary veno-occlusive disease all recruited to the NIHR BioResource – Rare Diseases study. They found that 1% of patients with a clinical diagnosis of pulmonary arterial hypertension actually carry the biallelic EIF2AK4 mutations. Patients who are diagnosed clinically with pulmonary arterial hypertension, but who had a transfer coefficient for carbon monoxide of less than 50% predicted and an age of diagnosis of less than 50 years were much more likely to carry these biallelic EIF2AK4 mutation. In fact, the diagnostic yield for genetic testing in this group was 53%.

                                                Radiological assessment alone was unable to distinguish reliably between these patients and those with idiopathic pulmonary arterial hypertension. Importantly, these patients with biallelic EIF2AK4 mutations had a worst prognosis compared to other patients with pulmonary arterial hypertension. Thus in summary, younger patients diagnosed with idiopathic pulmonary arterial hypertension but with a low transfer coefficient for carbon monoxide, have a high frequency of biallelic EIF2AK4 mutations and should be reclassified as pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. They have a poor prognosis and genetic testing can therefore identify these misclassified patients allowing appropriate management and early referral for lung transplantation.

                                                The next study identifies a novel molecular target for the treatment of pathological cardiac hypertrophy. This target is SIRT2 [inaudible 00:04:33] poorly characterized member of the Sirtuin family of proteins, which is a family of class III NAD-dependent deacetylases that regulate metabolism and age-related diseases including diabetes and cardiovascular diseases. In the current study, first authors Dr. Tang and Chen, corresponding authors Dr. Chen and Liu from the Chinese Academy of Medical Sciences in Peking Union Medical College used wild-type and Sirt2 knockout mice, and showed that SIRT2 protein levels and activity were reduced during pathological cardiac hypertrophy.

                                                SIRT2 deficiency promoted aging and angiotensin II induced pathological cardiac hypertrophy, and blunted metformin-mediated cardioprotective effects. On the other hand, SIRT2 overexpression repressed pathological cardiac hypertrophy. The molecular pathway involved deacetylation of liver kinase B1 at lysine 48 by SIRT2 to activate AMP-activated protein kinase sickling, which prevented hypertrophy of cardiomyocytes. Thus, SIRT2 is a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.

                                                The next study is the largest comparison of the prognostic value of coronary artery calcium with functional stress testing in patients with stable chest pain. In this study from first and corresponding author Dr. Budoff from Los Angeles Biomedical Research Institute and colleagues, authors looked at the PROMISE trial where patients with stable chest pain or dyspnea, and intermediate pre-test probability for obstructive coronary artery disease were randomized to functional testing or anatomic testing.

                                                Their main finding was that these chest pain populations referred for testing had a low event rate and both tests had different strengths. Coronary artery calcium had a high sensitivity for future cardiovascular events whereas functional testing had a high specificity. The clinical implications are that a normal coronary artery calcium score has a very low event rate and perhaps maybe used to avoid further cardiac testing in a stable chest pain population. On the other hand, an abnormal functional test result including information on exercise and symptoms has a moderate prognostic value.

                                                Of note, coronary CT angiography provided better prognostic and discriminatory power than either coronary artery calcium or functional testing. The implications of these important results are discussed in an accompanying editorial by Dr. David Newby from Edinburgh entitled, Can I Have My Cake and Eat It? On that intriguing note, we've come to the end of today's summaries, now for our feature discussion.

                                                For today's feature discussion, we are talking about an increasingly important population that is pediatric and adult patients with congenital heart disease undergoing cardiac catheterization. A little bit out of my usual comfort zone, but then you see, I'm with two spectacular experts today, Dr. Gerard Martin from Children's National Health System in Washington DC, one of the authors of today's feature paper; and Dr. Gerald Greil, Associate Editor from UT Southwestern. Welcome gentlemen.

Dr. Gerard Martin:           Thank you Carolyn.

Dr. Gerald Greil:                Thank you Carol.

Dr. Carolyn Lam:               Gerard, no that would be Dr. Martin. Enlighten people like me who don't think about this every day, why the importance of looking at cardiac catheterization, and adverse outcomes in this particular population?

Dr. Gerard Martin:           Carolyn, that's because of the tremendous advances in medicine, and particularly medicine that's dealing with children with congenital heart defects. Cardiac catheterization was once purely a diagnostic study. Now, it's a less invasive definitive treatment option for many of our pediatric and adult patients with congenital heart defects. As you may or may not know, congenital heart defects are the most common birth defects that impact nearly one out of every hundred live births.

                                                As I mentioned, we have these tremendous advances. As a result of that, there are now over a million children living with congenital heart defects. In the USA alone, improvements in care over the past 50 years, there are now more adults than children living with congenital heart defects.

Dr. Carolyn Lam:               Wow. Now, I understand. I mean, cardiac catheterization not just meeting diagnostic but therapeutic, and such an important patient population. Tell us about your study?

Dr. Gerard Martin:           As we said, cardiac catheterization is now replacing surgery for some of our defects. For some of the more complex defects, catheterization is providing treatments that make the surgery easier. Now in surgery, we've had registries for many years. These registries provided measurement of survival that allow comparison of programs, and we didn't have that ability with cardiac catheterization. The American College of Cardiology developed the IMPACT Registry. That was to solely provide measurements of the outcomes of catheterization procedures in the children and adults with congenital heart disease.

                                                Now, one aspect of the quality of the program is your rate of adverse outcomes; but simply measuring the number of adverse outcomes does not provide enough discrimination to compare programs. I think you can probably imagine that adverse outcomes will increase based upon the complexity of the type of patients you see, or the types of procedures that you might be performing. What we wanted to do was to create a risk standardization tool for our population where we can measure variation and performance between programs. If we can do that, then we can learn from the best performers to improve all the others.

Dr. Carolyn Lam:               That's beautifully put. Could you tell us what you found?

Dr. Gerard Martin:           Sure. The IMPACT Registry began on about 2011 and has grown from 50 sites to 111 sites in 2017. That's the majority of the sites in the United States that perform cardiac catheterization on children. We have now over 115,000 procedures. What we wanted to do with this is to look at some of the early procedures that were included and to see how adverse events were occurring. When we created the registry though, we used data variables from a previous research study in Boston called the CHARM.

                                                They created a tool to risk standardized outcomes during procedures. They did it by coming up with four categories of procedures, and some four markers of hemodynamic vulnerability. We tested their methodology with IMPACT, and it didn't really performed particularly well. In this study, what we did was to increase the number of risk categories. We took the nearly 200 types of procedures we do in the cath lab and divided them into six categories. We also increased the indicators of hemodynamic vulnerability from four to six.

                                                Now, what I mean by hemodynamic vulnerability? What is the patient's oxygen level when they go into the procedure? What is their blood pressure when they're in the procedure? Do they have one ventricle, or do they have two ventricles? What is the resistance in the lung vessels? All these are critically important. Lastly, we looked at some baseline patient characteristics. In other words, was age important? Sex, genetic conditions, or other comorbid conditions like the level of mechanical support that the patients were on. Then we put all that into our model to see if we could come up with a risk score.

Dr. Carolyn Lam:               Right. The final adjustment model? Which factors that they include in the end?

Dr. Gerard Martin:           We did find that there are lot of adverse events that do occur. We found major adverse events occurring in about same 7% of our patients. Most common adverse events were bleeding, or rhythm disturbances that require some medicine, or cardioversion during the procedure, or death during the hospitalizations. We did find that these major events were more common in the youngest patients or neonates, children under a month of age, or in patients with genetic disorders, or single ventricle physiology, and also patients that went to the cath lab with their kidneys not working very well.

                                                In the end, we did create a risk adjustment model that included the type of procedure that was done, the number of hemodynamic vulnerability indicators, and whether or not the patient had renal insufficiency, or single ventricle physiology, or coagulation, and we found really good discrimination. Our discrimination had a C-stat of 0.76 in the derivation cohort, and 0.75 in the validation cohort. The slope of the curve was excellent, so we really think we have something now that we can use as a tool.

Dr. Carolyn Lam:               Gerald, you're a pediatric cardiologist. Could you give us your perspective on how important these results are?

Dr. Gerald Greil:                I think it's the largest and the first study, which kinds of give us a calibration in our field how successful interventions are. How we can make centers better without finger pointing on specific centers, and how to advance the field as a whole? From that perspective, I'm quite excited that the group offered us to publish this paper in circulation. I was kind of asking a question to Dr. Martin because obviously, all essentials are closely monitored. There's obviously data publicly available. Do you think there's a risk that this way to monitor centers within the United States or probably worldwide, that it's potentially preventing innovation or risky procedures?

Dr. Gerard Martin:           I think that, that's a good question. I think it's one thing that whenever we talk about transparency or public reporting, it's an argument against it. I think that having a model like this, actually levels the playing field. In other words, centers that are risk averse who aren't particularly innovative, you'll be able to look at those centers, see what type of patients they're doing and look at their adverse events for a low-risk population. Then, you can also look and see some other centers that are doing more complicated procedures, higher risk, and you can see what their adverse event rate is.

                                                Certainly, this is only talking about the adverse events. This has to be put together with the outcome of the procedure. In other words, if you're trying to relieve an obstruction, did you relieve it? Did you meet the intended goal of the procedure? This is only half of the story. The other part of it is, did you get the intended goal of the procedure? When you put the two of them together, perhaps some of those centers that are risk averse have lower complications, but maybe their success rate is lower. This will be able to tell the public everything they know, and they'll be able to tell their providers what they need to know to get better.

Dr. Carolyn Lam:               I have to agree. Your paper does highlight, I think. Gerard, just one other question. What do you think our next steps?

Dr. Gerard Martin:           The next step is to test the data. We have a new version of IMPACT that has rolled out, version 2 that has new procedures in it. Now, we have to test the data and we actually have to look for variability. Can we see a variation between the programs? Then, once we see if there's variation, if we see there is best performers and those performers that could improve, a question then is how do we take from what the best performers are doing to try and lift those that need to improve up. That's going to be the true hard work for this registry.

Dr. Carolyn Lam:               Thank you so much for publishing it with us. Thank you so much audience for listening with us today. Don't forget to tune in again next week.

 

Nov 13, 2017

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

                                                What is the evidence we have for LDL-lowering therapy in primary prevention? For individuals with an LDL cholesterol above 190 mg/dL, well, you may think you know the answer, but today's featured discussion may surprise you like it did for me, and this is a must-listen in my opinion for those of us taking care of these patients. More soon right after these summaries.

                                                How can we enhance the survival and therapeutic potential of human pluripotent stem cell-derived endothelial cells? Well, the first paper in today's journal tells us how. The first author Dr. Lee, corresponding doctor Dr. Yoon, from Emory University School of Medicine in Atlanta, Georgia, developed a novel, fully-defined, cell culture system to generate endothelial cells from human pluripotent stem cells. They not only showed that these endothelial cells had pro-angiogenic activities and exerted favorable therapeutic effects in repairing limb ischemia, but also showed that encapsulation of these cells in a biocompatible peptide amphiphile nanomatrix gel improved long-term survival of these endothelial cells in an ischemic environment and improved vessel-forming properties. This novel cell culture system and gel-mediated transplantation may serve as a novel platform for cell-based therapy.

                                                The next study brings us one step closer to application of immunomodulatory therapies in pulmonary arterial hypertension. In the study, first author Dr. Saito, corresponding author Dr. Rabinovitch, and colleagues from Stanford University School of Medicine isolated lung immune complexes and pulmonary arterial hypertension target antigens from lung tissues from 16 patients with pulmonary arterial hypertension and 12 controls. SAM domain and HD1 domain-containing protein, which is an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from patients with pulmonary arterial hypertension. These immune complexes resulted from elevation in products of human endogenous retrovirus K. The human endogenous retrovirus K deoxyuridine triphosphate nucleotidohydrolase, or dUTPase, activated B cells, elevated cytokines and monocytes and pulmonary endothelial cells, and increased pulmonary arterial vulnerability to apoptosis, thus contributing to sustained inflammation, immune dysregulation, and progressive obliterative vascular remodeling. Furthermore, rats treated with the human endogenous retrovirus K dUTPase developed pulmonary hypertension. In summary, this study suggests that harnessing mechanisms that repress human endogenous retrovirus K expression and its sequelae could prevent and reverse pulmonary arterial hypertension.

                                                The next study looked at the association of timing of coronary angiography with ischemic outcomes of non-STEMI who are at high risk with a Gray score of more than 140 in the TAO Trial. In this report from first author Dr. Deharo, corresponding author Dr. Steg, and colleagues from L'Hopital Bichat from Paris, France showed that in these high risk, non-STEMI patients, a very early invasive strategy of coronary angiography within the first 12 hours was associated with a lower risk of death in MI at 180 days compared to an early strategy of between 12 to 24 hours or a delayed strategy of between 24 and 72 hours. The bleeding risk was not different between patients managed with the very early, early, or delayed strategy. These observations deserve prospective confirmation in a randomized trial.

                                                The next study provides contemporary mortality trends for STEMI and non-STEMI. In this paper from first author Dr. Puymirat, corresponding author Dr. Danchin, and colleagues from Hopital europeen Georges-Pompidou in Paris, France, the authors assess trends in the characteristics, treatments, and outcomes for EMI from five month-long registries conducted five years apart and spanning 1995 to 2015, including more than 14,000 patients admitted to cardiac intensive care units in metropolitan France. They observed major changes in the characteristics and management of both patients with STEMI and those with non-STEMI over the last 20 years. The mean age decreased in patients with STEMI and remained stable in patients with non-STEMI, whereas diabetes, obesity, and hypertension increased. At the acute stage, intended primary PCI increased from 12 to 76 percent in patients with STEMI. In patients with non-STEMI, PCI within 72 hours from admission increased from 9 to 60 percent. In parallel with these changes, six-month mortality consistently declined in patients with STEMI, whereas in patients with non-STEMI, six-month mortality reached a plateau after 2010. The authors concluded that future challenges will be to reduce pre-hospital mortality and to improve long-term survival after the acute myocardial infarction event.

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

                                                What evidence do we have from randomized trials supporting the benefit of LDL cholesterol lowering as primary prevention among patients with an LDL cholesterol above 190 mg/dL? You may be surprised to know that until today's journal, we had very little trial evidence supporting this. But I'm so pleased to have with us the corresponding author of our featured paper today, Dr. Kausik Ray from Imperial College, London, who's going tell us a bit more and discuss this very intriguing paper with our Editor for Digital Strategies, Dr. Amit Khera from UT Southwestern. Welcome, both.

Dr. Kausik Ray:                  Hi.

Dr. Amit Khera:                 Thanks for having us.

Dr. Carolyn Lam:               Kaus, you are a familiar voice and so pleased to have you here. Please tell us, is this the first evidence we have from a randomized trial for primary prevention in those with LDL above 190? Tell us about it.

Dr. Kausik Ray:                  Yeah, it is. It really came about because we were interested in familial hypercholesterolemia and we used the level of 190 to talk about either primary hypercholesterolemia, which may have a genetic basis, or not. I kept hearing that there is no trial evidence, so you're not going to be able to ethically do a trial today despite the fact there's not much evidence, because most of us think that it's a bad thing to leave people on placebo in patients above 190, so I thought the only way to do this was to go historically to the WOSCOPS Study, which is, as you remember, 6,500 people, elevated LDL cholesterol. Interestingly, you go to WOSCOPS, the median LDL in that population is very close to 190. So, that gives a good starting point, thinking that we'll have at least half the population.

                                                Now interestingly in WOSCOPS, although none of the patients had a history of myocardial infarction, a very small number of the 6,500, about 1,000 actually had evidence of some other vascular disease, so maybe a TIA, maybe angina, maybe some sort of ECG non-specific change of coronary disease. Today, you would say, well, actually, you've got to give these people a statin because there's evidence of vascular disease, PVD, et cetera. So we had to take those people out and that left us with 5,529. Once you break people down by LDLs above and below 190, you have 2,560. You could actually look at the randomized treatment effect of pravastatin, which was the statin chosen, over a five year period both above and below 190.

                                                But interestingly, this was the first study and what we showed was that in this population, even with as little as 23% reduction in LDL cholesterol, over a five year period, you saw a statistically significant 27% reduction in CHD and if you take the usual 3 point MACE of current clinical trials, there was a 25% reduction, already statistically significant. We also had the ability to link data over 20 years. Remember, after the five year randomized treatment period, it becomes observational in nature, but what it showed was that when you gave nearly 40% in each arm statins and you followed people up this legacy effect, over a 20 year period, the people with the LDL above 190, that translated into this 28% reduction in CHD death. It translated into a 25% reduction in CV death, and actually an 18% reduction in all-cause mortality, which you didn't see in the population with slightly lower LDL cholesterol.

                                                This is the best evidence we're ever going to get, really, and answer the question about what should we do in this patient population. Should we treat with lipid-lowering therapy? The answer, unequivocally, is yes, and the longer you treat, the more likely you are to see survival benefits.

Dr. Carolyn Lam:               Oh, my goodness! I just love his paper. I have to humbly admit. I mean, it's in the guidelines already that we should treat these individuals with LDL above 190, and it really made me think how I'd taken for granted that there would be a whole body of evidence behind it from randomized trials, and you are right! This is the first, and likely going to be the last we're going to get, because we can't randomize them. So, congratulations. What you said just now, I can already hear myself playing this podcast to my patients. May I just ask, are there other remaining questions to answer, and then what do you also say to those that say, well what are the harms? How do you balance that with any potential harms?

Dr. Kausik Ray:                  In this particular study, given there was overall safety data observed in the WOSCOPS Trial population and in their extended follow-up in the overall 6,500 person cohort, we didn't go on and look at that. There was no evidence of harm in the extended follow-up of 6.500 people, so we didn't see the potential added gain in specifically looking for that. The main question we wanted to answer, because people had always pulled primary and secondary prevention patients together, and in fact, your best evidence is actually from CTT, pooling of primary and secondary prevention patients where they break the data down by an upper limit of about 175. With patients above 175, they don't specifically answer that question. So, to answer your question, we didn't look at that in the overall WOSCOPS Trial population. There was no signal for harm that was noticed. Even things like glucose elevation, if you remember in WOSCOPS, tended to be a little bit lower.

Dr. Amit Khera:                 Let me comment on a few things about this paper. First, I want to congratulate Dr. Ray and his colleagues. I was a history major and I think this is a great use of a historical tool. At this point, I think we can talk about WOSCOPS. It's 22 years old. It is part of the medical history and a very seminal article. I think they got creative because, as he mentioned. We have guidelines that support this treatment, but this is almost an unanswerable question, whether you say it's from ethics, or from equipoise, it was essentially unanswerable. So, they had to go back and take this historical study where practice patterns were different, to be able to look at this question. It was pointed out, there's pretty clear evidence in here and I think if you look at that during the five-year study period of the randomized period, pretty clear evidence that treating participants with LDLs above 190 without vascular disease certainly lowers cardiovascular disease events.

                                                One of the best things about working on the editorial board is being able to work closely with authors, and I have to also thank Dr. Ray and his colleagues for being so gracious in working with us closely in some modifications as this went along. We hope, and I hope he feels this way, too, that at the end of the day, the product ends up being even better than where we started. That's our goal is to really help and work with authors in that way and they were incredibly responsive. The two things I thought they did really well that were insightful to the US guidelines and beyond. One is they also restricted to the group without diabetes, without ASCVD less than 7.5%, and some other parameters to really hone down on what we have in the current US guidelines and still the finding was consistent that the statin therapy benefited that group.

                                                The other part was just acknowledging that the legacy part, the long-term effect, is really valuable. They published heavily in this area, but at that point, it becomes an observational component. It's not part of the randomized period. The reason that adds value, if you look at our guidelines above the age of 21, an LDL above 190 can be treated with a statin, there would be less controversy if your LDL was 200 and you're 55, but if you're 22 or 23, I think there may be more angst. That's where the long-term data is important, because we're not looking necessarily always at 10 years, but we're looking at 20 or 30 or 40 or 50 years. I think this does at least shed some light. I appreciate the study population was older, but a least it helps us look at maybe some of the long-term benefits.

                                                If I may, Carolyn, I would love to ask Dr. Ray a question. Kaus, when you guys did this, the group with the LDL less than 190 had essentially similar benefit. The p-interaction was no. I think we have to acknowledge that the LDLs were higher in that group than what would seem because the lowest level was 155. Is it above 190, or should it be above 160 where we treat patients with statins?

Dr. Kausik Ray:                  Yes, and I really want to thank the editors, because there were certain things that you pushed us with analyses and I think that you could make the case that if you have a LDL cholesterol above 155, over a five-year randomized treatment period, there was a significant reduction in CHD and MACE as well. So, you could make that point that actually the cutoff should perhaps be pulled down even further to about 155. What's interesting is, these groups, when you broke them down, age was identical, BMI was identical, blood pressure, and everything else. The only thing that was different, really, was the LDL cholesterol, which impacted on total cholesterol. TGs, HDLs were absolutely identical. I think you could probably make the case.

                                                I think the one thing that we didn't see, although it's observational in those with slightly lower LDL cholesterols, is that over the 25 year period, they seem to get slightly less mortality benefits. Now, that could be a chance finding, because it's observational. We don't really know the implications of that, but I think over a five-year period, this is the best evidence you're going to get for primary prevention, right?

Dr. Amit Khera:                 Agreed. The US guidelines do say above 160, it's a point of consideration. It can be a factor to consider as we think about treatment, so perhaps this helps bolster that point as well.

Dr. Kausik Ray:                  It's not just the American guidelines. In the European guidelines, when they use score, if you look at LDL cholesterol levels, the European case fatality 10 year risk is 2.5%, which is equivalent roughly to 7.5% fatal and non-fatal MI in the pooled cohort equation. There they still have diet and lifestyle, but it says, "Consider pharmacological," and one of the things I thought was really interesting is if you did a 10 year risk calculation in this group, 67% of the population with an LDL above 190, you would have said the predicted 10-year risk was below 7.5%, but the 10-year observed risk was double that. It was 15%. If you did the same thing for the group between 155 and 190, your ten-year risk predicted would be in most of these people, you would have said about 90% actually are less than 7.5%, so you wouldn't have given them a statin. But, their observed event rates in the placebo group was about 11%.

                                                So, I think that it tells you if you have an isolated elevated cholesterol above 155, you're probably going to be underestimating risk if you're using global risk score, and perhaps a discussion with the patient about risks and benefits in the way that most of us try to do and citing data like this might encourage patients to actually start that therapy earlier, which most of us probably believe from genetic and legacy effect is probably beneficial. That's one of the other implications of this.

Dr. Amit Khera:                 This is why one has to read not just the abstract, but all the details, because there are so many kernels of interesting findings in this paper beyond just the highlights that we hit upon.

Dr. Carolyn Lam:               Thank you both for just a marvelous discussion of an incredible paper that is really, really going to be extremely clinically relevant. We're so proud to be publishing this in Circulation this week.

                                                Audience, you heard it right here. Don't forget to tune in again next week as well to Circulation on the Run for even more hot news.

Nov 6, 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 Center, and Duke National University of Singapore.

                                                In just a moment, we will take a deep dive into the issue of age and its association with outcomes of primary prevention ICDs in patients with non-ischemic systolic heart failure.

                                                Yes, a long-awaited discussion from the Danish trial. That, in just a moment. First, here's your summary of this week's Journal.

                                                The first original paper provides evidence of a true association between disturbed genetic imprinting and Preeclampsia. This paper is from co-first authors, Dr. Zadora, and Dr. Singh, and co-corresponding authors, Dr. Izsvak, from the Max Delbrück Center for Molecular Medicine; Dr. Hurst, from the University of Bath; and Dr. Dechend, from the Experimental and Clinical Research Center of Berlin.

                                                These authors performed an unbiased analysis of genome-wide molecular data on raw characterized patient material, from normal controls, and patients with  Preeclampsia, and identified DLX-5 as an imprinted target gene, with novel placental function in Preeclampsia. Due to loss of imprinting, DLX5 was upregulated in 69% of placentas from Preeclampsia patients. Levels of DLX5 correlated with the classical Preeclampsia markers.

                                                DLX5 was expressed in human, but not in urine trophoblast, underlying the known human specificity of Preeclampsia. Finally, DLX5-induced overexpression if trophoblasts faithfully modeled Preeclampsia in a cell culture system. In summary, this paper shows that disturbed imprinting is common, and may play a causal role in Preeclampsia.

                                                The next study affirms that stenosis severity is better discriminated using coronary invasive physiologic indices, than using coronary angiographic assessment. First author, Dr. Lee, corresponding author Dr. Koo, colleagues of Seoul National University Hospital, studied 115 patients with left anterior descending artery stenosis, who underwent both ammonia positron emission tomography, or PET, an invasive physiologic measurement.

                                                Myocardial blood flow measured using PET, and invasively measured coronary pressures, were used to calculate microvascular resistance, and stenosis resistance. They found that both fractional flow reserve, or FFR, and instantaneous weight free ratio, or IFR, decreased as angiographic stenosis severity, resistance, and pressure gradient increased, and hyperemic myocardial blood flow decreased.

                                                When the presence of myocardial ischemia was defined by both low hyperemic myocardial blood flow, and low coronary flow reserve, the diagnostic accuracy of FFR and IFR did not differ, regardless of cutoff values for hyperemic myocardial blood flow, and CFR. However, at any given stratum of a given stenosis, physiologic classification of stenosis severity using FFR or IFR showed better discrimination of a unique relationship between absolute myocardial blood flow, and pressure gradient, than anatomic classification using angiographic percentage.

                                                In summary, by demonstrating coronary physiologic responses to coronary stenosis, these authors showed that stenosis severity is better discriminated, using invasive physiologic indices, than using angiographic assessment.

                                                The next paper identifies a previously unknown angiogenic growth factor that can be enhanced therapeutically to repair the heart after myocardial infarction. This novel growth factor is endoplasmic reticulum membrane complex, Subunit 10, or EMC10, which the authors previously identified by bioinformatic secretome analysis in bone marrow cells.

                                                In the current paper, from co-first authors Dr. [Rabel 00:04:35], and [Krof Clengobill 00:04:37], and corresponding author Dr. Wollert, from Hanover Medical Center, and colleagues, the authors investigated the angiogenic potential of EMC10, and its mouse homologue, in cultured endo fetal cells and infarcted heart explants. They found that EMC10 and its mouse homologue signal a virus, small GTAPases; p21-activated kinase; and p38 mitogen-activated protein kinase, to promote endothelial cell migration.

                                                In mice with acute myocardial infarction, bone marrow derived monocytes and macrophages produced EMC10 endogenously, to enhance infarct vascularization, tissue repair, and heart function. Furthermore, subcutaneous treatment with recombinant EMC10 for one week, after myocardial infarction, augmented infarct vascularization and repair, and led to a sustained improvement in heart function and survival.

                                                The next study is the first prospective randomized trial of screening for atrial fibrillation, with a smartphone-based, single-lead, electrocardiographic system in 1,001 patients, aged 65 years and above, with a CHA2DS2-VASc score of two and above, and without a history of atrial fibrillation.

                                                In this paper, from first and corresponding author Dr. Halcox, from Swansea University Medical School, in the United Kingdom, and colleagues, patients were randomized, either to biweekly electrocardiographic recordings with the iPhone device, or to routine over a 12-month period.

                                                The smartphone-based electrocardiographic approach was at least three times more likely to identify incident atrial fibrillation, than routine care, and at a cost of just over $10,000 per case identified, and was judged to be a highly acceptable approach in this group of patients. These results support consideration of evaluation in an appropriately-powered, event-driven randomized trial, to confirm the clinical and cost effectiveness of such an approach to stroke prevention in atrial fibrillation.

                                                Well, that wraps it up for your summaries. Now for our feature discussion. The Danish trial really created a huge splash last year, when it was reported that a primary prevention ICD in patients with non-ischemic systolic heart failure, may not actually reduce all cause mortality. Something that we had, perhaps, taken for granted, and in fact, entered our guidelines.

                                                Now, however, there was a pre-specified subgroup analysis at the time, that suggested a possible age-dependent association, between ICD and mortality, in the Danish trial. This week, we are so pleased to be discussing an in-depth analysis of the association between age and outcomes in the Danish trial.

                                                I'm so pleased to have the first author of today's featured paper, Dr. Marie Bayer Elming, of Copenhagen, Denmark, as well as Dr. Sana Al-Khatib, who's not only an associate editor of circulation, but also the author of an accompanying, and she is from Duke, Durham, North Carolina. Welcome, ladies!

Dr. Bayer Elming:              Thank you. Happy to be here.

Dr. Sana Al-Khatib:          Thank you so much.

Dr. Carolyn Lam:               Sana, could you start by framing why this paper is so important, and why we've been looking forward in anticipation to these results?

Dr. Sana Al-Khatib:          Absolutely. As you know, data on the outcomes of primary prevention ICDs in patients with non-ischemic cardiomyopathy started emerging in the early 2000s, or so. Then in 2005, the sudden cardiac deaths and heart failure trial was published, that included a large number of patients with non-ischemic cardiomyopathy, and absolutely showed survival benefits from primary prevention ICDs in those patients. Of course, there were also patients with ischemic cardiomyopathy.

                                                But really, that trial formed the basis of the guidelines, recommendations, that have informed our practice for the last 12 years, that basically tell us that we should consider implanting a primary prevention ICD in patients with non-ischemic cardiomyopathy, who have an EF of 35% or less, who have Class II or III heart failure symptoms. As long as they are on optimal care at the end, they have a reasonable life expectancy.

                                                So that's what's we've been doing for years, and then, the Danish trial was published this past year, that really called into question the prior findings, and the current practice. Because Danish, as you stated, showed no survival benefit with primary prevention ICDs, but there are many aspects about the trial that people need to pay attention to, to put the results in perspective.

                                                The fact that 58% of patients in the trial, in those arms, received cardiac resynchronization therapy ... the fact that the trial required that patients have an elevated NTproBMB level, to be considered for enrollment ... that may have biased the results toward a higher risk of non-sudden cardiac deaths, so on, so forth.

                                                I think what was really interesting, and caught people's attention, when the paper was published, was this subgroup analysis that showed that younger patients may benefit more than older patients. I think, many of us, Carolyn, were really awaiting the results of a more dedicated analysis, looking at age in Danish, and Dr. Elming and her colleagues did a great job looking at this very closely in their paper, and showed great results, and probably will let Dr. Elming share those results with us.

Dr. Carolyn Lam:               Yes, absolutely, Sana. Actually, I just wanted to echo how surprised everyone was, and the immediate thing was, "Oh, my goodness. What do we do with the guidelines?" Maybe we should get back to that later, and Marie, please share with us, what did you do, and what did you find this time?

Dr. Bayer Elming:              The reason why we did this study was that, in this main Danish trial, age was the only one of the 13 pre-specified subgroups that had a significant treatment by a subgroup interaction. This suggested that a younger patient might have a survival benefit from ICD ... the implication, even though the overall study was neutral. So we wanted to further investigate this relationship between age and effective ICD implantation.

                                                What we did was to look at the relation between age and effective ICD, and we found that there was this linear relation, for each year of younger age, that was associated with a reduction, a 3% reduction in the hazard ratio, for the benefit of ICD.

                                                Also, we did this selection impact curve, which is a bit technical, but what it does is to describe the expected survival for the population, on as a whole, for the different age cutoffs for ICD treatments.

                                                So, if we take into account, both the patients receiving an ICD, and those who did not, we could see why we would get the highest survival for the population as a whole. What we found was that, when no one in the population received an ICD, around 70% would survive.

                                                If everyone in the population received an ICD, only 72% would survive, but if we chose 70 years as the age cutoff ... so, patients younger than 70 years received an ICD, and patients older than 70 years did not receive an ICD, we got the highest survival for the population, and 75% would survive.

Dr. Carolyn Lam:               Thank you, Marie. What important results. So, maybe, still consider ICDs for primary prevention ... in our non-ischemic systolic heart failure, patients were less than 70 years old. Is it as simple as that, Sana? You wrote a beautiful editorial. Tell us, what are the clinical implications?

Dr. Sana Al-Khatib:          This is an important question. Danish was an important trial, but in my mind, it truly doesn't refute the role of primary prevention ICDs in patients with non-ischemic cardiomyopathy. As I mentioned earlier, the majority of patients enrolled in Danish received a CRT device. And so, you end up questioning, what does that actually mean, for those patients who are not eligible for cardiac resynchronization therapy?

                                                So, I actually believed that, and as you know, Carolyn, and maybe Marie knows, as well, there have been several meta analyses that have been published, combining data on patients with non-ischemic cardiomyopathy only, and excluding patients with cardiac resynchronization therapy from Danish, that have actually now shown, consistently, a significant improvement in survival, with a primary prevention ICD ... including one that was done by our group.

                                                So, no, I don't think that, based on the results, we should say, "No, we shouldn't be offering primary prevention ICDs to patients with non-ischemic cardiomyopathy," and this beautiful analysis that was done by Marie and her group actually shows that, at least for those patients who are 70 years of age and younger, I think we should absolutely continue to consider them for the therapy, and offer them the therapy, if they're appropriate candidates.

                                                Then, of course, if the patients are older than 70,, and they meet criteria for cardiac resynchronization therapy, I think it will be important for us to be talking to the patients about ... is the RTD with a defibrillator, versus a CRTP only, with a pacemaker, and talking about the pros and cons, and everything else? But in those patients who are older than 70, who don't meet criteria for CRT, I think more research is needed, to really understand the role of primary prevention ICDs in those patients. We definitely need more data there.

Dr. Bayer Elming:              I definitely agree that, of course, for the patients older than 70 years were not candidates for CRT treatment. These patients, we do not know very much about 'em, and this study that we did, do not answer that question. Based on the Danish study, and this further analysis of the age inspection, the guidelines in Denmark also state that patients younger than, we say, 68 years, because that was the age cutoff used in the '08 Danish trial, you should definitely think of giving patients with non-ischemic cardiomyopathy an ICD.

                                                But for the older patients, it depends on a variety of co-factors, such as co-morbidity, or frailty, and it should be an individual assessment of the patient. So, I agree with you, Sana.

Dr. Carolyn Lam:               That's wonderful. Hey, just one more question. Sana, I'd like you to put on your AE hat, now, and sort of think with me. In circulation, we don't ... well, we're careful about publishing subgroup analyses, so to speak, right, of results. You articulated, in your editorial, reasons why this, perhaps subgroup analysis, may be different from others. Could you elaborate on that a bit?

Dr. Bayer Elming:              Yeah, and absolutely, that's a great question. As you pointed out, I mean, you really ... the conventional wisdom in clinical research is to be careful, interpreting subgroup analyses. I think there are some strengths in this particular analysis, as Marie stated: "Here's what we specified." The other thing is, I believe that Marie and her group then came, and did their very robust statistical methods, and really, probably most importantly, if you look at their findings, they actually really align well, and support their main conclusion.

                                                For example, looking at the fact that older patients had the higher presence of co-morbidities, that they had a higher level of [Co-BMP 00:17:00], they had had a longer duration of heart failure ... I mean, all those things most likely had an impact on their mode of death, really making it more likely for those patients to succumb to non-sudden cardiac death. I think the whole story makes a lot of sense.

Dr. Bayer Elming:              If I can elaborate a bit on this, I think one of the important findings from the study is that we show that mode of death varied according to age. So, the rates of sudden cardiac death were almost similar, between the younger and the older part of the population. But the rates of non-sudden death were almost twice as high in the older part of the population. This is a really good explanation why the ICD implantations have less impact in the older patients.

Dr. Carolyn Lam:               Yeah, because ICDs would definitely not be expected to reduce non-sudden cardiac deaths. Really, really, well put. Oh, thank you so much, Marie. We're so proud to be publishing your beautiful paper, as well as your editorial, Sana, and thank you for this great conversation.

                                                Well, listeners, I'm sure you enjoyed that as much as I did. Thank you for joining us this week, and don't forget to tune in next week.

Oct 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 Center and Duke National University of Singapore.

                                                This week's journal is really special. It is the 2017 cardiovascular surgery-themed issue of "Circulation." To summarize this issue, I am so privileged to have the editors, Dr. Marc Ruel from University of Ottawa Heart Institute, as well as Dr. Timothy Gardner from Christiana Care Health System. Welcome gentleman.

Dr. Timothy Gardner:     Hello.

Dr. Marc Ruel:                   Hi, Carolyn. Glad to be here.

Dr. Carolyn Lam:               Thank you for another beautiful themed issue, Marc. I see that there are four general themes within this theme, if I may. The first of which are a collection of papers on coronary disease and coronary surgery. Could you maybe start by giving us an overview of that?

Dr. Marc Ruel:                   One of the main topics that have been looked at in the surgical-themed issue this year is coronary surgery. We all know well that 2016, 2017, the academic year was quite fertile in providing new information around coronary surgery, especially with the release of the ART trial had actually scientific sessions of the American Heart Association the last November with simultaneous publication.

                                                Interestingly, the cardiovascular surgical-themed issue has several coronary papers and one that deals with essentially with graft failure, if you will. There's an in-depth review written by Mario Gaudino, who is well known and does fantastic work at Cornell, who essentially put a team together looking at several aspects of coronary graft failure. I guess we can say that these are looked in quite great depth, and they deal with several aspects of what would lead to a coronary bypass graft to fail.

                                                First and foremost, Mario and the team look at the blood components. Then the artery and the native bed itself. Then they focus a lot on the conduit, not only the nature of the conduit being a venous versus arterial conduit, but also the way of storing the conduit prior to performing the bypass. Also, the technique that's used around the use of that conduit.

                                                Finally, I'd say that the review culminates with the patient bioreactor, for lack of a better term, aspect. Endothelial dysfunction in the patient with diabetes, age, gender, hypertension, dyslipidemia, etc., all these things that do act as a significant substrate for the fate of the conduit vessel.

                                                A very unique, I think, first-time, in-depth review that, certainly, the "Circulation" editorial team and reviewers were very excited about. I think this will be quite impactful and provide very, very detailed information for future research and future improvement and fate of the coronary graft conduits.

Dr. Carolyn Lam:               And, Dude, I agree. It's the new look at perhaps a classic, old, central surgery, the cardiovascular surgery. Very nice, indeed.

Dr. Marc Ruel:                   Precisely, thank you. We also have a couple of important, seminal original papers within the realm of coronary surgery. In fact, these also deal, to some extent, with the fate of conduits and certainly how they work in the patient population in long ago bypass surgery.

                                                One is a randomized control trial, a single center randomized control trial that was performed in South Manchester. It's called the VICO trial, a study comparing vein integrity and clinical outcomes. Essentially, the study looked at open vein harvesting versus two types of endoscopic vein harvesting for coronary artery bypass grafting.

                                                The study was performed at a single center in England with three sound methods, having three groups of 100 patients who were compared with regards to the vein harvest technique. The primary outcome was with regards to actual vein integrity, looking at muscular damage and endothelial function and integrity on microscopy.

                                                Surprisingly and actually quite reassuredly that there were very few differences between endoscopic vein harvest and open vein harvest. Certainly the investigators also looked, as one of their secondary outcomes, at quality of life. It was quality of life that was gained in patients who had endoscopic vein harvest versus those who had open vein harvest.

                                                Overall, there was no difference in major adverse cardiac events. Therefore, showing at least in an internally valid fashion that these investigators at their center could do endoscopic vein harvesting as well as open vein harvesting.

Dr. Carolyn Lam:               I know that there are other original research papers, perhaps. Would you like to highlight any of them?

Dr. Marc Ruel:                   Yes, for sure. Carolyn, there's also one more coronary surgery paper, which I wanted to highlight and that is the paper entitled, "Does Use of Bilateral Internal Mammary Artery Grafting Reduce Long-Term Risk of Repeat Coronary Revascularization?"

                                                This is a multi-center analysis with first author is Iribarne from Northern New England. Essentially, seven medical centers got together and took about 20 years of consecutive CABGs with a total number of 50,000 operations, or just shy of 50,000 operations.

                                                The median duration of follow-up was 13 years, and these patients were well matched together using a propensity matching scheme. I think this paper and this research is unique and of high impact. Even though it does have shortcomings of not being a randomized control trial, it is very welcome information, especially in light of the recent ART trial, which, as you know, did not show any difference at five years analysis between single and bilateral internal thoracic artery use.

                                                The particularity of the Iribarne paper is that it is a very large data set up with close to 50,000 patients. It is multi-centered, therefore, it is real life. It is a consecutive series. The patients are extremely well matched, and it is remarkable to hear that the patients, in fact, had no difference in mortality until about five years after the operation.

                                                As opposed to many previous series where single versus bilateral internal mammary grafting shows a mortality difference very early on, which always raises the suspicion of poor matching or confounding by indication, if you will, this paper did not have that.

                                                Finally, the follow-up was quite long and at about six years, there was really a mechanistic signal with regards to repeat revascularization events, which seemed to match the difference in late mortality. There was no difference in early and five-year mortality, but afterwards as repeat revascularization events started to occur more frequently in the single mammary group, this was matched by a difference in mortality, as well.

                                                I think a very useful, large, long follow-up mechanistically-based information that I think adds very significantly to the current information we have about bilateral versus single mammary use.

Dr. Carolyn Lam:               Thank you, Marc. Two original papers, highlighted, dealing with really very important modern controversies in this area. Open vein versus endoscopic vein harvesting, single versus bilateral mammary artery bypass. Excellent.

                                                Let's move on now to the next sub-theme, if you will. And that is the collection of papers on "Adult Congenital Heart Conditions," really, really an increasingly important and growing population that we're seeing. Tim, would you like to summarize maybe some of the highlights of the papers there?

Dr. Timothy Gardner:     The first paper, as you point out, is focused on adult patients with repaired tetralogy of Fallot. This series came from the UK and it examines the course of almost 60 patients, at a mean age of 35 years following a repair of tetralogy as infants or young children, developed right heart failure and required pulmonary valve replacement.

                                                This is a common scenario that we're seeing, successfully repaired children who appear to do well but as they get into their late 20s and 30s, their pulmonary valve function, which is often inadequate or not even present valve, require an intervention.

                                                The important learning here is that pulmonary valve replacement, either surgically or by catheter technique, was shown to be highly effective in salvaging right ventricular function. That is based on imaging studies as well as hemodynamic studies of right ventricular function. There was an almost, in this group of patients, almost an immediate reverse remodeling of the right ventricle after placement of the valve, that continued to improve over time.

                                                This was, I think, quite reassuring. There, historically, was a bit of a reluctance to operate on these patients as their right heart was failing, despite the fact that without some intervention to take the volume load off of the RV, the patients didn't do well. This is good news for an important group of patients who we are all seeing, who oftentimes present to the adult cardiologist because of this right ventricular failure problem. A nice, reassuring study.

                                                Actually, the other two congenital papers are, again, focused on the infant. They both deal with the infant with hypoplastic left heart syndrome or single ventricle pathology. The first paper seems sort of specialized in terms of its focus, "The Optimal Timing of Stage-2-Palliation for Hypoplastic Left Heart Syndrome." This was a report from the NIH Pediatric Heart Network. They had a single ventricle reconstruction trial.

                                                This network is comprised of about 10 North American centers, both in the U.S. and Canada and has provided excellent data about the management of pediatric heart disease but, in particular, the single ventricle trial has been excellent.

                                                In this particular paper, they look at the optimal timing for stage-2 repair. Just to remind ourselves, the first part of the three-stage treatment for hypoplastic left heart syndrome is the Norwood procedure, which has to be done shortly after birth, as the patent ductus arteriosus closes and converts, essentially, the single right ventricle into the systemic ventricle.

                                                The stage-2 comes along, usually done with a Glenn-type of shunt, increases pulmonary blood flow and stabilizes these infants until they can reach the age for, and the heart function for definitive repair. This has been a particularly difficult problem for the congenital heart surgeons. What is the optimal timing?

                                                This study, which involved over 400 patients, identified optimal timing for the second stage between three and six months after the Norwood. I think this was very reassuring, is reassuring or supportive for the congenital heart community in terms of both patients and also good evidence base that a delay of three to six months does, in fact, produce the best transplant-free survival.

                                                In fact, the other aspect of this observation was that infants who developed the need for another second stage operation sooner than that did not do well, and the reasons for the required earlier surgery could be failure of the initial operation or additional anatomic risk factors. But this, I think, was an important, large series, multi-center study that will prove to be very helpful in sorting out this complex timing of a three-stage repair.

                                                Just to comment, again, for readers who don't deal with infant congenital heart treatments very often, there's been a remarkable amount of success over the last two decades in salvaging and saving these very difficult infants with the hypoplastic left heart syndrome. In fact, an additional paper in this surgery-themed issue, comes from the UK and is, in fact, a report on the findings from the UK-wide audit of the treatment of infants with hypoplastic left heart syndrome.

                                                In fact, their findings, in this sort of real world, not in the Pediatric Heart Network trial group, is very similar. They found that infants who got to the second stage without additional refinement of the initial Norwood procedure and were able to be successfully treated with a Glenn shunt somewhere in the four-to-six-month age range, did well. They actually made the point that the anatomy was more of a determinant than anything else.

                                                I think that this particular review will reinforce what the congenital heart surgeons have learned about optimal timing for this three-stage treatment of what previously were unreconstructable children.

Dr. Carolyn Lam:               Thank you so much, Tim. Isn't it wonderful the way papers come in and they're actually complementary and consistent with one another. We're just so lucky to be publishing all of these great, high-quality, impactful papers in "Circulation."

                                                Moving on, the next paper actually reminds us why this is a cardiovascular surgery-themed issue and not just a cardiac surgery-themed issue. Didn't we just say that earlier, Marc? This one is on abdominal aortic aneurysm treatment. A population-based landscape of this. Could you tell us a little bit more about that one?

Dr. Marc Ruel:                   Absolutely. Carolyn, you're entirely right. We must remember that "Circulation" is also about peripheral vascular disease, saying this earlier, or cardiovascular surgery and anesthesia consult also when it encompasses vascular surgery. Precisely to that effect, one of the papers in our cardiovascular surgical-themed issue is a landscape population based analysis from Finland that looks at the incidence of abdominal aortic aneurysm between the years of 2000 and 2014.

                                                Finland has a population of about 5.5 million and remarkably has a very circumscribed healthcare system. They do not have an organized system of AAA care as some other countries have shown to have and potentially benefit from, but rather they have a treatment of this condition at several institutions, many of which may not be high volume.

                                                I think the paper is remarkable is that it is very well nested in terms of a population. It provides a comprehensive landscape of where this condition has evolved to over the last few years. Obviously, we see in the results from the authors that the mortality has decreased quite a bit, but also the incidence, probably as a result of better control of risk factors. And also the incidence of rupture outside the hospital.

                                                One thing that came out of this paper, as well, is a potential cohort of the benefits gained from developing an organized system of AAA care, from the reason that the mortality of AAA rupture in Finland was still quite high, despite this being a modern series. In fact, when you include ruptures, before arrival to hospital and at arrival to hospital, the overall mortality was almost 80% for ruptured AAA.

                                                Perhaps one message that comes out of this is that there may be a benefit in having specialized centers dealing with these conditions, especially as they are in the process of rupturing. One last observation was, obviously, the increasingly prevailing role of endoscopic vascular repair in the treatment of this condition, which, in fact, has now surpassed open repair as the dominant method of elective repair.

                                                I think, overall, a very comprehensive, well-nested, country-wide with good follow-up landscape of the AAA condition in a country that has essentially a similar socioeconomic status to much of the western world. Therefore, with external generalized ability to some extent.

Dr. Carolyn Lam:               Exactly, and contemporary data. I really enjoyed that you paired those with an excellent editorial, as well. Finally, before we wrap this up, I have to ask Tim to comment on this next paper, and it's on ventricular assist device malfunctions, I love the title, "It's More Than Just The Pump." Of course, as a heart failure physician, this one's very close to my heart. Forgive the pun. But, Tim, could you tell us about that?

Dr. Timothy Gardner:     This paper comes from the University of Pittsburgh and their artificial heart program. Robert Kormos is the first author and he's been one of the stalwart leaders in the use of LVADs and other pump devices. He reports on their experience with over 200 both HeartMate and HeartWare ventricular assist devices.

                                                It was interesting when we reviewed this paper by the editors, there was some thought that maybe this was a little too engineering focused and so on, but I think the point of the paper is that, as they say in the very first line in their report, reports of LVAD malfunction had focused on pump thrombosis.

                                                But they point out very appropriately that, in fact, controller failure, battery failure, cable failure and other causes of device failure, which can be critical and life threatening and so on, are engineering issues. It reminds us that when we're managing this difficult group of patients, and we're seeing many more patients today with getting LVADs than 10 or 20 years ago, we need to have the bioengineering abilities and resources available.

                                                Even the surgeon and the critical care physician who is dealing with these patients either has to acquire this kind of knowledge or capacity himself or herself, or needs to have a good bioengineer nearby.

                                                What's interesting, I think, that all of us define that these mechanical failures were more common in this pretty big experience than what we've more clinically worried about, which was thrombosis of the pump.

Dr. Carolyn Lam:               Exactly. That's so wonderful. And you know it just leads me to really thank you both, Marc and Tim, for this extraordinarily excellent selection of original research, state-of-the-art and perspective articles and editorials on congenital, coronary, vascular and heart failure surgery. This really appeals not just to the cardiovascular surgeons but really to the vast readership of "Circulation."

                                                Thank you for a wonderful themed issue and thank you for this great podcast.

Dr. Timothy Gardner:     Well, thank you.

Dr. Marc Ruel:                   Thank you very much, Carolyn.

Dr. Carolyn Lam:               Listeners, don't forget to tune in again next week.

Oct 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 Center and Duke National University of Singapore. Today's feature discussion centers on the population burden of sudden death associated with hypertrophic cardiomyopathy. These are novel data from the ongoing Oregon sudden unexpected death study, results that may surprise you. Stay tuned and that's coming up right after these summaries.

                                             The first original paper in this week's journal tells us that risk reductions from air pollution control yields health benefits comparable to the control of systolic hypertension and smoking in a high risk segment of the urban Chinese population. First author Dr Huong, corresponding author Dr Gu and colleagues from Fu-Wai hospital in Beijing China projected the life years gained if urban China were to reach one of three air quality goals. First, Beijing Olympic games level. Second, China class 2 standard. Third, the WHO standard. They further compared projected air pollution reduction control benefits with the potential benefits of reaching WHO hypertension and tobacco control goals.

                                             Now to do this, the authors used the Cardiovascular Disease Policy Model: China, which is a computer simulation state transition mathematical model of coronary heart disease and stroke incidence, prevalence, mortality, non-cardiovascular deaths, and costs of health care in the Chinese population. They found that air quality improvement under the different scenarios could lead to a great health benefit, ranging from 241,000 life years gained to much greater benefits, benefits that were greater to or equal to the combined benefits of a 25% improvement in systolic hypertension control, and a 30% smoking reduction. Thus, the authors called for joint efforts of the whole society for air quality improvement in China.

                                             The next study describes six differences and similarities in atrial fibrillation epidemiology, risk factors, and mortality in the community. First author Dr [Magnusson 00:02:42], corresponding author Dr [Schnabel 00:02:44] and colleagues from University Heart Center Hamburg Eppendorf studied 79,793 individuals without atrial fibrillation diagnosis at baseline from 4 community-based European studies, namely, FINRISK, DanMONICA, Molisani, and Northern Sweden, all followed for a medium of 12.6 years. They found that cumulative incidence increased markedly after the age of 50 years in men and after the age of 60 years in women. The lifetime risk was similar in more than 30% for both sexes.

                                             Subjects with incident atrial fibrillation had a three and a half fold higher risk of death compared with those without atrial fibrillation. Among the classical risk factors, body mass index explained the largest proportion of atrial fibrillation risk. Six interactions were seen for the risk associations of body mass index and total cholesterol, wherein body mass index was associated with a greater risk increase in men than women, whereas total cholesterol was inversely associated with incident atrial fibrillation with a greater risk reduction in women than men.

                                             The next study describes a novel circular RNA as a potential target in diabetic proliferative retinopathy. Circular RNAs are a novel class of non-coding RNAs that regular gene expression and they're characterized by closed loop structures with neither five-prime, nor three-prime polarity nor a polyadenylated tail. In today's study, first author Dr [Shah 00:04:33], corresponding authors Drs. [Yen 00:04:33] and [Zhao 00:04:36] from Shanghai Medical College Fudan University in China characterized the expression and regulation of the circular RNA, circHIPK3 in retinal endothelial cells and diabetic retinal vascular dysfunction.

                                             CircHIPK3 expression was significantly up regulated upon high glucose stress in vivo and in vitro and regulated retinal endothelial cell function and vascular dysfunction by acting as an endogenous microRNA 30A-3P sponge that sequestered and inhibited its activity. In summary therefore, the circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking microRNA 30A function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that the circular RNA may be a potential target for diabetic proliferative retinopathy.

                                             The next study identified important new principles of endogenous chromatin structure that have key implications for epigenetic therapy. In this study from first author Dr Rosa-Garrido, corresponding author Dr Vondriska, and colleagues of David Geffen School of Medicine in UCLA, the authors examined changes in chromatin configuration in cardiomyocytes isolated from mouse hearts subjected to transverse aortic constriction or hearts subjected to Tamoxifen inducible cardiac specific excision of CTCF, which is a ubiquitous chromatin structural protein.

                                             There was several important findings from this work. Firstly, the authors found that depletion of CTTF was sufficient to induce heart failure in mice and human heart failure patients receiving LVADs also showed increase CTCF abundance. Pressure overload or CTCF depletion selectively altered the boundary strength between topologically associated domains, which are regions of DNA in which physical interactions occur frequently. The authors showed that there were changes in the compartmentalization of active chromatin and inactive chromatin segments, which is a measure of genomic accessability.

                                             Heart failure involved decreased stability of chromatin interactions around disease causing genes. In summary, these finding provide a high resolution chromatin architectural resource for cardiac epigenomic investigations and also demonstrate that global structural remodeling of chromatin underpins heart failure.

                                             The final study is the first to provide insights into the fluid mechanics of transcatheter valve thrombosis. First author Dr Midha, corresponding author Dr Yoganathan and colleagues from Georgia Institute of Technology and Emory University in Atlanta analyzed post-procedural four dimensional volume rendered CT data of transcatheter aortic valve replacement, or TAVR patients, enrolled in the Resolve trial, excluding patients on anticoagulation. Patients were classified as having transcatheter heart valve thrombosis if there was any evidence of hypoattenuated leaf thickening. The authors studied the flow characteristics within the neo sinus which is formed followed deployment of a transcatheter valve into a native aortic valve.

                                             The authors found that post deployment valve geometry and final implant position affected the flow within the neo sinus, which in turn, may affect the predisposition to thrombus formation. The impact of geometry and position varied according to the different valve types. A supra-annular transcatheter heart valve deployment resulted in a nearly seven fold decrease in stagnation zone size when compared to an intro-annular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. In summary, deployed transcatheter heart valve geometry may have implication on the occurrence of thrombosis and a supra-annular neo sinus may reduce thrombosis risk due to reduced flow stasis. While additional prospective studies are clearly needed, these results may help identify patients at higher thrombosis risk and aid in the development of the next generation of devices with reduced thrombosis risk.

                                             Well, that wraps it up for our summaries. Now for our feature discussion.

                                             Sudden death in hypertrophic cardiomyopathy has been and still is a very hot topic in cardiology. Of course it's understandable given all the high profile deaths that have occurred in young athletes ascribed to hypertrophic cardiomyopathy and the fact that these deaths may potentially be preventable with implanted defibrillators. However, we're so proud to have in this week's journal, some of the first data on the population-based burden of sudden death associated with hypertrophic cardiomyopathy. I'm so happy to have with us the corresponding author of this research letter, Dr Sumeet Chugh from Cedar Sinai Medical Center, as well as Dr Mark Link, associate editor from UT Southwestern. Welcome, gentlemen.

Dr Sumeet Chugh:            Thank you.

Dr Mark Link:                    Thank you.

Dr Carolyn Lam:               Sumeet, you know as I said in the introduction, sudden death in hypertrophic cardiomyopathy, we've talked about it a lot. There's been lots published. What makes your data so novel?

Dr Sumeet Chugh:            There is indeed a large body of work related to hypertrophic cardiomyopathy but most of it came from registries. Probably what's a bit unique about our work is that it was done in one large, US community over a number of years.

Dr Carolyn Lam:               Indeed. So population-based statistics, not just of hypertrophic cardiomyopathy, but of sudden death related to it, isn't it?

Dr Sumeet Chugh:            That's correct, Carolyn.

Dr Carolyn Lam:               I think the other thing that we were just actually chatting about is the fact that it's contemporary. Could you tell us maybe the period you're looking at and then give us your findings?

Dr Chugh:                           Yes. The study was initiated in 2002 and is now in it's 16th year, so this particular analysis was conducted between the time period 2002 and 2015. What we do in the process of this community-based work is that we track prospectively every cardiac arrest that happens in the community centered around Portland, Oregon in the USA. The work in performed in the process of doing a multiple-source ascertainment where we take the help of the first responders or the ambulance personnel, the hospital emergency rooms, as well as the police, and the coroner network. It's a fairly comprehensive way of ascertaining sudden cardiac arrest.

Dr Carolyn Lam:               That is a very unique and valuable data set. Could you summarize the top line results, because they were rather surprising?

Dr Sumeet Chugh:            We are already learning that over time, with more awareness, education, and modern management of hypertrophic cardiomyopathy, the risk of sudden cardiac arrest and the overall morbidity from hypertrophic cardiomyopathy may be on its way down. What this study is showing is, that actually the risk of sudden cardiac arrest and the burden of sudden cardiac arrest from hypertrophic cardiomyopathy in the community may be quite low. Those are the main findings.

Dr Carolyn Lam:               Yeah. In fact, I was just so impressed because first of all, you excluded the individuals in this population and found that hypertrophic cardiomyopathy was responsible for 1 in 30 of the cardiac deaths, but that the incidence of the sudden deaths were 0.2 to 0.3% among these hypertrophic cardiomyopathy patients, perhaps less than others may have expected.

                                             Mark could I bring you in on this for a moment? What do you think are the take home messages for something like this, because in a young and middle age population, is any rate really too low?

Dr Mark Link:                    I think this is great data because it encompasses an entire population, so it gets us good data on the true incidence of sudden cardiac death. In the study, if you look at the total number of patients that either had an ECHO or had an autopsy, about 5%, a little over 5% of them, had hypertrophic cardiomyopathy. Roughly 5% of the individuals dying suddenly, under age 60 are dying secondary to hypertrophic cardiomyopathy. That's the sort of data that we really didn't have before because we didn't have such a nice population-based study.

                                             It was interesting also, they tended to be younger, 10 years younger than the others dying suddenly, so it was a younger cohort. They more often had ventricular fibrillation or ventricular tachycardia than the others dying suddenly. It really does give us some nice data on the true incidence of sudden death due to HCM in the community.

Dr Carolyn Lam:               What I thought was also valuable was the fact that the diagnosis of hypertrophic cardiomyopathy was quite often missed prior to the cardiac arrest and I'm trying to wrap my head around about what that implies.

Dr Sumeet Chugh:            That's a very important point, Carolyn. These findings also give us the message that our risk classification methodology continues to need more work. The fact remains that a significant proportion of patients with hypertrophic cardiomyopathy are also going to be asymptomatic. Sometimes they just don't come to our attention.

                                             Another important point, however, that's related to this work is that there may have been during the course of this time period, at least a few patients in this community who would have received an implantable defibrillator and their sudden cardiac arrest would have been averted, so we're not able to count those individuals who were already found and managed.

Dr Mark Link:                    That's a very important point because if a person is found with HCM and has risk factors, they would get a implantable defibrillator. Those individuals would not show up in this database because they wouldn't die.

Dr Carolyn Lam:               Mm-hmm (affirmative)-

                                             That's a very, very important point. Thank you for highlighting that. I think it goes back to why these data are so important, because they are contemporary as well and we really need such estimates, so congratulations Sumeet and thank you for giving us these valuable data.

                                             I'd like to switch tracks a little bit though, and point out this was a research letter, a big data set, important findings, but published as a research letter. Should I even say but? Mark could you comment a little bit about research letters in circulation versus original articles?

Dr Mark Link:                    We increasingly are using research letters in circulation for original research that drives home a basic single point. If that basic single point can be made in 1,200 words, we actually like the research letter format. It's a quick read, people remember it, it's cited. It is something that authors that we ask to turn a full length manuscript into a research letter, should be taking that as a positive sign, because that means that we're interested in the topic and would like to see it in print.

Dr Carolyn Lam:               I completely agree and in fact, Sumeet, if I could ask you to weigh in. Sometimes it's harder, isn't it, to write a research letter than to write a full length manuscript? How was your experience?

Dr Sumeet Chugh:            I have to admit that the first responses as you said, where you feel, "Oh, I've spent a lot of effort in writing this large paper, and now I have to squeeze it into 1,200 words," but the second thought for me was, "The fact is that this is a one bullet message and why not make it shorter and snappier as it is?" I think I've come around in the appropriate situation to appreciating this opportunity of writing a research letter.

Dr Mark Link:                    when you read the research letters, they're very succinct. I actually like them. They get the message across quickly and I think it's a great way to produce science and to show what you've done.

Dr Carolyn Lam:               Yeah. The thing is that we also restrict to a single figure, or a single table and I cannot tell you how many times I've referred to that single figure because it usually tells the full story and it's beautiful summary.

                                             So, listeners, you've heard about the research letters in circulation. Please have a look at them. I'm pretty sure that you will fall in love with the format just like we all have.

                                             Thank you so much, Sumeet and Mark for joining me today. I'm afraid our time is up, but I've so enjoyed talking to you. Thank you, listeners, for following us today. Don't forget to tune in again next week.

 

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

                                                Our feature discussion this week centers on the temporal changes in natriuretic peptides preceding heart failure hospitalizations and patients at high risk. Data that are really novel and have implications for the way we perhaps monitor and categorize these high risk patients. Well, more soon right after these summaries.

                                                The first original paper this week provides the first epigenome-wide association study in patients with heart failure. Now, epigenetics refers to biochemical DNA modification such as methylation of gene bodies, and post-translational modification of histones, which is increasingly recognized to play a crucial, regulatory interface between genes, environment, and the transcriptome.

                                                The lack of availability of myocardial specimens from patients has been a major roadblock for elucidating the impact of such epigenetic changes on complex cardiovascular traits. However, in today's paper from first author, Dr. Meder, corresponding author, Dr. Katiz and colleagues from University of Heidelberg, Germany. The authors performed the first multi-omic study in myocardial tissue and blood of patients with dilated cardiomyopathy compared to controls.

                                                They detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy, with three of them reaching epigenome-wide significance. 29 of these loci could be replicated in independent cohorts and authors further linked a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression.

                                                Finally, they identified distinct epigenetic methylation patterns that are conserved across tissues. Thus representing novel, epigenetic biomarkers for heart failure.

                                                The next study is the first to assess a diagnostic and prognostic value of cardiac myosin binding protein-C in patients presented with possible acute myocardial infarction or AMI. Cardiac myosin binding protein-C is a cardiac restricted protein that is more abundant than the cardiac troponins and is released more rapidly following AMI.

                                                In today's paper, first author, Dr. Kaya, corresponding author, Dr. Marber and colleagues from the Rayne Institute In St. Thomas's hospital in London evaluated cardiac myosin binding protein-C as an adjunct or alternative to cardiac troponins in the early diagnosis of AMI in 1,954 unselected patients presenting to the emergency department with symptoms suggestive of AMI.

                                                The final diagnosis of AMI was independently adjudicated in 340 patients. The authors found that concentrations of cardiac myosin binding protein-C at presentation were significantly higher in those with versus without an AMI. The discriminatory power for AMI quantified by the area under receiver operating curve was comparable for cardiac myosin binding protein-C to high sensitivity cardiac troponins T and I, and even superior to standard sensitivity cardiac troponin I. The use of cardiac myosin binding protein-C more accurately classified patients with a single blood test and to rule out or rule in categories in early presenters, meaning those with chest pain of less than three hours.

                                                The improvement in rule in or rule out classification with cardiac myosin binding protein-C was larger compared with higher sensitivity cardiac troponins T and I. Finally, cardiac myosin binding protein-C was superior to high sensitivity and standard troponin I and similar to high sensitivity cardiac troponin T at predicting death at three years. Thus in summary, this paper shows that cardiac myosin binding protein-C at presentation provides discriminatory power comparable to high sensitivity troponins T and I in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset.

                                                The next paper describes the discovery of a novel candidate cardiomyopathy or arrhythmia gene. First author, Dr. Barryfield, corresponding author Dr. McNally from Center of Genetic Medicine in Chicago and colleagues studied a family with dilated cardiomyopathy and associated conducted system disease in whom prior clinical cardiac gene panel testing was unrevealing. Whole genome sequencing however, identified a premature stop codon in the gene encoding a novel myo filament component, the myosin binding protein-H-like.

                                                Having identified this gene, they turned to experimental approaches. The myosin binding protein-H-like gene was found to have high atrial expression with low ventricular expression. The truncated protein failed to incorporate into the myo filament. Human cell modeling demonstrated reduced expression of the mutant allele. Heterozygotes and nullumites exhibited a reduction in fractional shortening and increased diastolic ventricular chamber size, aberrant atrio-ventricular conduction and an increased rate of arrhythmia associated with the expression of the myosin binding protein-H-like in the atria, as well as in discrete puncta throughout the right ventricular wall and septum.

                                                These findings therefore support that myosin binding protein-H-like truncations may increase the risk for human arrhythmias and cardiomyopathy.

                                                Transplantation of cells into the infarctant heart has significant potential to improve myocardial recovery. However, low efficacy of cell engraftments still limits the therapeutic benefit. In today's paper, authors describe a method for the unbiased, in-vivo selection of cytokines that may improve Mesenchymal stromal cell engraftment into the heart. In this paper from first author, Dr. Bortolotti, corresponding author Dr. Giacca, and colleagues from University of Trieste in Italy, an arrayed library of 80 secreted factors were individually cloned into adeno-associated viral vectors.

                                                Pools from this library were then used for the batch transduction of bone marrow derived Mesenchymal stromal cells ex-vivo, followed by intra myocardial cell administration in normal and infarctant mice. Three weeks after injection, the vector genomes were recovered from the few persisting cells, and identified by sequencing DNA barcodes that were uniquely labeled for each of the tested cytokines.

                                                Using this novel, competitive, engraftment screening methodology, the authors identified that the most effective molecule was cardiotrophin-1 a member of the IL-6 family. Intra cardiac injection of Mesenchymal stromal cells preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size parallel to the persistence of the transplanted cells in the healing hearts for at least two months after injection. Thus, preconditioning with cardiotrophin-1 might represent an efficient manner to improve the currently poor cell retention in patients treated with Mesenchymal stromal cell therapy.

                                                The final paper presents results of the early myo trial, a non-inferiority trial comparing a pharmacoinvasive strategy with half-dose alteplase versus primary PCI in patients with STEMI, presenting six hours or less after symptom onset but with an unexpected PCI related delay.

                                                First author, Dr. Poole, corresponding author, Dr. Hua and colleagues from Shanghai Jiao Tong University in China randomized a total of 344 patients from seven centers to a pharmacoinvasive arm or a primary PCI arm. They found that pharmacoinvasive strategy was non-inferior to primary PCI for the primary endpoint of complete epicardial and myocardial reperfusion after PCI defined as TIMI flow grade 3, TIMI myocardial profusion grade 3, and ST-segment resolution of more than 70%.

                                                There was no significant differences in the frequency of the individual components of the combined endpoint. Infarct size and left ventricular ejection fraction were similar in both groups and there was no significant differences in 30-day rates of total death, re-infarction, heart failure, major bleeding events, or intracranial hemorrhage. However, minor bleeding was observed more often in the pharmacoinvasive group.

                                                Thus the authors concluded that a pharmacoinvasive approach with reduced dose alteplase seems to offer effective and safe reperfusion in low-risk patients with STEMI with an unexpected PCI related delay. Further large, randomized control trials powered for clinical endpoints are needed.

                                                Well, that wraps it up for your summaries. Now for our feature discussion.

                                                The measurement of natriuretic peptides BNP, NT-proNP have certainly become the cornerstone of heart failure management. We measure these levels by guidelines in patients who are presenting with symptoms and suspected heart failure, in patients who are hospitalized. We measure them for prognostication purposes at discharge. However, what we don't really know is how the preceding changes in natriuretic peptides may precede heart failure hospitalization in patients who are at high risk of developing heart failure.

                                                For example, patients with a recent coronary event or type-2 diabetes. And this is the very subject of our feature paper today, and I am so pleased to have the corresponding author of today's paper which is really a research letter. Dr. Brian Claggett from Brigham and Women's Hospital as well as Dr. Biykem Bozkurt who's our senior editor from Baylor College of Medicine.

                                                Welcome both, and maybe I could start, Biykem could you let us know, what are the unanswered questions in heart failure relating to natriuretic peptides and how do you see this paper falling in, clinically?

Dr. Biykem Bozkurt:        Carolyn, this is a wonderful I think prelude to perhaps preventing heart failure events. And as you are aware, we in the recent year changed our guidelines at the ACC, AHA, and the HFSA incorporating screening high risk patients for development of incident heart failure. And the study that resulted in this consideration was a STOP-HF trial which was utilizing natriuretic peptides in high risk patients to determine whether their closer follow up in a multidisciplinary fashion would result in earlier detection and prevention of heart failure, and which it did.

                                                And this study I think is straddling the concept of high risk or stage A or B patients because they are individuals who have had heart attacks, coronary events, and they have type-2 diabetes so they are definitely high risk. And doing natriuretic peptides as an outpatient, whether that would predict the heart failure hospitalizations.

                                                And in essence I think it's a good concept. Perhaps the challenging concepts are how often should we screen our patients, and what will be the threshold of the rise that would potentially make us act in either earlier diagnostic strategies, or management strategies. I think those are the two unanswered questions that remains.

                                                How are we gonna screen our patients? Our high risk patients to determine when they are developing heart failure before they become symptomatic? So, what threshold are we going to use?

Dr. Carolyn Lam:               That is a perfect set up. I just wanted to add as well in addition to STOP-HF there was the PONTIAC study in diabetics which is very relevant to today's paper that also sort of used NT-proBNP to risk stratify patients for prevention of heart failure. But neither of these studies talked about the temporal changes in natriuretic peptides. And I think a lot of the reason for that is, is that the methods, I mean the statistical methods to do that sort of thing are mind-blowing.

                                                And so Brian, could you now please share with us what you did, the methodology and basically what you found before we discuss the two questions that Biykem brought up?

Dr. Brian Claggett:           What was really interesting is the method that we came up with to look at these questions. It's something that we like to believe will be generalizable and can be used in other scenarios and for other biomarkers. But the idea that we have is that we are always used to thinking about the design of a clinical trial as being very regimented. So, you see a patient once at baseline, and then maybe six months later, and then maybe six months after that, and so on. And so it's hard to know what's going on, on a day to day or week to week basis.

                                                But if you think backwards, and you think backwards from the time of any sort of event, because those events whether they're hospitalizations or MIs or death, they happen not on that same schedule. And so odds are at the end of a trial, you had a patient who came to a scheduled visit and then had an event the next day. And you probably had a patient who came in for a visit two days before an event, and another patient who came in a week before an event. So if you start thinking on that time scale, you can piece together all these different time frames when you do have data collected and try to reconstruct something that looks like an actual continuous natural history of what that biomarker would have looked like over say a two year period, if it had been measured continuously.

Dr. Carolyn Lam:               So, tell us what you found. First of all, let's just make sure that everyone knows you were looking at the ELIXA cohort, right?

Dr. Brian Claggett:           Yes, the data that we had available for this analysis comes from the ELIXA trials, it was 6,068 patients all with type-2 diabetes and a recent ACS event. Recent meaning within the last 180 days. And they were randomized placebo versus a diabetes drug, lixisenatide. And they were followed up for cardiac outcomes.

                                                Beyond that, the natriuretic peptides were measure systematically at baseline, month 6, month 18, and month 24 in all patients who were participating in the trial. So this was the richest collection of a large number of patients being measured multiple times, systematically and not in just a sub-sample of the population. So, we felt like this was a great opportunity to learn something about what happens. What can you learn when you measure these natriuretic peptides over and over again.

                                                And even more interesting than that, the fact that this wasn't a heart failure trial meant that some of the patients already had heart failure at baseline. Other patients didn't have heart failure, but as the trial went on, they developed or were hospitalized for heart failure for the first time. And so we were able to also look at differences between patients experiencing their first heart failure, versus those with more long standing disease.

Dr. Carolyn Lam:               And that was very, very unique methodology that you spoke about. And I fully agree that it's going to be used more. I am staring at your beautiful figure one right now. That really, really says it all. Could you walk us through the results?

Dr. Brian Claggett:           Sure, I think our key finding is that, I guess no matter when you measure patients. Patients with a higher level of NT-proBNP, or a higher level of BNP at any given time are going to be at higher risk of developing heart failure in the future.

                                                But as we start looking at this as a temporal process, what we see is that there seem to be a noticeable acceleration in these increases, specifically in the last six months before development of heart failure. Or, before a hospitalization for heart failure. And that increase in the final six months seems to occur both in patients who had no prior history of heart failure and also in patients with a history of heart failure. So that six month window I think is something that we learned that we didn't necessarily know before.

Dr. Carolyn Lam:               But, going back to Biykem's questions, do you think we have answers to how often we need to survey natriuretic peptides in these high risk patients and what threshold we need to act on?

Dr. Brian Claggett:           I think both are very important. I think maybe the timing and the thresholds are somewhat separate questions. I think we're better able to answer the timing question. At the very least we can say that if dramatic changes are happening over a six month window that measuring patients only once every six months probably isn't enough. Whether that means it needs to be every three months, or two months, or one month, or something more than that, I think it's hard to know exactly what the right answer is. But I think we are confident in saying that things happen relatively quickly and we need to be measuring these things more frequently.

                                                As far as the question of thresholds, I think that's maybe even a more difficult question. Or even the idea of a threshold means that we think that there's some magic number and I am not sure that we know for sure what's more important, the absolute number or is it the ... if someone starts relatively low and that relatively low number doubles over the course of six months. That might still be prognostically just as important as someone who's been consistently edging just below or just about that threshold level.

                                                I'm not sure that we're confident enough to say that the changes, the speed of the changes, or the relative changes, or some absolute threshold is the most important thing to be paying attention to. But, I think where these two are related is the more ... that we can start to collect this data more frequently and be able to analyze it. I think that gives us a lot better chance of being able to successfully answer that question about thresholds.

Dr. Carolyn Lam:               Indeed. Stuff for future work, huh? Biykem, what do you think?

Dr. Biykem Bozkurt:        I wanted to point out two things from Brian's study which was quite interesting. One is the trajectory of the rise, or the delta changes in the natriuretic peptides was quite different in the patients with no history of heart failure compared to those with a history of heart failure. The trajectory, or the linear rise, or the delta changes were more prominent in the individuals with no history of heart failure. Probably intuitively expected so because their baseline levels are not as high as the individuals with history of heart failure.

                                                So, it almost gives the impression that maybe in low low risk, the screening or the frequency may need to be lower, and if low, then probably the likelihood of the rise may be less. But those individuals who, as you said, are edging upward, then maybe the frequency may need to be higher and there may be perhaps a linear rise or a more prominent rise about six months before the incident event.

                                                So, it's an interesting concept just to look at people's trajectories. But, as you said, probably individualization and monitoring or targeting may need to be individualized according to personal risk and other features. And one then wonders futuristically if this would be a concept that would be point of care testing maybe done by the patients similar to glucose monitoring. And in the event that we were to be able to carry the platform to self-test.

Dr. Brian Claggett:           You're talking to a statistician, so I am always going to be in favor of collecting more data all the time. So I agree with that.

Dr. Carolyn Lam:               Wow, what an insightful discussion. Thank you both for joining us on this podcast today.

                                                Ladies and gentlemen out there, you heard it right here in Circulation on the Run. Tune in again next week.

Oct 10, 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 Center, and Duke-National University of Singapore.

                                                We know that excessive sedentary time is bad in terms of health outcomes, but does it matter how that sedentary time is accrued, whether in short or long bouts? Today's feature paper gives us some answers. More soon, right after the summary of this week's journal.

                                                The first original paper in this week's journal provides insights into the mechanisms underlying neointima formation in arterial restenosis. Co-first authors, Dr. Cheng and Shi, corresponding author Dr. Li from Wuhan University in China, and their colleagues, performed an elegant series of experiments in which they demonstrated that interferon regulatory factor 4, or IRF4, which is a member of a family of key, innate, immune regulators known to play a role in cardiometabolic disease, actually protects arteries against neointima formation.

                                                They further probed the mechanism underlying this protective effect and found that IRF4 promoted the expression of Krüppel-like factor 4 by directly binding to its promoter. Genetic over-expression of Krüppel-like factor 4 in smooth muscle cells reversed the neointima promoting effect of IRF4 ablation. Whereas, ablation of Krüppel-like factor 4 abolished the protective function of IRF4, thus indicating that the protective effects of IRF4 against neointima formation were Krüppel-like factor 4 dependent.

                                                These findings suggest that the previously undiscovered IRF4 Krüppel-like factor 4 axis plays an important role in vascular proliferative pathology and thus may be a promising therapeutic target for the treatment of arterial restenosis.

                                                The next paper highlights that high-spacial resolution in gene expression signatures can reveal new regulators, genetic pathways, and transcription factors that are active in well-defined regions of the heart.

                                                Now we know that traditional genome-wide transcriptome analysis has been disadvantaged by the fact that the signals are derived from tissue homogenates. Thus, the authors of this current paper, including Co-First authors Dr. Lacraz and Junker, corresponding author Dr. Van Rooij from University Medical Center Utrecht in the Netherlands used tomo-seq to obtain genome-wide gene expression signature with a high spacial resolution, spanning from the infarcted area to the remote areas to identify new regulators of cardiac remodeling.

                                                Using this technique, they identified SOX9 as a potent regulator of cardiac fibrosis. In vivo loss of SOX9 reduced the expression of many extracellular matrix genes, which coincided with a blended cardiac fibrotic response upon ischemic injury.

                                                These data therefore were able to unveil currently unknown relevance of SOX9 as a key regulator of cardiac fibrosis, thus underscoring that tomo-seq can be used to increase our mechanistic insights into cardiac remodeling, and to help guide the identification of novel therapeutic candidates.

                                                The next paper reports the primary results of the effect of ferric carboxymaltose on exercise capacity in patients with iron deficiency and chronic heart failure, or EFFECT-HF study, which is a randomized control trial of intravenous ferric carboxymaltose, compared to standard of care on the primary end point of change in peak Vo2 from baseline, to 24 weeks in patients with symptomatic, chronic heart failure with reduced ejection fraction and iron deficiency.

                                                In this report from Dr. van Veldhuisen from University Medical Center Groningen and colleagues, intravenous ferric carboxymaltose was shown to significantly increase serum ferritin and transferrin saturation. At 24 weeks, peak Vo2 had decreased in the control group, but was maintained in the group receiving intravenous ferric carboxymaltose.

                                                Although a favorable effect on peak Vo2 was observed with ferric carboxymaltose, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak Vo2 among patients who died.

                                                They also reported that patient's global assessment and functional class, as assessed by New York Heart Association, improved on ferric carboxymaltose compared to standard of care.

                                                Whether ferric carboxymaltose is associated with an improved outcome in these high risk patients, deserves further study.

                                                The final study provides important long term clinical data to guide lead management decisions in patients with cardiac implantable electronic devices.

                                                Dr. Pokorney from Duke University Medical Center in Durham, North Carolina, and colleagues, analyzed over 6,000 Medicare patients and found that device extraction was associated with a lower adjusted five year infection rate, compared with a cap and abandon strategy. There was a lower absolute five year mortality with extraction, but after adjustment there was no association between extraction and a lower five year mortality.

                                                In summary, therefore, elective lead extraction for non-infectious indications in this Medicare cohort had similar long term survival, but lower risk of device infections at five years, compared to capping and abandoning leads.

                                                Patient and provider preferences are critical to decision making when considering extraction versus capping and abandonment of leads.

                                                Well, that wraps it up for your summaries. Now for our feature discussion.

                                                For today's feature discussion, we are talking about sedentary time and a metabolic risk of having too much of it. But, today's paper is so interesting because it tells us that it's not just the total amount of sedentary time that may matter, but how we accrue the sedentary time. Very, very novel concept in my point of view and I'm so pleased to have the first and corresponding author of this paper, Dr. Keith Diaz from Columbia University Medical Center with us, as well as Associate Editor from Johns Hopkins, Dr. Wendy Post.

                                                So pleased to have you both. Keith, could we just dive right into it? Tell us what population you were looking at, and what you found.

Dr. Keith Diaz:                    Sure, so we were studying a population of participants enrolled in the Hispanic Community Health Study, so it's a US populations of over 16,000 Hispanic adults. And essentially what we found was that sitting for prolonged bouts, so sitting for one, two hours at a time, was associated with poor glucose regulation.

Dr. Carolyn Lam:               Well, yikes. I've actually been sitting for a few hours in a row right now, actually. I think these results are phenomenal, but could you maybe expand a little bit on the details, like how long is too long? And, how often a break needs to happen for you to see differences in the metabolic risk?

Dr. Keith Diaz:                    It's a good question and, to be honest, we don't know. I think that's where the research needs to head, but right now it seems to be that taking a break every 30 to 60 minutes could be beneficial. I think that's what we've found thus far.

Dr. Wendy Post:               Keith, we were really excited to get your paper in. I think everyone on the Associate Editorial Board was especially interested in it because we can all relate. As Carolyn said, she's been sitting for a long time and when we have these meetings we have two hour meetings at a time and maybe we need to start saying that in the middle we should all stand up and take a break. So we can all relate to this.

                                                But I think one the biggest questions that we had related to data itself, was the association between the total sedentary time and the sedentary bout duration. Maybe you can tell us a little bit more about those correlations in the interaction and tell us also how you also measure sedentary bout duration and total sedentary time in this observational cohort.

Dr. Keith Diaz:                    Sure, so I'll start with that latter question. So, we measured sedentary time [inaudible 00:09:32] subjectively. So we actually used an activity monitor called an accelerometer to see how sedentary they are. And how we quantified sedentary bouts is we just looked at how long consecutively a person sat without moving. That was considered sedentary bout. In terms of correlation, what we found is that there are very closely linked. So, people who sit for long hours during the day for total volume, also sit in long bouts. And so what we wanted to do was try to figure out and piece apart, which one is more important? When we're trying to ... If we're thinking about guidelines and what we should be doing about our sedentary time, is it important to reduce our volume or interrupt our bouts? And so what we found is that they're not independent, and that they're in many ways synergistic. And that the association of prolonged sedentary bouts with glycemic biomarkers varied according to how much total volume you sit and vice-versa.

Dr. Wendy Post:               Can you expand a little bit more on that? So tell us about the interaction that you found between sedentary bout duration and total sedentary time.

Dr. Keith Diaz:                    Sure, so we did find that there was a specifically significant interaction between the two variables and so what we tried to do is actually categorize people as to whether they were high for both characteristics or high for just one of them. And so what we found was that those participants who are high for both, so they had high volume and sat in long bouts, they had the worst glucose regulation, and that those individuals that were high for just one of the characteristics had a little bit better glucose regulation. And so really what we thought the take home message was when thinking about how do we improve our sedentary behaviors is that it's targeting both. It's not sitting for large volumes during the day, but also making sure to take frequent breaks every 30 or 60 minutes.

Dr. Wendy Post:               And tell us about the glucose measures that you included in your study.

Dr. Keith Diaz:                    Yep, we had a couple glucose measures. One we had people do a two hour glucose tolerance test, so they took a glucose drink and then we measured their blood sugar levels two hours after having that drink. We also measured their H1Ac levels as well as their fasting glucose and fast to link insulin measures from which we can then derive measures of something called HOMA IR, which is a measure of insulin resistance.

Dr. Wendy Post:               And the associations that you saw were primarily with the HOMO IR and the two hour glucose levels but less with the hemoglobin A1c?

Dr. Keith Diaz:                    Correct.

Dr. Wendy Post:               So it really appears to be that insulin resistance that's most affected by the total sedentary time and sedentary bout duration. Tell us about potential confounders and how you factored that into your analysis.

Dr. Keith Diaz:                    Yeah, there was quite a number of potential confounders between this relationship of sedentary behavior and glycemic biomarkers. One of them in particular that we were concerned about most were things like body mass index or exercise or physical activity levels. And so we took a look at what we adjusted for those confounders how the relationship changed. And what we did find was that there was an attenuation and association between sedentary behavior and the glucose markers, but there was also ... were still statistically significant. So suggestive that maybe they're partly in the pathway of body mass index or exercise but they didn't make the relationship go away. I should add that we looked at a couple other confounders, we looked at things like inflammation, C-reactive protein, as well as whole bunch of other measures of cardiovascular risk factors. I'll stop there.

Dr. Wendy Post:               And what about the fact that study is cross-sectional, are there any caveats related to the study design that you'd like to point out to the audience?

Dr. Keith Diaz:                    Yeah, I think that's an important point, that this is cross-sectional, so by no means can we infer causality that sedentary behavior causes glucose dysregulation, it's just purely an association. So I think anyone listening to this podcast should keep that in mind when reading this paper or listening to this podcast.

Dr. Wendy Post:               So if you were writing the next set of guidelines what would you recommend in terms of how you implement these findings into guidelines? Not to imply that we think that these cross-sectional observational data mean that we're ready to change guidelines but, if these were replicated in randomized trial or some other more objective data study design, how do you think we should use these results to change our behaviors?

Dr. Keith Diaz:                    I think these guidelines point ... or, with the current guidelines are, sit less, move more, where the guidelines that came out from AHA in October of 2016. In part, they were not as specific because we don't have quite the quality of guidelines or data that we need for more qualitative guidelines, or quantitative guidelines. I think if we're able to replicate these data with [inaudible 00:14:10] or point us towards at least is, also, that we should be interrupting our sedentary bouts. And so what I'd like to see hopefully if we can replicate something I'd like guidelines that say every 30 minutes or every 60 minutes of sitting you should stand up and move. And hopefully with future studies that are coming out that we can make them even more specific and something along the lines of every 30, 60 minutes you stand up and walk for 5 minutes or you just stand up for 1 minute. That's where I'd like to see the science head and I think this study points us in the that direction of maybe we have to start thinking about breaking up our sedentary bouts.

Dr. Carolyn Lam:               All right you guys, I don't know about you, but I am literally standing up right now while I'm listening to you both. This is so interesting and I love the way, Wendy, you reflected the robust discussions we had as team when we were working through this paper. Congratulations again, Keith, for just this remarkable paper. Actually, maybe I could just ask, Wendy, what do you think? What do you think our next steps that may need to get these kinds of recommendations, perhaps into guidelines?

Dr. Wendy Post:               I think as was alluded to before, these are observational data so they're important for hypothesis generation, but really to have evidence that would lead to changes in guidelines maybe having a randomized trial, where obviously you can't have very hard outcomes, but randomized trials of some duration that could potentially lead to changes and important outcomes, would then maybe lead to changes in guidelines. But there isn't anything that we would lose from trying to implement these kinds of behavior, changes into our lifestyle since the downside and the risk is pretty low. So even if they don't make the strongest level of evidence at this point, I think we can still all be mindful of this and so.

                                                One thing that we've been trying to do in our preventive cardiology group at Hopkins is trying to implement walking meetings. In fact, I just had an email discussion with one of my colleagues about meeting tomorrow and she said, "Well, where do you want to meet?" And I said, "Well, why don't we go for a walk? The weather should be nice." And so I think if we're all mindful of trying to, not only increase our amount of physical activity, but trying to limit the sedentary bout duration by being creative and trying to change, sort of, long standing traditions of having meetings sitting in an office, then that could be helpful.

                                                So, just something for our audience to think about as well.

Dr. Carolyn Lam:               That's brilliant. You know, the one thing that I was thinking, though, just thinking about the reception of these data in my country, in where I practice, in Asia. This was a purely Hispanic or Latino population. I suppose there is a perception that that population may be predisposed to cardiometabolic disease and so on, and so you know, what's the applicability to us in Asia? So, I'm really happy, particularly to hear how you've taken it on. I mean, it's a simple thing, why not, right? Just to be more active. There's surely can't be something wrong with that. What do you think of that?

Dr. Wendy Post:               Totally, I think it's important to emphasize the unique nature of these data and that they come from a Hispanic study, which is a really important addition to our literature in epidemiology and cardiovascular disease and certainly there are significant differences in lifestyle among different communities within the United States and across the globe, as you've experienced having lived in different countries. And so, I think we need obtain more data about how there might be differences based on various traditions and different lifestyles, and try to target those who are at greatest risk.

Dr. Carolyn Lam:               Keith, did you have anything to add to that?

Dr. Keith Diaz:                    Yeah, I think Wendy is right on and certainly I don't think we have any reason to suspect that sedentary behavior acting differently in Hispanics versus other populations, and so I still think going forth with this notion that we all should be reducing our sedentary behaviors is important to highlight.

Dr. Carolyn Lam:               Fantastic. Well, thank you both for a really wonderful discussion. This is really cool, I think a lot of people will be talking about this.

                                                Listeners, you've heard it first, though, in Circulation on the Run. Thank you for joining us today and don't forget to tune in next week.

 

Oct 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 Center and Duke National University of Singapore.

                                                Today's issue features striking results from the ASSERT 2 trial of the prevalence of subclinical atrial fibrillation detected with implantable monitors in a group of high-risk older individuals. Much more soon, right after these summaries.

                                                The first original paper in this weeks' journal shows for the first time that myocardial edema, in the week after STEMI in humans, is a bimodal phenomenon. First off, there is Dr. Fernandez Jimenez and Barreiro-Perez, corresponding author Dr. Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that the time course of edema reaction in 16 patients with anterior STEMIs successfully treated by primary angioplasty compared to 16 matched controls using cardiac magnetic resonance and assessing its implications for myocardium at risk quantification. The STEMI patients were scanned serially within the first three hours after reperfusion and at, one, four, seven and 40 days, while controls were scanned once. Furthermore, they performed an experimental study of 20 pigs undergoing 40 minute ischemia reperfusion, followed by serial cardiac magnetic residence exams at 120 minutes, one, four and seven days after reperfusion.

                                                The authors found that am initial wave of edema appeared abruptly at reperfusion, but it was significantly attenuated by 24 hours. The initial wave of edema was followed by a second or differed healing related wave of edema several days after reperfusion, reaching a plateau around four to seven days after myocardial infarction. Of note, cardiac magnetic resonance myocardium at risk quantification at 24 hours post-reperfusion severely underestimated the infarct size.

                                                In summary, post-MI edema in patients follows a bimodal pattern, which affects cardiac magnetic resonance in estimates of myocardium at risk. The dynamic changes in post-STEMI edema, highlight the need for standardization of cardiac magnetic resonance timing to retrospectively delineate myocardium at risk and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day four and seven, post-MI, seems a good compromise for standardization. However, further studies are needed to study the effect of other factors on these variables.

                                                The next paper sheds light on molecular mechanisms underline the progression of atherosclerosis, involving multiple inflammatory events, as well as the counteraction by inflammatory responses in cells such as the endothelium, circulating monocytes and resident macrophages in the arterial wall.

                                                Co-first authors, Dr. Li and Martin, corresponding author Dr. Shyy from Xi’an Jiaotong University Health Science Center and University Health Science Center and University of California, San Diego and colleagues, analyzed RNA seek data to identify cholesterol oxidation and e-flux genes regulated by Kruppel-like factor 4, which is a key anti-inflammatory transcription factor. They found that Kruppel-like factor 4 upregulates cholesterol 25 hydroxylase and liver X receptor in vascular endothelial cells and macrophages. In further in vitro and in vivo experiments, they show that access enhanced reverse cholesterol transport from the vascular wall, mitigated inflammation through suppression of sterile regulatory binding protein two and NOD-like receptor family hiring pyrin domain containing protein three inflammasome in endothelial cells and also promoted cholesterol e-flux in M1 to M2 transition in macrophages.

                                                In summary, Kruppel-like factor 4 trans-activates cholesterol 25 hydroxylase and liver X receptor, promoting the synergistic effects between individual cells and macrophages to protect against atherosclerosis susceptibility, and this may therefore be a therapeutic target for cardiovascular disease.

                                                The next study provides data on the safety and efficacy of a novel cobalt alloy-based coronary stent eluting the antiproliferative agent, ridaforolimus, for treatment of patients with coronary artery disease.

                                                Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia and colleagues, reported the primary results of the bionics trial, which was a prospective international, one-to-one randomized trial conducted to evaluate in a noninferiority design, the relative safety and efficacy of ridaforolimus-eluting stents compared to slow release zotarolimus-eluting stents among 1,919 patients at 76 centers undergoing PCI. At 12 months, the primary endpoint of target lesion failure was 5.4% for both devices, thus meeting the prespecified criteria of noninferiority of ridaforolimus stent compared to the zotarolimus stent.

                                                Angiographic and intravascular ultrasound measures of restenosis, late lumen loss and nepintimal hyperplasia measured at 13 months, were similar in both devices. Treatment with the ridaforolimus-eluting stent resulted in low rates of myocardial infarction, repeat revascularization and stent thrombosis, and results were consistent in predefined patients and lesion groups. The authors therefore concluded that these results support the safety and efficacy of ridaforolimus-eluting stents in patients representative of every day clinical practice.

                                                Well, that wraps it up for your summaries. Now, for our future discussion.

                                                Today for our future discussion, we are going to talk about a true global public health problem. It's a condition that affects 33 million people worldwide, a number that is expected to double by 2050, and what we're talking about is atrial fibrillation. Those are the numbers of just what we know of detected atrial fibrillation, but today's paper deals with silent subclinical atrial fibrillation and the results of the ASSERT 2 trial. I'm so pleased I have the first and corresponding author with us today, Dr. Jeff Healey from Population Health Research Institute at McMaster University in Hamilton, Ontario. Welcome, Jeff.

Dr. Jeff Healey:                 Good morning.

Dr. Carolyn Lam:               Also on the show today is Dr. Sami Viskin, associate editor from Tel Aviv Medical Center. Hi, Sami.

Dr. Sami Viskin:                 Hi. Hello, everybody.

Dr. Carolyn Lam:               Jeff, from ASSERT to ASSERT 2, could you give us a bit of the picture of what made you do ASSERT 2 and what have we learned?

Dr. Jeff Healey:                 The ASSERT trial was a large 2,500 patient trial in patients in with pacemakers and also implantable defibrillators and it was really an easy first place to study this entity of sub-clinical atrial fibrillation because, of course all of these patient had implanted devices with electrodes in their atrial where they could report all of the internal activity continuously for many years at a time. This was done with really no incremental costs or inconvenience to the patient, the data were already being collected, so in ASSERT we asked the question, how common is atrial fibrillation as it is not detected clinically and is it associated with stroke? What we found was that over time, somewhere between 30% and 40% of patients with an implemented device developed atrial fibrillation, which we termed subclinical atrial fibrillation, because this was not detected by the usual clinical mean. Great results, very interesting, but begged the question, is this a unique entity that we see only in pacemaker patients or if you just took older individuals in the more general population, would you see subclinical atrial fibrillation as well? That was really the impetus for doing that ASSERT 2 trial in patients who are over the age of 65, had cardiovascular condition, placed them at increased risk or stroke in atrial fibrillation, but did not have implanted devices.

Dr. Carolyn Lam:               Indeed, Jeff. That's a beautiful set up. The ASSERT was really quite a landmark study suggesting that what we know as clinical may be just the tip of the iceberg, isn't it? Now you've extended it, and I think it'd be really important for the audience to understand that ASSERT 2 was really a high risk cohort. Could you maybe tell us a little bit more of what you did and what more we learned?

Dr. Jeff Healey:                 Sure. These were typical patients who might be attending a cardiology clinic, an outpatient general medicine clinic who did not have pacemakers and did not have any history of atrial arrhythmias, but you're right, they were high-risk. These were patients over 65 who have had clinical risk factors, things like hypertension, or diabetes, but also some other marker of increased risk such as a BNP that was elevated or left atrial enlargement.

Dr. Carolyn Lam:               Yeah and your findings were so striking. Tell us.

Dr. Jeff Healey:                 What was quite was surprising was, indeed, we found that in the non-pacemaker, non-defibrillator population from ASSERT 2, we also found high prevalence of subclinical atrial fibrillation. This was really quite surprising. In fact, it was many times higher than we had predicted. We found that over time, the annual risk of developing atrial fibrillation in this cohort was 34.4% per year, which is truly astounding number of patients who developed atrial fibrillation.

Dr. Carolyn Lam:               That's like one in three of such patients experiencing at least one of these episodes lasting at least five minutes? That's really impressive.

Dr. Jeff Healey:                 It was high.  You could look into that study and find groups where the risk was even higher, so we chose to cut off left atrial volume of 58 millimeters and not correspondent with the median volume of the population series of Olmstead County for people over the age of 65 who came in for an echocardiogram, and that was the minimum left atrial size to get into the trial. If you then looked at within the ASSERT 2 trial and looked at the volumes within the trial, somewhere around 72 1/2 milliliters, if you looked at the patients who had the top of atrial size, that risk was as high 50% per year, so one in two.

Dr. Carolyn Lam:               Another thing I noticed though about your results is that the frequency of these episodes, it's not that frequent, and so what we would do typically in a 24-hour monitoring or even a seven-day monitoring would have captured only a small proportion of these. Isn't that the case, Jeff? Could you give us some numbers there?

Dr. Jeff Healey:                 Yes, of course. The episodes that qualified were at last five minutes in duration, we then do longer episodes in course, but these were much less frequent in the single digit percent risk, and what we found was there were, as you say, quite infrequent. So with the standard 24-hour halter monitor, for example, you would have had a very low pickup. It really goes to show that the longer you monitor, the more you will find. I think that's the key message out of this study and other studies like it.

                                                I think conversely, you also have to realize that the more you look, or the harder you look, you may be uncovering atrial fibrillation that behaves differently than atrial fibrillation you find, for example, in the single 12 lead ECG. We have found, and others have found, that the risk of stroke we find when we would have short episode picked up only with long term continuous monitoring is real but it's much lower than we see with atrial fibrillation that was picked up by ECB where patients are presenting in emergency rooms stroke with symptoms.

Dr. Carolyn Lam:               That's such relevant points, and it really brings up the unanswered questions perhaps, exactly what is the correlation with stroke risk? What should we do about it? Sami, I'm sure you have other questions when you handle this paper and we had so many discussions among the editor, would you like to just start the ball rolling in some of these considerations?

Dr. Sami Viskin:                 Well, actually, we understood from the beginning of the study was not powered to show any difference in outcome by intervention, by treating any of these patients that had discovered atrial fibrillation with anticoagulation, so we took this paper as what it is, a paper that shows the unexpectedly high privileges of atrial fibrillation in patients who have neither symptoms nor electrocardiographic documentation of atrial fibrillation when they undergo implantation of our recording device. So we took this paper for what it is, a very interesting finding that opens the door for new studies, testing perhaps the value of intervention with anticoagulation at an earlier stage.

Dr. Carolyn Lam:               Yeah, I agree. I'd love to hear Jeff’s thoughts on what those next steps may be, but just to point out to the audience, I mean, at the moment, our decisions on whether to anti-coagulate, like the CHADSVASC score and so on, doesn’t really take into account the type of atrial fibrillation or the duration of atrial fibrillation? Does it? What do we do now? What do we do in the context of the fact that results, like the COMPASS trial, that maybe just based on the presence of vascular disease, we should anti-coagulate, right? Jeff, how about your thoughts? What are the next steps?

Dr. Jeff Healey:                 You're right. I mean, is there a value for empirically anticoagulating individuals. That's really going to boil down to the individuals with an absolute risk of stroke and how well they do on anticoagulants. Good question.

                                                In the post-stroke world or post-cryptogenic stroke, which we now report to as [inaudible 00:16:48], these individuals are being evaluated with two large clinical trials, looking at this idea of just empiric anticoagulation with low dose, NOAC in comparison to aspirin.  These trials are ongoing, and they expect to report findings by the end of 2018.

                                                In the general population, no such large scale trial is ongoing at the present time. You mentioned COMPASS and the big COMPASS results were clearly a big result at the European Society meeting, but it must be clarified that the dose of NOAC or rivaroxaban used in COMPASS was not the typical dose that we would use in the treatment of patients with atrial fibrillation, so much lower. I think we have to be careful when we're talking about doses that may be different 5 to 10 fold and what is then coagulating a patient and what is not. I think, certainly, I would not consider the COMPASS tests right now to be an effective atrial fibrillation dose, but as we've discussed, subclinical atrial fibrillation is different and we may have further data in the future.

                                                Now, how do we get there? I think many people are aware of two ongoing trials, the ARTESIA trial, which is run by our group, the NOAH-AF Trial run by Kirchof and the group from Birmingham and the AF-NET organization, and these two ongoing trials have taken this question back again, so the pacemaker population that we are enrolling thousands of patients with pacemakers and defibrillators who have these short episodes, and they're being randomized treatment with a full dose new oral anticoagulant vs aspirin. These trials are ongoing, and I think these trials and the pacemaker population will actually give us the answer to what is the risk benefit for treating, so interesting course of event. We started in the pacemaker population to show there was risk for these short episodes, that this was hotly debated 10 - 15 years ago, and now we take ASSERT 2 and other trials into the non-pacemaker population to show that this is actually a problem for older individuals in general, and now the third step, go back into the pacemaker clinic again and to do trials to study the effectiveness in therapy.

Dr. Carolyn Lam:               Great point and great takeaways. How about, Sami? What do you think would be the take-home message for clinicians at this moment based on what we know now and based on this new data?

Dr. Sami Viskin:                 Well, the message is clear, the message is that atrial fibrillation is far more prevalent than what we think it is, the message is that for every event of atrial fibrillation that we feel we probably have many events that we don't feel we should be distrustful about judging the decision to anti-coagulate or not based on symptoms, and I'm referring now to patients who already have one event documented of atrial fibrillation and are waiting until they feel the next one, before they start taking anti-coagulations. This is another warning about how we should be careful about trusting symptoms when deciding to treat and when not to treat. I just said this opens a new door for a new line of studies, looking at how early to intervene with anticoagulation, what dosage should be used for these patients who probably have lower burden of atrial fibrillation. If you can see that the patients who have atrial fibrillation documented on the electric cardiogram, as patients who simply have a higher burden and therefore they are more likely to come up with documentation on a regular ACG, so perhaps those only have subclinical atrial fibrillation have a lower burden, perhaps they can benefit from lower doses of anticoagulation, but these are all fit, that need to be proven by trials.

Dr. Jeff Healey:                 It is not only an issue for implanted devices but with the implantable cardiac monitors, this is now relevant for many other patients who have these devices implanted for things like syncope, but also there's been a lot of progress in the last 5 to 10 years on surface-attached based monitors or other types of monitors that can be with patients for days, weeks and even months, and we're all grappling with this in clinical medicine, what to do with a person with 25 beats of an atrial tachycardia or 37 seconds on a 30-day monitor? It's all an issue of the density, the burden of arrhythmia, and we do believe there is some gradience in the risk of stroke ... You're right, the treatment is not obvious, but we should take our treatment for patients who are in atrial fibrillation a lot or all the time, and simply apply it upstream like, that we may have very different treatment or approaches that are more tailored to individual patient risk.

Dr. Carolyn Lam:               Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff. We discussed a lot of other questions that need to be answered, but you've really opened the door to look at some of these questions with your paper today and we're really very proud to be publishing your paper in this week's journal.

                                                Thank you very much, listeners for joining us this week. Don't forget to tune in again next week.

 

Sep 25, 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 Center and Duke National University of Singapore. Our featured discussion today centers on new data from the Framingham Heart Study that addresses the question of the prognosis of pre-hypertension among individuals who never progressed to hypertension as well as the role of early versus late onset pre-hypertension in this context. Well, more soon, right after your summary of this week's journal.

                                                The first original paper provides mechanistic insights on the relationship between low and oscillatory wall shear stress, together known as disturbed flow, and atherosclerotic arterial remodeling and stiffness. Co-first authors doctors Kim and Pokutta-Paskaleva, co-corresponding authors Dr. Brewster and Jo from Georgia Institute of Technology in Emory University in Atlanta, Georgia used a novel mirroring model of disturbed blood flow to stimulate arterial stiffening through collagen deposition in young mice. They discovered a critical role for Thrombospondin 1, or TSP1 in activating TGF beta and stimulating arterial stiffening, all of which was significantly attenuated in the TSP1 knockout animal.

                                                Blockade of TSP1 activation of TGF beta decreased the up regulation of pro-fibrotic genes that contributed to arterial stiffening. Furthermore, they show that TSP1 localized to regions of disturbed flow in arteries from patients with peripheral artery disease and these arteries had similar increases in collagen gene expression. Thus, this work links TSP1 up regulation to arterial stiffening and identifies TSP1 as an important promoter of pathologic arterial remodeling in peripheral artery disease.

                                                The next study provides international insights on the degree to which secondary prevention treatment goals are achieved in clinical practice among patients with diabetes and cardiovascular disease. First and corresponding author, Dr. Pagidipati from Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina, looked at 13,616 patients from 38 countries with diabetes and cardiovascular disease in the TECOS trial. They found that only 30 percent of patients met all 5 secondary parameters of aspirin use, lipid control, blood pressure control, angiotensin-converting enzyme-inhibitor, or ARBUs, and non-smoking status.

                                                Only 58 percent of individuals with diabetes and cardiovascular disease attained blood pressure control. Furthermore, the degree to which secondary prevention goals were met in this trial varied by the world region and country. In summary, patients with diabetes and cardiovascular disease are still being undertreated globally with respect to secondary prevention, and especially with regard to blood pressure control. These gaps in care provide clear opportunities for improvement in this high risk population.

                                                The next study is the first to directly compare data from an electronic data research network to a large cardiovascular disease cohort. First author Dr. Ahmed, corresponding author Dr. Allen from Northwestern University in Chicago and colleagues sought to evaluate the degree of agreement of electronic data research networks compared with data collected by standardized research approaches in a cohort study. To achieve this goal, authors linked individual level data from the multi-ethnic study of atherosclerosis, or MESA community based cohort with Healthlink, a 2006 to 2012 database of electronic health records from 6 Chicago health systems.

                                                They identified areas of agreement and disagreement between blood pressure, cardiovascular risk factor diagnosis, and cardiovascular events between the two data sources. The correlation was low for systolic blood pressure, compared with MESA, Healthlink overestimated systolic blood pressure by 6.5mm mercury. Conversely, there was a high correlation between body mass index in MESA and Healthlink. Healthlink underestimated body mass index by 0.3 kilograms per meters square.

                                                Using ICD-9 codes and clinical data, the sensitivity and specificity for Healthlink queries for hypertension were 82.4 percent and 59.4 percent. For obesity these figures were 73 percent for sensitivity and 89.8 percent for specificity and for diabetes they were 79.8 percent for sensitivity and 93.3 percent for specificity.

                                                Finally compared with adjudicated events in MESA, the concordance rates for myocardial infarction, stroke, and heart failure were at 41.7 percent, 61.5 percent, and 62.5 percent, respectively. These findings therefore illustrate the limitations and strengths of electronic data repositories compared with information collected by traditional standardized epidemiologic approaches for the ascertainment of cardiovascular risk factors and events.

                                                The next paper helps physicians and patients to make an informed decision about whether or not to stop low dose aspirin use. First and corresponding author Dr. Sundstrom from Uppsala University in Sweden and colleagues investigated whether long term low dose aspirin discontinuation increased the risk of cardiovascular events in a cohort study of more than 600,000 users of low dose aspirin for primary or secondary prevention in the Swedish prescription register between 2005 and 2009.

                                                They found that patients who discontinued aspirin had a 37 percent higher rate of cardiovascular events than those who continued, corresponding to an additional cardiovascular event observed per year in one out of every 74 patients who discontinued aspirin. The risk increased shortly after discontinuation and did not appear to diminish over time. Thus, in long term users, discontinuation of low dose aspirin in the absence of major surgery or bleeding seemed to be associated with a more than 30 percent increased risk of cardiovascular events, thus adherence to low dose aspirin treatment in the absence of major surgery or bleeding may be an important treatment goal.

                                                The final study raises the possibility of using Histone Methyltransferase Inhibitors for the treatment of heart failure. Dr. Papait from Humanitas Clinical and Research Center in Italy and colleagues focused on G9A, a histone methyltransferase that defines a repressive epigenetic signature. Using normal and stressed cardiomyocytes from a conditional cardiac specific G9A knockout mouse, and a specific G9A inhibitor, they showed that the histone methyltransferase G9A was important in defining the epigenetic landscape that maintained the transcription program of the cardiomyocyte. It was also important for the regulation of gene expression reprogramming during cardiac hypertrophy.

                                                Furthermore, impaired G9A function promoted cardiac dysfunction. Thus, these findings suggest that G9A may represent a therapeutic target for early stages of cardiac hypertrophy.

                                                That wraps it up for your summaries, now for our feature discussion.

                                                For today's feature discussion, we're talking about the very important topic of the prognosis of prehypertension without progression to hypertension. Now, we've always known that mild blood pressure elevations that we call prehypertension are associated with cardiovascular risk. However, this risk could be attributable to the fact that these patients with prehypertension eventually progress to overt hypertension. But, what happens to the patients with prehypertension who do not progress to hypertension, and what is the role of early versus late onset prehypertension?

                                                Well, we have some answers today and I am so pleased to have the first and corresponding author with us, Dr.  Teemu Niiranen, from Boston University's Framingham Heart Study. Welcome, Teemu.

Dr. Teemu Niiranen:       Thank you very much, great to be here.

Dr. Carolyn Lam:               And to help us along in this discussion, we have a familiar voice. Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back, Wanpen.

Dr. Wanpen Vongpatanasin:       Thank you Carolyn. Happy to be here.

Dr. Carolyn Lam:               Teemu, you know, I sort of set the background that you so nicely articulated in this research letter, but could you tell us a little bit more of what you were looking at, how you did it, and what you found?

Dr. Teemu Niiranaen:     My boss, Dr. Vasan, was also a coauthor in this paper, he already showed some 15 years ago that prehypertension carries greater cardiovascular risk than perfectly normal blood pressure. However, it's pretty much unclear what happens to people who are prehypertension but never go on to develop hypertension because even the name suggests that if you have prehypertension you will get hypertension. We also looked at what effect does the age of developing prehypertension and hypertension have in this context.

                                                We used a case cohort setting in the Framingham Heart Study in the way that we only looked at 5 1/2 thousand decedents. These were people who had already passed away. Then we categorized those decedents into 5 categories, people who never got prehypertension or hypertension, people who developed prehypertension late in life, who never developed hypertension, and people who developed early onset prehypertension but never developed hypertension, and then people who went on to develop late or early onset hypertension. We used a cutoff of 55 years as the definition of early onset versus late onset.

                                                Then, in a case cohort setting, we estimated case versus controls, adjusted case versus control odds ratios, for the 4 prehypertension/hypertension categories versus those who died without ever developing prehypertension.

Dr. Carolyn Lam:               Teemu, could I just stop you here before you share the intriguing results. I just wanted to remark that it's so amazing how the Framingham Heart Study really enables analysis like this, simply because of the long follow up and just the great detail and the standardization of blood pressure measurements and so on. I mean, as I said, I worked at the Framingham Heart Center, and we were trained to do this in a standardized fashion.

                                                Define prehypertension and hypertension, just in case, and then please tell us your results.

Dr. Teemu Niiranaen:     Prehypertension was 120 to 135 systolic blood pressure, and a diastolic blood pressure of 80 to 89 millimeters mercury, and then hypertension was 140 over 90 millimeters mercury, or antihypertensive medication, and yes, your correct that the Framingham Heart Study provides a very unique setting. Especially for defining early versus late onset hypertension because we can define the age of hypertension or prehypertension or prehypertension onset objectively because these people have been followed up, they have attended so many exams, especially the original cohorts.

                                                But, to the results, so we observed that basically people who develop prehypertension, either early and especially late in life, but did not ever develop hypertension, their risk, or odds of dying of cardiovascular disease versus non-cardiovascular disease was pretty much similar to those who never develop prehypertension or hypertension, while conversely the people who went on to develop either late or especially early onset hypertension, or developed early onset hypertension they had considerably greater risk of cardiovascular death versus those who developed either prehypertension or hypertension. That's our main result. I won't go into conclusions yet.

Dr. Carolyn Lam:               Okay, but maybe at this point, I could ask Wanpen to share some thoughts. I mean, this is very striking findings. Curious what you think the clinical implications were, and especially as we discussed among the editors.

Dr. Wanpen Vongpatanasin:       It is very important study that, as Teemu outlined it, to look at the fate of people with prehypertension and I think that's the first time we had this kind of data to show whether the earlier versus late prehypertension and even hypertension itself. I don't think people have looked at in the large number in terms of outcome people who have early versus late onset hypertension. I found the result to be fascinating.

Dr. Carolyn Lam:               Yeah, what does this mean though when we see a patient with this sort of borderline hypertension, you know, falling in the prehypertension range. We don't know whether they're going to develop hypertension. What do you think the clinical implications are? Teemu?

Dr. Teemu Niiranaen:     Unfortunately a lot of the people who develop prehypertension as the name suggests they go on to develop hypertension, but there is still a considerably great part that never develop hypertension, and our study shows basically that if you are able as a doctor or a patient to prevent progression to hypertension you are much better off and this really hasn't been previously shown, so it just should motivate patients and also doctors to strive to, if they see a prehypertensive individual, try to through lifestyle and other interventions try to prevent the progression to hypertension.

Dr. Carolyn Lam:               Yeah, I think that was one of the take home messages for sure. Were there any other plans for future work you think that needs to be done?

Dr. Teemu Niiranaen:     There's the everlasting problem with observational studies, so definitely it would be great if our results could be taken into clinical trials or anything to test whether interventions, A, that preventing the progression from prehypertension to hypertension could then impact cardiovascular outcomes.

Dr. Carolyn Lam:               Indeed, and if I may comment, I've always wondered about ethnic differences when it comes to this. The one thing that Framingham, you know, it's difficult to see from there, is what happens in other ethnicities other than white ethnicities, isn't it? Still, very striking findings. Wanpen did you have any other comments or questions from Teemu?

Dr. Wanpen Vongpatanasin:       Well, I think that one thing also that's interesting to me is even the people who had early onset prehypertension, although the number of CHD deaths were not significant, but the odds still 28 percent higher than the control that will never have prehypertension so, I think that that the signal is there but perhaps because the number of people who had prehypertension but never really progress to prehypertension is relatively small. It could be underpowered to see the significance and I think that from this study, it tells me that the exposure to blood pressure to our life, I think is the blood pressure lowered on the cardiovascular system, I think that's the one that really determine the cardiovascular outcome the most. I think that we should not discount that this is not a truly benign phenomenon, I think hopefully they'll be some more data from the Framingham group or other group.

                                                Also, I think that this study also very important to show that early onset hypertension actually have the worst prognosis, and often time when people come to see a doctor when they're 30 and 40 years old, they don't really want to take medicine, and the physician often time are reluctant to prescribe the drug, and I think that this study say that we probably need to be a little bit more serious about it, because they actually have the most cardiovascular events.

Dr. Carolyn Lam:               What excellent points, and you know what? At this point I just want to highlight that beautiful figure that you have in your research letter, Teemu. I think it says it all. It highlights that point estimate for the prehypertension groups is not exactly 1. If anything, it is above 1, right? For the odds of poor outcomes, so I do take Wanpen's point as well. Beautiful figures, and I also actually want to use that to ask you a different question Teemu. You have 1 figure, because this is a research letter that only allows 1 figure and 800 words, and you've put so much important information into that space. I'd love for you to share that experience with our listeners too, of a research letter versus a full paper. Why did you choose to submit yours as a research letter, and how was that?

Dr. Teemu Niiranaen:     One of the important take home messages from this was the differences between early onset versus late onset hypertension that we'd been also recently publishing on, so we wanted to delve more in depth on this prognosis of prehypertension versus hypertension so we don't have to be repetitive too much. We decided to focus on this very small topic most intensively, therefore we decided that maybe a research letter would be the most effective way so we could communicate all the really novel stuff that we have in just one figure. Well, it has 3 panels, but it still counts as 1 figure.

                                                I just wanted to point out that maybe the early onset prehypertension, yeah the confidence intervals are somewhat wide, but the panels sees for coronary heart disease versus non-cardiovascular disease deaths, so that's maybe a bit more underpowered than the back panel B, so the CHD deaths are part of the CBD deaths, so with CBD deaths, the early onset prehypertension, the odds ration was 1.09, but still of course the confidence intervals reach up to 1.49. Just to clarify the difference between panel B and panel C, so B's better powered.

Dr. Carolyn Lam:               It's a very nice figure, and indeed, I think it works very, very well as a research letter, and I think the fact that we're discussing it right now shows that length doesn't dictate importance. Wanpen you had a few comments about that. What do you think of a research letter format?

Dr. Wanpen Vongpatanasin:       Yes, I think this research letter is a really important part of articles in Circulation. I think that all the others should be aware that we're trying to enter at submission if it's suitable, just like this one. It actually show up in the pub med exactly like the full article and gets cited as much and sometimes much more than a regular article because it capture the essence of one more focused problem and the figures and table allow to show only one or two at a time, so they really capture the essence or the guts of the article and the reader can go through that quickly and grasp the concept and learn within flipping through a few pages.

                                                I think we should have many more interesting research letter like this.

Dr. Carolyn Lam:               Congratulations again Teemu for a beautiful paper, a very important one. Thank you Wanpen for shepherding this one.

                                                And thank you listeners for joining us today. Don't forget to tune in again next week.

 

Sep 18, 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 Center and Duke National University of Singapore.

                                Today we will be discussing the cost effectiveness of statin use guidelines for the prime and prevention of coronary heart disease and stroke. Comparing the 2013 American College of Cardiology American Heart Association guidelines with the adult treatment panel three guidelines. A very important and current discussion that you don't want to miss. All coming up right after these summaries.

                                The first original paper in this week's journal is the largest study yet reported that assessed the long term outcome of Takayasu's Arthritis. First author, Dr. Comarmond, and corresponding author Dr. Saadoun and colleagues from Hospital Pitie-Salpetriere in Paris performed a retrospective, multi-centered study of 318 patients from the French Takayasu network including patients with Takayasu Arthritis fulfilling the American college of Rheumatology and/or Ishikawa criteria. They found that, firstly, 50% of  Takayasu arthritis patients relapse and experienced a vascular complication at ten years. Secondly, male sex, elevated CRP, and carotidynia were independently associated with relapse and with a two-fold higher risk of relapse. And thirdly, patients at high risk for vascular complications could be identified according to presence of two or more of the following risk factors: progressive clinical course diagnosis, thoracic aortic involvement, and or retinopathy. In summary, these factors identify patients with a high risk of relapse or vascular complications and may therefore serve to adjust more aggressive management and close follow up in Takayasu's Arthritis.

                                The next study provides experimental evidence for a pathogenic role of the transcription factor interferon regulatory factor five or IRF-5 in atherosclerosis. In this study from co-first authors, Dr. Seneviratne and Dr. Edsfeldt, corresponding author Dr. Monoco from Kennedy Institute of Rheumatology in Oxford, United Kingdom, and colleagues. The authors showed that atherosclerosis prone apple-E negative mice who were also deficient in IRF-5 showed reduced atherosclerosis lesions and necrotic core formation. They found that the development of the lesion necrotic core was controlled by IRF-5 through impairment of macrophage dead cell removal, or spherocytosis. They further demonstrated that the CD-11C gene was a direct target of IRF-5 in macrophages and that IRF-5 was important in maintaining CD-11C positive macrophages in atherosclerotic lesions. In summary IRF-5 was shown to be a potential therapeutic target since its inhibition could reduce plaque inflammation and necrotic core size, thus potentially promoting a stable plaque phenotype with a lower risk of acute clinical complications.

                                The next study is the first to assemble a transcriptomic framework of multiple cardiac cell populations during post natal development and following injury, thus enabling comparative analysis of the regenerative or new natal state, compared to the non regenerative or adult state. In this study from first author Dr. Quaife-Ryan and co- corresponding authors Dr. Porrello from the Royal Children's Hospital and Dr. Hudson from the University of Queensland, Australia. The authors isolated cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarct and non infarct neonatal and adult mouse hearts. The then performed RNA sequencing on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair and regeneration. They further, surveyed the epigenetic landscape of cardiomyocytes during post natal maturation by performing deep sequencing of assessable chromatin regions. This comprehensive profiling of cardiomyocytes and non myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non regenerative time points. The majority of transcriptional changes in all cardiac cell types resulted from development maturation from neo natal stages to adulthood. Rather that activation of a distinct regeneration specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state.

                                But in contrast cardiomyocytes failed to reactive the neonatal proliferative network following infarction which was associated with loss of chromatin accessibility around cell cycle genes during post natal maturation. In summary these findings are significant because they defined a regulatory program underpinning the neonatal regenerative state and identified chromatin modifications in adult myocytes that could restrict cardiac regenerative potential after birth and may need to be overcome to facilitate cell cycle re entry in adults.

                                The final study reports results of two studies investigating the pharmicokinetic and clinical outcomes of a new drug coated balloon to treat femoral popliteal disease. The first study is the Illuminate pivotal study in which 300 symptomatic patients were randomized to stellarex drug coated balloon or standard angioplasty. The primary safety outcome was freedom from device and procedure related death through 30 days and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency through 12 months. The second study was the illuminate pharmicokinetic study in which paclitaxel plasma concentrations were measured after last balloon deployment and at pre specified times until no longer detectable. In this report my first in corresponding Dr. Krishnan from Mount Sinai Medical Center in New York. In the pivotal study the primary safety endpoint and the primary patency rate was significantly higher with the drug coated balloon. The rate of clinically driven target lesion revascularization was significantly lower in the drug coated balloon cohort. pharmicokinetic outcomes showed that all patients had detectable Placitexal levels after drug coated balloon deployment that declined within the first hour.

                                In summary these findings demonstrate the safety profile and superior patency of the stellarex drug coated balloon for femoral popliteal disease compared to standard angioplasty. This therefore suggests that this drug coated balloon may be a valuable treatment option for patients with superficial femoral and popliteal artery disease.

                                Well those were your summaries now for our feature discussion.

                                Today we are discussing the highly relevant and also highly controversial issue of Statins for primary prevention of cardiovascular disease and when do we start a statin. How cost effective is it, and of course all this discussion really began with the 2013 ACC/AHA guidelines that expanded the recommended statin use. I am so pleased because this week’s journal actually provides, for the first time, some cost effectiveness data that may help us in making this decision and in facing our patients. I can't tell you the number of times I've had an individual patient come to me and just want to discuss all the pros and cons of starting a statin for primary prevention and I'm sure, listeners out there you identify with this. Well hang because today we have the corresponding author of today's feature paper Dr. Kirsten Bibbins-Domingo from University of California, San Francisco  as well as the editorial list on this wonderful paper, Dr. Rodney Hayward from University of Michigan and VA Ann Arbor. Welcome Kirsten and Rod.

Dr. Kirsten Bibbins:          Thank you.

Dr. Rodney Hayward:     Great to be here.

Dr. Carolyn Lam:               Kirsten, could you please tell us the top line results of what you found in this paper, it's such an important paper.

Dr. Kirsten Bibbins:          We use simulation modeling to compare three approaches to giving Statins for primary prevention. The older guideline in the US called ATP-3, the one that you mentioned in your introduction the ACC/AHA guideline that broadened the use of Statins to many many more people and then an even broader strategy where we don't look at cardiovascular risk, and in each of these approaches we found that the use of Statins for primary prevention was very effective and in fact cost saving, when we did a cost effectiveness analysis. And regardless of the assumptions that we made about more side effects then we had known from the literature or could anticipate or regardless of the parameters that we put into the model we found that, pretty much that the broad use of these medications is effective and, in fact, cost saving.

Dr. Carolyn Lam:               Could you give us an idea of what you used in that simulation model, what population was it, how applicable is it to people outside the US, for example.

Dr. Kirsten Bibbins:          Simulation modeling is a way to take the evidence that we have from multiple types of studies and to try to synthesize that evidence and apply it to, in this case, the population of the US. So our simulation model uses the demographics of the US and takes the primary studies and the effect rises that we know from those studies and using that model we found that each of these three approaches had both health benefits and cost saving benefits. It's applicability might be somewhat variable if this were applied to a different population, but the effects are pretty substantial and so it suggests that Statins are likely to be beneficial using these approaches in a broad array of populations.

Dr. Carolyn Lam:               Could you give us an idea of the estimated effect size, you know, when you say cost effective, for example, how, how much and for what. Give us everyday clinician some kind of take home of numbers that would make sense for them.

Dr. Kirsten Bibbins:          One way to think about these types of cost effectiveness analysis is that often times they give us numbers that suggest that we have to pay a certain amount to get the type of health benefit that we want. In this case because we found that they were cost savings, it actually suggests that the amount that we pay for Statins, to give Statins to a broad population of individuals actually saves us money. It saves us money in terms of the heart attacks that are avoided, and the other types of health care costs that are avoided and probably a number that might be relevant to your audience might be that the number that one would need to treat in order get one additional year of life, through using these Statins for primary prevention, is on the order of about 35 individuals and so that's a small number that we would be treating in a primary care practice in order for an additional quality adjusted year of life.

Dr. Carolyn Lam:               I thought that was really one of the most remarkable figures, you know, that the ATP-3 guidelines would result in 8.8 million more statin users than the status quo and that was an entity of 35 per quality of life. Was that correct?

Dr. Kirsten Bibbns:           That's exactly right.

Dr. Carolyn Lam:               Whereas the ACC/AHA guidelines could potentially result up to 12.3 million more statin users than the ATP-3 guidelines with a marginal number needed of 68 per quality of life. So very, very useful figures, but you know, I began by saying my individual patient. These feel like population bases statistics, you know, and my individual patient kind of wants to know but for me, what's a long term risk and so on. And these are issues that you have discussed so elegantly, Rod, in your editorial. Could you enlighten us a bit on these considerations.

Dr. Rodney Hayward:     Sometimes decisions that we have to make in policy are inherently population based decisions, like putting fluoride in the water, in which the average benefit of cost for population is what you have. Cause you can't treat individual separately with that type of intervention, but with a statin, the average that a population gets is not the important thing to our patients across the room. And it's sort of the number needed to treat for them, how likely are they to benefit. And what I think this paper establishes very well, and I think it's important to start with why the areas of agreement here, this establishes that the new guidelines are a great idea. There's no assumptions in this model that would change that starting people on a statin between 7.5 and 10 % ten year risk isn't a good idea. And that aspect of the paper even some of the issues I have about some of the assumptions are not going to be relevant, where it starts to become concerning, and will always be controversial is how low of risk to start it at. Do we go from 7.5 to a 5% risk? Do we start putting everyone at age forty on a statin?

                                And at that case, certain elements of this simulation model are very important, the likelihood of an individual benefiting becomes very, very small. And even a small dislike of the medicine, would outweigh that. But also you have to assume in this model that we know all the bad things of a statin at 20-25 years, because you're starting to put people on a daily medicine that's biologically active for 30 years. And it's impossible statistically, epidemiologically, to know with any degree of certainty whether or not being on these medicines for 20-30 years would have unheard effects. We don't have that ability, currently, even if we had the databases so how should individuals think about that, well my feeling is that is part of the shared decision making of how much a patient worries about unknowns, about being on a medicine long-term versus they worry more about the potential for a heart attack prevention which are likely there. I want to emphasize again these are not relevant concerns when we're talking about the current guidelines, these are only concerns when we start pushing it down to a 5% risk or everyone over 40 where you're extending to tens of millions more people, in which the population benefits would be substantial.

                                As long as people don't mind taking a pill every day at those ages and we know all of the harms being on a statin for 20 years. And that's something that no one knows.

Dr. Carolyn Lam:               Rod that was just so eloquently stated, and listeners out there, you just have to read this editorial. It states these things very clearly, and I think it's really helpful in our thinking of what to tell patients when we do see them. Kirsten, I'd love to invite your thoughts on what Rod just said, you acknowledge this, fully in your paper. Curious, any steps you took to maybe address this and what you would say as a take home message for clinicians?

Dr. Kirsten Bibbins:          I think that Rod's bringing out exactly the point. And, I think, we have seen the shift from the earlier guideline to the most recent guideline in putting more people on Statins and these medications certainly have the benefit, but as you bring more and more people on who have lower overall cardiovascular risk, their likelihood of benefiting while there, is always smaller. And so then other things do come in to play, and I think the thing that probably was most surprising to us as we put this work together, was how sensitive our results were to, essentially, a patients preference as we moved down into including more of these lower risk individuals. That means that an individual who's lower risk may not directly benefit or their likelihood of benefiting in terms of avoiding a heart attack is lower, and so therefore the facts that their tolerance for taking a daily medication is in fact, then becomes relevant in to their particular trade off for taking this medication. And I think that is clinically important as we think about including more and more lower risk people into these types preventative guidelines, the threshold for any given individuals tolerance for taking a daily medication and of course, as Rod said, if you're doing this over many years and decades the fact that we don't actually know what will happen over the long term, also becomes relevant.

Dr. Carolyn Lam:               Just maybe one last question for both of you. What do you think our next step is here, what more do we need?

Dr. Kirsten Bibbins:          I just think we still want to continue to expand our understanding of what the long term effects and side effects of daily use of statin therapies are, again I'd want to emphasize as you said it's always important to understand patients preference, but, as Rod said, our current guidelines which really have focused on higher risk individuals, I wouldn't want it to be lost that these medications are in fact very effective and so I think having an understanding of the long term use of these medications and what the potential side effects when used over a long period time are, I think that's a critically important area. As well as really developing continuing to develop the tools that can help doctors and patients together engage in the conversation about the trade off for given individual.

Dr. Rodney Hayward:     I would definitely agree with that, but I would focus on three bits of science. That are critically important for refining this issue. The one is something we currently don't have and that's post marketing surveillance of medicines long term. That when you look at the data we have, that, most of them follow patients either a short period of time and don't have enough continuity or their smaller studies in which outcomes that are long term might be found. And this is a place where big data, but also combining and sharing data across health systems could really help us monitor. This is not just an issue for Statins but as more medicines are recommended for younger individuals with life expectancy we need to work on that. Two the results are insensitive meaning that it always looks good, for people in the current guidelines but two elements of the model for people at a 5% risk or starting people at age 40 are assumptions that are being made with the best available data now, but have some considerable concerns and could be improved.

                                One is, we don't know the impact of a non fatal heart attack on future outcomes, my personal opinion is the assumption in this model, is probably an overestimate. Unimportant for the current guidelines but would be critically important for these younger risk people and ways to really understand the impact of non fatal events on future risk are epidemiologically tricky and it's very easy to pick up things that are markers that aren't causal and then when you run your models you think you're extending life years where you really aren't. And the other is we still don't know how much a Statins relative benefit varies by a persons LDL level, that might seem astounding but there's evidence on both sides. That it is related to baseline LDL and it's not. This is a completely solvable question, the CTT group has the data and we really need them to publish and tell us how much the relative risk of a statin varies by that. The current assumption in the ACC/AHA guidelines is that it is not correlated, the assumption in Kirsten's model is that it is.

                                Either could be correct, my personal opinion is it's probably in between, those two, but that would help us in terms of thinking of extending to the lower people. If LDL is a partial factor that probably should be considered, if it's not then only risks should be considered. That is completely answerable for those that have access to the RCT data and I'm hoping that this paper may encourage that publication.

Dr. Carolyn Lam:               Wow, those were such insightful comments, I can't thank you enough, Rod and Kirsten for joining us today.

                                Listeners I'm sure you enjoyed that and learned so much just like I did. Don't forget to join us again next week.

Sep 11, 2017

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week contains novel data from the TOPCAT trial, this time relating physical activity to prognosis in patients with heart failure and preserved ejection fraction. A great discussion coming right up after this weeks' summaries.

                                                Our first paper tells us that pericarditis may be a marker of occult cancer and augurs increased mortality following the cancer diagnosis. Authors, Dr. Sogaard and colleagues from our host university hospital in Denmark used the Danish medical databases to conduct a nationwide cohort study of all patients with a first-time diagnosis of pericarditis from 1994 to 2013. Among 13,759 patients with acute pericarditis, 1,550 subsequently were diagnosed with cancer during followup.

                                                Patients with newly-diagnosed pericarditis had higher risks than age and sex match members of the general population of being diagnosed with lung cancer, Non-Hodgkin lymphoma, and myeloid leukemia during the first three months following a pericarditis diagnosis, but increased risks for lung cancer and Non-Hodgkin lymphoma and bladder cancer persisted beyond one year following a pericarditis diagnosis. The increased cancer risk was not restricted to patients with pericardial effusion.

                                                Furthermore, pericarditis was a prognostic factor for survival after lung cancer, breast cancer, and bladder cancer. Thus, the clinical take-home message is that patients with pericarditis, particularly when complicated by pericardial effusion, may need to be considered for workup targeted at diagnosing or ruling out cancer.

 

The next paper provides insights into mechanistic processes leading to stent thrombosis in the largest contemporarily available series of patients undergoing optimal coherence tomography, or OCT imaging, during stent thrombosis presentation. The first author, Dr. Adriaenssens, corresponding author, Dr. Byrne from Munich, Germany, and colleagues of Prestige Consortium, performed a prospective multicenter study to evaluate OCT findings in consecutive patients presenting with stent thrombosis enrolled in a registry that was using a centralized registration system.

                                                In 231 patients with stent thrombosis undergoing OCT, uncovered and malapposed struts were frequently observed, with the incidents of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to the time intervals from index stenting. Uncovered struts and stent underexpansion were the most common observations in acute or subacute stent thrombosis, whereas neoatherosclerosis and uncovered struts were the most common findings in late or very late stent thrombosis. The impact of dedicated clinical strategies for the prevention and treatment of mechanisms underlying stent thrombosis should be investigated in future clinical studies.

                                                The next study identifies a new type of capillary malformation, arteriovenous malformation. Now, we know that most arteriovenous malformations are localized and occur sporadically. However, they also can be multifocal in autosomal dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation arteriovenous malformation or CMAVM. RASA1 mutations have been identified in 50% of patients with CMAVM.

                                                In the current study, first author, Dr. Amyere, corresponding author, Dr. Vikkula from Brussels, Belgium and colleagues studied non-RASA1 patients and found that EphB4 mutations occurred in patients with multifocal capillary malformations associated with arteriovenous malformations. This phenotype named CMAVM2 mimicked RASA1-related CMAVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120-RasGAP was a direct effector of EphB4. Furthermore, the study implicated EphB4-RAS-ERK signaling pathway as a major cause of arteriovenous malformations. Thus, patients with multifocal capillary malformations need to be screened, not only for an inherited RASA1 mutation, but also for EphB4.

                                                The final study identifies a novel potential therapeutic target in the treatment of atherosclerosis, and that is Dickkopf-related protein 3, or DKK3, a secreted protein previously known for its involvement in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but very little studied in atherosclerosis. In the current study, first author is Dr. U.N. [inaudible 00:05:51], corresponding authors, Dr. Qu from Capital Medical University in Beijing, and Xu from Kings College London used both epidemiological and experimental approaches to test the hypothesis that DKK3 was atheroprotective.

                                                In the prospective population-based Bruneck study, they found that the level of plasma DKK3 was inversely related to carotid artery intimal medial thickness and five-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, they demonstrated that DKK3 promoted re-endothelialization in murine models of atherosclerosis and wire-induced femoral artery injury, thus revealing its atheroprotective role.

                                                They further explored the mechanism of DKK3-induced endothelial cell migration, which was via noncanonical Wnt signaling pathways.  The study, therefore, provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair with potential therapeutic implications.

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

                                                For today's feature discussion, we are talking about physical activity and prognosis in heart failure with preserved ejection fraction, or HFPEF. To discuss this paper, which contains really neat results from the TOPCAT trial, we have none other than the first author, Dr. Sheila Hegde, corresponding author, Dr. Scott Soloman, both from Brigham and Women's Hospital, as well as Dr. Jarett Berry from U.T. Southwestern, who was the editorialist on this paper. Welcome, everyone.

Dr. Scott Solomon:          Thanks, Carolyn.

Dr. Sheila Hegde:             Thank you.

Dr. Jarett Berry:                Thank you, Carolyn.

Dr. Carolyn Lam:               Hey, Scott. Could you set the background a little bit and let us know what was the rationale of looking at physical activity in TOPCAT?

Dr. Scott Solomon:          As you well know, heart failure with preserved ejection fraction is a disorder in which we don't currently have a therapy, or for which we currently don't have a therapy, and we know that people would also have a lot of comorbidities. Sheila has been extremely interested in the role of physical activity in heart failure and patients with heart failure, has studied this in the atherosclerosis risk in community studies, and we thought TOPCAT would be a great overall trial dataset to understand the importance of physical activity in HFPEF patients and the relationship with outcomes.

                                                As you know, TOPCAT is a study that was funded by the NIH in patients with heart failure, preserved ejection fraction. Patients were randomized to spironolactone or placebo and then followed for outcomes, and it was a very rich dataset for which we have a lot of physical activity information.

Dr. Carolyn Lam:               Indeed, and I wasn't even aware of the extent of the physical activity information in TOPCAT. Sheila, could you explain a bit how physical activity was captured and graded, and tell us about your findings?

Dr. Sheila Hegde:             Each participant’s physical activity was assessed by self report. Subjects were asked about the amount of heavy, medium, and light exercise in the preceding two weeks. They were given some examples of what those might be and what we did was, we converted these to AHA, American Heart Association categories of poor, intermediate, and ideal activity. As you know, the ideal activity category corresponds to 150 minutes of moderate intensity activity per week or 75 minutes of vigorous activity per week. What we found, using these categories, was that the majority of subjects actually met criteria for poor activity, so at least 75%. Also, a majority were New York Heart Association Class II heart failure.

                                                Those with poor activity were more likely to be women, have diabetes, chronic kidney disease, and a previous history of heart failure hospitalization. Interestingly, there was no significant difference in history of myocardial infarction, stroke, atrial fibrillation, or COPD. The median follow-up time for this group was 2.4 years, and we did sort of focus on the first two years because there was an interaction with times and randomization and, using Cox regression models, we found that those with poor or intermediate activity had approximately a two-fold higher risk of a primary composite outcome, which was heart failure hospitalization, cardiovascular mortality, or aborted cardiac arrest.

Dr. Carolyn Lam:               Wow! You know what the question is? Chicken or egg? Does this mean those who were exercising had better outcomes or they were just better and, therefore, they could exercise?

Dr. Sheila Hegde:             That's a very good question. This is a post hoc analysis, so it will be difficult to say, but we did sort of look at excluding those with a history of stroke or MI and found that the same two-fold increased risk of outcomes existed for those with poor intermediate activity.

Dr. Scott Solomon:          This is always the problem, as you know, Carolyn, with observational data. We don't know if the patients who are exercising more are doing better because they're exercising more or is it that the people who feel better can exercise more? You try to adjust as much as you can, but I don't know that there's any way to determine that for sure without doing a randomized trial of exercise in patients with HFPEF.

Dr. Carolyn Lam:               Certainly and, in fact, I thought that was one of the good messages, that it's time that we do a proper trial of that, don't you think? Jarett, would you have some questions for Sheila and Scott, too?

Dr. Jarett Berry:                I was really interested in your figure 3, this dose response analysis. In figure 3, you divided the exposure into deciles. You don't begin to see a decremented risk until you begin to see the ninth and tenth decile of exercise. If you look at other observational data, you really see this different pattern where just getting off the couch seems to be beneficial in other observational data for preventing coronary disease events but, both in our work and also in this paper here, particularly your figure 3, you see that this higher dose of physical activity was required to see a reduction in risk. I don't know if you could comment a little bit on that.

Dr. Sheila Hegde:             I agree that there is a difference in what appears to be a dose response at lower levels of activity. In this analysis, we actually included amount of light intensity of activity since the majority of people had no moderate or vigorous intensity activity to account for. In that sense, there's even sort of a higher threshold, perhaps, required to achieve benefit and reduction of risk, and it may be that heart failure has a different mechanism for physical activity in terms of achieving those benefits.

Dr. Jarett Berry:                I'm wondering, I guess getting back to Carolyn's original point there about, and Scott's comments, as well, about the need for a trial. If you look back at HF-ACTION where we saw some relatively modest benefit for exercise training and heart failure with reduced ejection fraction. Some of our prior work would suggest that, actually, the benefit of exercise is much more apparent in HFPEF patients. When you train HFPEF patients, they tend to improve much more dramatically with regard to VO2 peak, compared to heart failure with reduced ejection fraction. I'm just wondering what your thoughts were about the next steps. It seems like a trial of some type would be of great interest. What are your thoughts about that?

Dr. Scott Solomon:          I agree with you 100%. It would be a great idea for a trial. There have been small trials, as you know. Dalane Kitzman did a trial and Frank Edelmann and Burkert Pieske did a trial, and I think they're actually even doing another one now. The relatively small numbers of patients do show improvement in myocardial oxygen uptake, improvement in quality of life, and some improvement in some measures of echocardiographic measures of diastolic function, as well, with exercise training which is, frankly, more than we've gotten with drug therapies, so I agree 100%.

                                                It's also important to note that it's actually hard to get our patients with HFPEF in the United States into cardiac rehab because it's currently not paid for by Medicare, and I'm hoping that will change, as well.

Dr. Carolyn Lam:               You know, that's so well put, Scott. I've got a question, though. Every time you think TOPCAT, you think regional variation, right? How did this look in the different regions, in the U.S. versus elsewhere?

Dr. Scott Solomon:          First of all, let me just tell the audience that TOPCAT was a study in which we enrolled patients both in the Americas, which was the U.S., Canada, Argentina and Brazil, and in Russia and the Republic of Georgia. As you know, when we unblinded the trial, we found that the event rates in Russia and the Republic of Georgia were considerably lower, about five-fold lower than they were in the Americas. We believe that many of these patients may not have had heart failure.

                                                We've also recently found that many of these patients probably weren't taking spironolactone, as well. For many of our TOPCAT analyses now, including this one, we excluded the patients in Russia and Georgia and just focused on the Americas. Sheila, did you happen to look at the results in Russia and Georgia, just as a tweak?

Dr. Carolyn Lam:               I can tell you that the majority of patients were active, so very much different than our majority in active patients in the Americas region.

Dr. Jarett Berry:                This is an amazing study that really puts forward an important hypothesis that needs to be tested. Before, I know we've discussed that a couple of times already, but I really believe that we are exercising the wrong heart failure patients. As the Director of Cardiac Rehab here at Southwestern, we are including a lot of heart failure with reduced ejection fraction but, as Scott points out, there aren't currently funding available or billing is not allowable for patients who have heart failure with preserved ejection fraction.

                                                I think it's only studies like this that are going to move the field for it and how we can begin to think about caring for these patients and treating their comorbidities and treating their disease process through what we believe is probably one of the most important therapeutic strategies we have that we're not using, and that would be the exercise training, so I think this is a fantastic study and a wonderful contribution as we begin to think more about the future of treatment for patients with HFPEF.

Dr. Carolyn Lam:               Thank you so much, everyone. Listeners, I'm sure you enjoyed that conversation as much as I did. Don't forget to tune in again next week.

 

Sep 5, 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 Center and Duke National University of Singapore. Today's feature paper looks at the early use of N-Acetyl Cysteine with nitrate therapy in patients undergoing primary PCI for STEMI. More soon right after this week's summary of original articles.

                                                The first paper identifies a novel association between Phosphatidyl Choline Transfer Protein, or PCTP expression, in the blood, and death or myocardial infarction in patients with cardiovascular disease. Now, PCTP regulates intermembrane transfer for phosphatidyl choline. Platelet PCTP expression has been shown to be associated with increased platelet responses upon activation of protease-activated receptor four thrombin receptors. In today's paper, first authors Dr. Mao and Songdej, corresponding author Doctor Rao, and colleagues from the Temple University School of Medicine in Philadelphia used DNA protein binding studies and human erythroleukemia cells, as well as luciferase reporter studies to show that PCTP is a direct transcriptional target of RUNX1, a major hematopoietic transcription factor that regulates platelet production and function. Furthermore, in 587 patients with cardiovascular disease, the authors showed that PCTP expression in the blood correlated with RUNX1 expression and was independently associated with future death or myocardial infarction. Thus, regulation of PCTP by transcription factor RUNX1 may play a role in the pathogenesis of platelet-mediated cardiovascular events.

                                                The next paper provides molecular insights into cardiac fibrosis and shows that bone marrow cells are involved in cardiac fibrosis during pathological stress. Drs. Kishore, Verma and colleagues from Lewis Katz School of Medicine and Temple University of Philadelphia hypothesize that interleukin-10 inhibits pressure overload-induced homing of bone marrow fibroblast progenitor cells to the heart, and inhibits their trans-differentiation to myofibroblasts, thus attenuating cardiac fibrosis. To test this hypothesis, the authors used pressure-overload in wild-type and interleukin-10 knockout mice by transverse aortic constriction, and used chimeric mice to determine bone marrow origin. They further isolated fibroblast progenitor cells from mouse bone marrow for mechanistic studies.

                                                They found that, in addition to resident cardiac fibroblasts, bone marrow-derived fibroblasts significantly contributed to progression of pathological cardiac fibrosis, and that pliotropic antiinflammatory interleukin-10 inhibited the recruitment and trans-differentiation of bone marrow fibroblast progenitor cells in the pressure-overloaded myocardium. At a molecular level, they showed that interleukin-10 inhibited TGFβ SMAD2-3 signaling in activated bone marrow fibroblast progenitor cells. Furthermore, inhibition of TGFβ SMAD2-3 signaling mediated micro-RNA21 maturation was a novel mechanism by which interleukin-10 inhibited bone marrow progenitor cells-mediated cardiac fibrosis. Thus, selective inhibition of bone marrow cells homing to the heart and of fibrotic signaling using interleukin-10 or selective RNAs might inhibit the transition of physiological hypertrophy to heart failure, and may be a potential therapeutic target to treat or prevent the development of hypertrophic remodeling.

                                                The next study looks at the risk of major bleeding in patients receiving ticagrelor compared to Aspirin after a TIA or Acute Ischemic Stroke in the SOCRATES study. As a reminder, the SOCRATES trial was the first outcome study with ticagrelor in patients with Acute Ischemic Stroke or TIA, who were given ninety days of monotherapy with ticagrelor, 90 milligrams, twice daily and compared with those given aspirin 100 milligrams daily. The trial found that ticagrelor was not superior to aspirin in reducing the primary composite endpoint of stroke myocardial infarction or death. In today's study, Dr. Easton and colleagues from University of California San Francisco aimed to describe the bleeding profile of monotherapy with ticagrelor versus aspirin in this population of patients with Acute Ischemic Stroke and TIA, to characterize major bleeding based on the PLATO, TIMI and GUSTO bleeding definitions, and to identify factors associated with major bleeding.

                                                They found that PLATO major bleeds occurred in 0.5% of patients on ticagrelor and 0.6% of patients on aspirin. The most common locations of major bleeds were intracranial and gastrointestinal. Intracranial hemorrhage was reported in 12 patients, or 0.2%, on ticagrelor and 18 patients, or 0.3%, in aspirin. Independent of bleeding classification, PLATO, TIMI or GUSTO, the relative difference between treatments for major or severe bleedings was similar. However, non-major bleeds were more common on ticagrelor. Thus, this paper contributes important data on the bleeding profile of ticagrelor in patients with acute cerebral ischemia, provides some reassurance that there's no increased risk of major bleedings with ticagrelor compared to aspirin, including intracranial bleeds, however, a numerical increase in minor bleedings with ticagrelor.

                                                The next paper tells us that single 24-hour urine collections may be useful for estimation of average sodium intake in populations. However, for a reliable estimation of cardiovascular and renal risk, multiple 24-hour urine collections may be needed. First author, Dr. Olde Engberink, corresponding author, Dr. Vogt and colleagues from Academic Medical Center Amsterdam selected 574 adults with EGFR above 60, an outpatient 24-hour urine sample, and at least one collection during a seventeen year follow-up. Sodium intake was estimated using a single baseline collection, and the average of samples that were collected during a one, five, and fifteen year follow-up.

                                                They found that estimates of daily sodium intake changed more than 0.8 grams in half of the subjects when using multiple follow-up collections instead of a single baseline collection. The way of estimating sodium intake significantly affected the observed relationship between sodium intake and long-term outcome. Hazard ratios for cardiovascular and renal outcomes changed up to 85% when multiple follow-up 24-hour urine collections were used, instead of a single baseline collection. Thus, in summary, relative to a single baseline, the use of subsequent 24-hour urine samples resulted in different estimations of an individual's sodium intake, while population averages remained similar. This had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcome.

                                                That wraps it up for your summaries this week. Now to our featured discussion.

                                                Today for our featured discussion, we are talking about approaches to cardio protection. Now, we all know that the mortality rates in STEMI has improved over the last few years, because we've gotten better at reperfusion therapy with primary PCI, as well as effective secondary prevention therapy. However, the incidents and severity of heart failure following STEMI has been rising and thus, cario-protective therapies are of great interest to prevent heart failure and improve overall clinical outcomes following STEMI, following primary PCI. Over the years, a number of cardio-protective therapies have been tried, but have either been unable to reduce MI size or improve clinical outcomes following STEMI, but in this week's journal, we have an exciting trial, very interestingly of two old cardio-protective therapies showing a lot of promise in this area. And to do discuss this, I am so pleased to have the corresponding author, Dr. John Beltrame from University of Adelaide in Australia, as well as associate editor from Brigham and Women's Hospital in Boston, Massachusetts, Dr. Laura Mauri.

                                                John, you know, in my introduction I said this is very interesting. You're actually combining two old therapies, N-acetylcysteine and nitroglycerin in your approach in this trial. Now, both these drugs have been around for a long time. Please share with us what led you to think that a combination would work, what made you test the combination, and what makes your trial different from the other reperfusion studies before.

Dr. John Beltrame:           So, nitroglycerin, of course, has been utilized to treat myocardial infarctions for many years, has been shown to reduce the chest pain in that scenario, but little reward in perhaps reducing infarct size. And one of the main benefits of that people don't know is the vasodilation effect that it has on the coronary arteries, as well as reducing the wall stress. So, what we thought to combine it with N-acetylcysteine, which potentiates nitroglycerin effects, but also is a free radical scavenger. So therefore it would actually also work on reperfusion injuries. So these have a very synergistic effect, and therefore we expected to have good benefits.

                                                The ... because we're also looking at an anti-ischemic therapy with a reperfusion protective therapy, we wanted to introduce it as soon as possible. And so this drug was initiated in the emergency department as patients arrived, and then taken off to the cath lab where it was continued. We also began to ensure that we had adequate N-acetylcysteine, which I'll probably refer to as NHC from now on, as much on board as possible before we actually opened the artery. We gave high dose N-acetylcysteine at 20 milligrams in the first thirty minutes, and then at a slower rate for the next twenty-four hours. So for the first hour we gave it at 20 milligrams a minute, and then thereafter 10 milligrams a minute. And then, the actual study. We had patients randomized and double-blind placebo control trial, multiple sites here within South Australia with the primary endpoint being myocardial infarct size on early cardiac MRIs.

                                                So they got to see the opportunity to have a smaller sample size than many of the conventional infarct studies, and the key finding was in that early MRI, we saw an absolute 5% reduction in infarct size, which was an exciting find for us and this we expect to translate to a significant reduction in cardiovascular events and that's where I guess we're going in the future, is that we need to now undertake a study where we show that the combination of these two drugs also impacts on cardiac events.

Dr. Carolyn Lam:               How beautifully summarized, John. And really, congratulations on such an impactful and elegantly done study. I like the way you highlight it, though. Basically, you gave this drug earlier than most other trials of reperfusion therapies, because you gave it even before the primary PCI procedure as most cardio-protective strategies were tried within the cath lab. Would that be accurate?

Dr. John Beltrame:           Exactly right. So, whereas a number of the studies would take the patient with the STEMI to the cath lab, undertake the diagnostic angiogram and the diagnostic angiogram would then confirm that this was occluded, then they would introduce the cardio-protective agent and then proceed on to open up the artery. Whereas we had an opportunity for sort of ... at least twenty to thirty minutes before the artery was opened to actually have those drugs on board. And so, in a number of cases, we improved the patency of the vessel when we got to the diagnostic angiogram. So it's a two-point strategy, one anti-ischemic and one cardio-protective in terms of reperfusion injury. And we think that future trials in this area need to address both those conditions.

Dr. Carolyn Lam:               I can think of no better person to comment on being able to do these trials and the future of these trials than Laura. Laura, what are your thoughts?

Dr. Laura Mauri:               Thanks Carolyn. John, that was a great summary and I think you're really to be commended, because this is just such a challenging area to be doing trials in, but that's really what we need. And you know, most of the trials have focused on early procedure success for therapies that we currently use, rather than showing documented benefit in longer-term endpoints. But as you mentioned earlier, Carolyn, we really do still have patients who would benefit from therapies that may reduce infarct size. I think it's really remarkable, John, that your study was able to intervene early in the emergency room, as we know as clinicians that's not easy to do, not only to activate the quick pathways of care that we need for STEMI, but then on top of that to lay on a randomized trial, but I think it's incredibly important.

                                                What are you foreseeing as the challenges? As you think about your next steps in rolling this out to a ... potentially a larger trial and implementing such a study?

Dr. John Beltrame:           As with many trials, it's ways of recruitment, because a study like this is not gonna be funded by industry, you need to be looking at ... here within Australia, be looking at government authorities to put in an application for funding and then, it's a matter of recruiting. That's one of challenges we came across in doing this particular study, and this relates particularly, I guess, to the MRI endpoint, is the number of patients that were claustrophobic and therefore we couldn't actually perform the cardiac MRI, and so your primary endpoint ... you missed out. And so again, there's going to be frustrations like that and a much larger trial, which will need to involve even more centers. But funding that's ... for much of the research, I guess, it will be the challenge, because we've got two agents as Carolyn mentioned in the beginning that have been around for a long time and are certainly unlikely to attract any industry funding.

Dr. Carolyn Lam:               John, I have a question about the design as well. Of the current and maybe a future trial, because I'm left with the question, was it your early intervention? Was it the outcome you chose? Or was it one drug or the combination? And so, you did not do a factorial design in this trial. Are there plans to look at that, or do you the combination ... it's so obvious that two separate drugs don't need to be tested?

Dr. John Beltrame:           Very good question. So, you're quite correct, we can't be absolutely confident in terms of the mechanism, because we had one opportunity, I guess, to do the study and so we wanted to keep a simplified design, and that's what we gave everyone; a background of nitroglycerin and then just randomized the N-acetylcysteine. But we think it's actually the combination of the two that makes the benefits, because as you would be aware, the synergistic benefits is that the N-acetylcysteine potentiates the effect of the nitrates, potentiates the vasodilating properties, potentiates it's anti-platelet properties also. And so we think it's a combination of the two.

Dr. Laura Mauri:               John, it's interesting ... the use of the cardiac MRI endpoint, as we've all seen, it's being used more and more frequently, but at the same time, it's new for us, right? So you've raised some of the challenges and the practical execution of getting patients who can tolerate it, especially after an acute hospitalization. But the classical endpoint has been SPECT imaging as a surrogate endpoint for mortality in myocardial infarction. Of course, that's based on very large trials showing correlation, but the MRI should really give much better resolution, so I think that's really a very logical next step. But I think the more data that we get across multiple different trials, the better we can validate that endpoint and see how it might differ from the classical surrogate endpoints that we've had for myocardial infarction.

                                                Other than the efficiency of looking at MRIs, do you have other observations when you look at MRIs at endpoint compared with some of the traditional endpoints like SPECT?

Dr. John Beltrame:           Not SPECT so much, but to follow on exactly what she was saying, we all also measured serum creatine kinase, so CK, values. And because of the larger spread of the data and therefore the need to have a larger sample size, although we certainly saw a trend of improvement in CKs as a marker of infarct size, we didn't achieve statistical significance, but with the MRI because we had more precise measurements, that gave us a smaller margin of error and therefore, we were able to see a difference between the two treatments. So certainly I think in the future, the MRI is certainly a very good way to evaluate agents in this particular area.

Dr. Laura Mauri:               It's nice to see the consistency that you saw across the different endpoints.

Dr. Carolyn Lam:               That's true, but I do have a question though, as an Echo cardiologist here, your three-month assessment of the ventricular remodeling, if I read it right, there was no change detected at three months. Would you like to comment on that?

Dr. John Beltrame:           What we saw in terms of the infarct size, we still saw a difference. I think what you might be referring to, the infarct size was a little bit smaller, so that's just ... over time the we feel like the scar contracts down. But I'm not sure if you're also referring to the ...

Dr. Carolyn Lam:               LV dimensions and injection fraction.

Dr. John Beltrame:           The injection fraction's interesting, because when we looked at that ... because we found no difference in the injection fraction. Now, if you take a look at the actual values, they're almost normal and I think that says something to where we are in terms of the management of acute STEMIs, because we preserved the left ventricular function, because there were normal ejection fractions, so we couldn't make them better than what we had in placebo, so that is something to primary PCI, I think.

Dr. Carolyn Lam:               That's a great answer. Thank you, John. And Laura?

Dr. Laura Mauri:               John, your group is really to be commended for conducting such a high-quality trial in this very challenging area. We've been victims of our own success, I think, in this space because the mortality rates have obviously declined after MI, infarct size is on the decline with early reperfusion. Getting in there with attempted therapies is a race when you're also trying to achieve fast door-to-ballon times, but it's still an important area and one we can only address with careful, randomized trials with important therapies. So I want to congratulate you and your group, it's really a step in the right direction.

Dr. Carolyn Lam:               You've been listening to "Circulation On The Run", thank you so much for joining us, and don't forget to tune in next week!

 

Aug 28, 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 Center and Duke National University of Singapore. Our feature paper this week tells us more about aortic wall inflammation, and how this predicts abdominal aortic aneurysm expansion, as well as need for surgical repair. Much more, right after these summaries.

                                                Our first original paper sheds light on a novel mechanism for adult cardiac regeneration. This is a paper from first authors Drs. Wang, and Lee, and corresponding authors Dr. Chen, Houser, and Dr. Jeng from Third Military Medical University from Chongqing, China.

                                                In an elegant series of experiments using mouse models, the authors showed that mature adult cardiomyocytes could re-enter the cell cycle and form new cardiomyocytes though a three-step process: of dedifferentiation, proliferation, and redifferentiation. Intercellular calcium signals from neighboring functioning cardiomyocytes through gap junction induce the redifferentiation process. Furthermore, they showed that this mechanism contributed to new cardiomyocyte formation in post MI hearts in mammals. In summary, this study contributes to our understanding of adult cardiac regeneration and could lead to novel strategies to repair the injured heart.

                                                The next paper provides mechanistic data that may explain why thrombotic complications are more prevalent in patients with diabetes, and why some anti-platelet drugs may have limited efficacy in patients with diabetes. In this paper by first author, Dr. Hu, corresponding author Dr. Ding, and colleagues from Fudan University in Shanghai, China, the authors show that platelets of patients with Type 2 diabetes express high levels of activated P2Y12 receptor.

                                                The P2Y12 inverse agonist inhibited P2Y12 activity of platelets from diabetic patients and rats, more than Cangrelore, leading to a stronger in-vivo antithrombotic effect in thrombosis rat models with diabetes. Increased platelets P2Y12 receptor expression in diabetes was mediated by a high-glucose reactive oxygen species, NF-kappaB pathway. In summary, platelet P2Y12 receptor expression was shown to be significantly increased, and the receptor was constitutively activated in Type 2 diabetic patients, which contributed to platelet hyperactivity, and limited anti-platelet drug efficacy in Type 2 diabetes. 

                                                The next paper tells us that the majority of cardiovascular disease events are now occurring amongst adults with a systolic and diastolic blood pressure of less than 140 over 90 millimeters mercury. Prior data have shown us that the majority of incident cardiovascular disease events occurred among U.S. adults with higher systolic and diastolic blood pressures of above 140 over 90. However, over the past several decades, blood pressure has declined and hypertension control has improved. Thus, in the current study, Dr. Tajeu and colleagues from Temple University College of Public Health in Philadelphia estimated the percentage of incident cardiovascular disease events that occur at blood pressures below 140-90 in a pooled analysis of three contemporary U.S. cohorts: the Reasons for Geographic and Racial Differences in Stroke, or, REGARDS study, the Multi-Ethnic Study of Atherosclerosis, or MESA study, and the Jackson Heart study.

                                                In these three U.S. cohorts that enrolled after 2000, more than 60% of incident cardiovascular disease events occurred among participants with blood pressures below 140 over 90 millimeters mercury. In the 2001 to 2008 National Health and Nutritional Examination survey mortality follow-up study, 58% of cardiovascular disease stats occurred in U.S. adults with blood pressures below 140 over 90. Among participants taking anti-hypertensive medication, with blood pressures below 140 over 90, only one-third of those who are eligible for starting treatment were taking one, and approximately 20% met the SPRINT eligibility criteria.

                                                In conclusion, while higher blood pressure levels are associated with increased cardiovascular disease risk, in the modern era the majority of incident cardiovascular disease events occur in U.S. adults with blood pressure below 140 over 90. Although absolute risk and cost effectiveness should still be considered, additional cardiovascular disease risk reduction measures for adults with blood pressure less than 140 over 90, and at high risk for cardiovascular disease, may be warranted.

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

Dr. Carolyn Lam:               On today's podcast discussion, we will be talking about aortic wall inflammation as a possible functional, or biological, imaging bio-marker that may add to the usual structural measurements of size that we use to predict abdominal aortic aneurysm expansion and rupture. Now, to discuss this very important paper, we have the corresponding author, representing the MA3RS study investigators, Professor David Newby from the Center for Cardiovascular Science in Edinburgh, as well as a familiar voice now, Dr. Joshua Beckman, associate editor from Vanderbilt University. Welcome, gentlemen.

Professor David Newby: Hi, there.

Dr. Joshua Beckman:      So great to be here again, thanks for having me.

Dr. Carolyn Lam:               So great that you're back again, Josh! But David, let's start with you. Could you just summarize what this trial was about and your main findings?

Professor David Newby: Sure, so this was a major clinical trial that we undertook in the U.K. and Scotland. We approached patients who were in a surveillance program who had an abdominal aortic aneurysm, and we asked the question, "Is there anything we can do better than just serial ultrasound measurements that currently are stunned to this care?" So, in Edinburgh, we developed a technique using ultrasmall, superparamagnetic particles of iron oxide, which is a bit of a powerful ... so we shortened that to USPIOs; these are really small iron particles that are so small they can cross vascular spaces and they get gobbled up by tissue resident macrophages, and then causes a signal that we can detect on magnetic residents' scanning MRI.

                                                So we were really asking the question, "Can we do better than ultrasound by using what we call USPIO-enhanced MRI?"

Dr. Carolyn Lam:               So a biological or functional imaging parameter versus just structural. And so, what were your main findings?

Professor David Newby: We recruited around 361 patients and ultimately 341 went into the trial because of various exclusions, et cetera. And we followed these patients up for, on average, around three years. And so we were following it up every six months with ultrasound, with other various assessments, and ultimately what we found was that the USPIO-enhanced magnetic residents' scan was positive in around half of patients, and in those patients that took up the USPIOs in their abdominal aortic aneurysm wall, those patients, their aneurysms expanded quicker. So rate of expansion was higher, and they went on the have the primary event of either elective repair, or rupture. And, don't forget, that the clinicians who were looking after these patients, they didn't know the results of the MRI so it didn't influence their clinical minds, when this was completely independent of the clinical team.

                                                So, for the first time, we demonstrated that imaging or tracking macrophages in the abdominal aortic wall could, indeed, predict both disease progression and clinical outcome.

Dr. Carolyn Lam:               And Josh, you know, no one can say it better than you: could you just describe what we discussed as the editors about the significance of such a finding?

Dr. Joshua Beckman:      I think there's a few things to take home from these three that are really incredible. First, David, were you surprised at the concordance between the USPIO-enhanced imaging and smoking, or was that something that you expected?

Professor David Newby: That was a big surprise. That was, actually, as we discussed in the manuscript, quite an interesting finding, and as always with an interesting find, we dig around in the background, and it actually gets more and more exciting and plausible because of the mechanistic work that we'd seen in the pre-clinical science that preceded our trial. So yes, it was a surprise, but actually the more we got into it, the more it made sense.

Dr. Joshua Beckman:      One of the other things that I think is really important to talk about is how you get this study done, and one of the things I found incredibly impressive ... I am unaware of any other multi-sensor MRI study like this. How did you organize this amongst the different institutions?

Professor David Newby: It can be a bit of a challenge. So I've done quite a few multi-sensor trials in Scotland, and imaging trials, and the community in Scotland actually is very, very supportive and we got a good network of folks. So the three centers are actually two imaging centers: one in Edinburgh one in Glasgow, a further recruitment center in a city just in the center of Scotland, Sterling. And the patients ... we were able to obviously make sure the scanners did the same protocols; fortunately, they were the same scanner, make and model. So that all obviously helped, but we had a lot of inundation, phantom work, to make sure both centers got things right.

                                                But there was a huge motivation to get this done, and I'm indebted to Charles Riditi and Colin Barrie in Glasgow for doing the, and supporting the, imaging work, and also a medical physicist here in Edinburgh, Scott Semple, who'd done a lot of the work to get this to happen. So there's a teamwork in Scotland and the NHS, where the access to patients are in the screening program as well, which made recruitment really well and very efficient. And we started exactly to target, which is pretty unusual in clinical trials, often takes longer to recruit patients, but it was a great team effort. The imaging quality, we checked, verified, centrally read, and it was really good to see it delivered in that way.

Dr. Joshua Beckman:      Do you think that agent, the iron oxide particles, is going to be the contrast agent, I guess, of the future, or do you think because it is now so consistent with smoking, it's gonna be more of an investigational tool?

Professor David Newby: So there's a couple of things to say here on ferumoxital, which is the USPIO we used. It's currently licensed in the U.S. for the treatment of anemia and chronic renal failure, but it can also be used as an imaging agent and actually this, I think increasingly, might have a role; not just in aneurysms, but elsewhere. So the first thing you can do is actually do angiography with this agent. [Obviously gadolinium is getting a lot of press at the moment, with problems with warnings coming out, of residual brain deposition, and so on. With the USPIOs, you can use this in renal failure patients, so again, another contraindication for us to concern about: NSF in renal failure patients. So actually, for angiography, I think it's going to have an increasing role.

                                                For imaging of inflammation, we've previously demonstrated that you can track inflammation post-myocardial infarction, so you can see air is lighting up following myocardial infarction. We have some papers out on that, and I think, if you are in the business of looking at cellular inflammation, macrophage trafficking, then this technique really can be helpful.

                                                When we come to aneurysm studies, I think it is less clear because ultimately, doing a quick ultrasound, in fact can give you the information together with all of the clinical risk factors, like smoking, and you get to the same end point without doing the MRI. Then, clearly, it's not going to be that impactful. Having said that, I think sometimes we will have patients who've got all this information and we're not sure which way to go. So I think it could be used as an almost umpire test, if you're not sure whether to proceed with surgery or not. And I think, also, if we discover new agents that are anti-inflammatory that may impact on disease progression, with a normal therapy, then clearly this might be a good buyer market to use in future therapeutic trials.

Dr. Joshua Beckman:      Yeah, I actually see a huge potential for the testing of new agents, to see whether or not it reduces the inflammation that's associated. I'm gonna ask you a theoretical question, if that's okay with you. Part of the inflammatory process in the aneurysm is based on oxidative stress, but I've always wondered if you provide more oxygen, which may enhance the oxidative stress reaction, are you actually worsening the reaction at the time you're doing the study? Is that possible, or am I just concerned about nothing and making it up?

Professor David Newby: Well, obviously your [inaudible 00:13:19] stressors is important in all of cardiovascular disease, and if you increase oxygen supply, maybe you indeed induce more oxidative stress. In the context of an aneurysm, often there's quite an hypoxic state in the aneurysm wall, because obviously the intraluminal thrombus can buffer the wall itself from it, obviously the vasovasorum come in, but they may not be as efficient in doing that. Some of the areas that we're seeing light up probably are quite hypoxic, so they'll be in an oxygen-deprived state. So I think that needs to be put in the balance, too, and there has been some suggestion that iron particles can increase oxidative stress, and it has been suggested maybe harmful; we've not seen that, we've had absolutely no adverse reactions at all in all of our patients. We had one patient whose blood pressure fell a little bit, but we didn't have to medically intervene at all, so it was just observed and it passed; of course it might be due to many things.

                                                We've also studied this in patients with myocardial infarctions, I've said, also bypass surgery, people who've had bypass surgery. We've also published on using these agents there, and again, we've seen absolutely no adverse reactions. And you would've thought, in the context of those situations, if you were going to see an adverse effect you would've seen it behind.

Dr. Carolyn Lam:               David, I've got a question for you. I think you mentioned, a little bit earlier, that end of the day this enhanced MRI did not improve the risk stratification beyond the current predictors of clinical outcome in abdominal aortic aneurysms, but what are the next steps for you?

Professor David Newby: There's a couple of things, which we've been thinking through. Firstly, I think the primary end point of the trial was mostly driven by repair, and when we looked at the emergent events, so dying, and rupturing, the signal got stronger and very close to statistical significance. And obviously when you've got a population of patients whose elective surgeries mostly dominated by the ultrasound scan decision, therefore makes it difficult to prove, on top of that, the MRI will have value. So it's quite high, and on a difficult bar to cross, so some of the thoughts we've had are thinking about predicting rupture, rather than repair. And there will also be potential for actually doing a trial, where we actually base decisions on the aneurysm, and if you've got an intermediate category of patient, where you're not sure which way to go, those patients you then do use as an arbiter, and that might have, therefore, proof or value for it.

                                                And the final area that we're probably thinking about exploring is, "Okay, paths for macrophages." Is there other pathophysiological processes that we might want to explore with other agents, that might predict aneurysm growth and rupture even stronger, and macrophage inflammation? So those are some of the thoughts that we've had about where the next steps will be.

Dr. Joshua Beckman:      This is an incredible amount of work and I always think it's important to make clear to everybody who's listening to this podcast that, even though we may not all do the same kinds of research, it needs to be made clear that having a multi-sensor study in this topic, with this technique, is incredibly impressive. And the physiology that was brought forth, in addition to the clinical stuff that we just heard about, I think is what makes this worthy of a podcast.

                                                Dr. Newby, thanks so much for participating.

Professor David Newby: Thank you so much, that's very kind. And just to reiterate, it has been a long journey and a huge effort, but we're reaping the rewards now, and it's nice to see the data being published in circulation.

Dr. Carolyn Lam:               Gentlemen, it has been so wonderful having you here to discuss this. Thank you so much for your time.

 

Aug 21, 2017

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

                                What is the effect of obesity and underweight status on perioperative outcomes of congenital heart operations?

                                Our feature paper this week sheds light from the Society of Thoracic Surgeons Database. More soon, right after these summaries.

                                The first original paper highlights the role of micro RNAs in metabolic remodeling and heart failure. As a reminder, micro RNAs are small, noncoding RNAs important in post transcriptional modification and influencing many cellular processes simultaneously.

                                First author, Dr. Heggermont, corresponding author, Dr. Heymans, and colleagues from Maastricht University in the Netherlands use mice subjected to pressure overload by means of endotension to infusion or transverse aortic constriction. They show that micro RNA 146A was up regulated in whole-heart tissues in these murine pressure overload models, as well in left ventricular biopsies of aortic stenosis patients. Over expression of micro RNA 146A in cardio cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of micro RNA 146A blunted the hypertrophic response and attenuated cardiac dysfunction in Vivo.

                                Mechanistically, micro RNA 146A reduced its target dihydrolipoyl succinyltransferase or DLST, a mitochondrial protein that functions as a TCA cycle transferase. DLST protein levels were reduced in pressure overload mice, while they were partially maintained in micro RNA 146A knockout mice. Furthermore, overexpression of DLST in wild type mice, protected against cardiac hypertrophy and dysfunction in Vivo. Thus, micro RNA 146A and its target DLST are important metabolic players in LV dysfunction. These results also opened the door to novel therapies to treat metabolic disturbances and improve energy efficiency of a failing heart.

                                Program cell death is critically involved in ischemic cardiac injury, pathologic cardiac remodeling, and heart failure progression. Our next paper sheds light on the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure. Using genetic mouse models, first authors Dr. Guo and Yin, corresponding author Dr. Liu, and colleagues from University of Washington in Seattle, identified a critical role for a tumor necrosis factor receptor associated factor 2 or TRAF2 in myocardial survival and homeostasis by suppressing necroptosis.

                                The authors delineated an important TRAF2 mediated NF-KB independent pro-survival pathway in the heart by suppressing necroptotic signaling. They identified novel molecular mechanisms whereby TRAF2 suppressed TNF receptor 1 mediated, receptor interacting protein 3 dependent necroptosis, which is critical for myocardial survival and homeostasis. Thus, this finding suggests that the necroptosis suppressing TRAF2 signaling pathway and its effectors may serve as novel therapeutic targets for pathologic cardiac remodeling and heart failure.

                                Our next paper tells us that cerebral hyperperfusion may be associated with accelerated cognitive decline and an increased risk of dementia in the general population. First author Dr. Walters, corresponding authors Dr. Ikram, and colleagues from Erasmus University Medical Center in Rotterdam, The Netherlands, measured cerebral blood flow by 2D phase contrast MRI in non-demented participants of the population based Rotterdam study. A 4,759 participants with a median age of 61 years, and a median follow up of 6.9 years, 123 participants developed dementia.

                                Lower cerebral perfusion was associated with higher risk of dementia and this risk was even higher with increasing severity of white matter hyperintensities on MRI. At cognitive reexamination after an average of 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition, which was similar after excluding those with incident dementia, and again, most pronounced in individuals with higher volumes of white matter hyperintensities.

                                Thus, lower cerebral perfusion was associated with accelerated cognitive decline and increased risk of dementia in the general population. This association was modified by hypertension and cerebral small vessel disease, possibly reflecting impaired arteriola and capillary function. This paper calls for further long term study and evaluation of optimizing cerebral perfusion as a means to prevent cognitive deterioration, for example, in patients with heart failure or carotid artery stenosis.

                                Well, that wraps it up for our summaries. Now for our feature discussion. For today's feature discussion, we will be looking at data from the Society of Thoracic Surgeons Database. This time looking at the effect of body mass index on perioperative outcomes of congenital heart operations in children, adolescents, and young adults. To discuss this, we have none other than the first and corresponding author, Dr. Michael O’Byrne from Children's National Medical Center in Washington D.C., as well as Dr. Naveed Sattar, Associate Editor from University of Oxford. Welcome gentlemen.

Dr Michael O’Byrne:       Good morning.

Dr Naveed Sattar:            Good morning.

Dr Carolyn Lam:                Michael, we know that extreme body mass indices, very high or very low, has been associated with increased risk of at first, perioperative outcomes in mainly older adults undergoing cardiac surgery. We also know about the obesity paradox in conditions like heart failure, so why was it important to look at this specific group of patients? Congenital heart patients and children, adolescents, and young adults?

Dr Michael O’Byrne:       Yeah, I think that as a pediatric cardiologist, a lot of the data that we use to guide our management is extrapolated from adult studies. However, in this particular case, it wasn't clear necessarily that adult data would necessarily be applicable to children and adolescents and young adults. We are aware that there are epidemiologic trends that congenital heart disease population ages and there are also in increasing problems of obesity among children in the United States.

                                The convention wisdom among surgeons in the United States is that obesity would increase perioperative risk and the thought is that some combination of exposure to hypertension and diabetes and peripheral vascular disease might impede wound healing and that body habit as itself might be a risk for the technical approach in wound healing. Acknowledging that there's a lot of evidence both for extreme BMI being a risk in surgical patients and adults, but also the idea that obesity paradox might be important in children because the biological mechanisms might be different.

                                Children themselves are exposed, their sort of dose response or dose exposure is less, they're younger, and so haven't been obese for a prolonged period of time, so that the integrated effect of having diabetes, hypertension, and obesity might be less. At the same time, we also acknowledge that in children with heart disease, we have congenital cardiac disease, the same issues with cachexia and frailty are present. i.e. that children with very low body mass index might be assigned to their own medical frailty, or a part of a heart failure cachexia syndrome.

                                One of the challenges in dealing with children with congenital heart disease, however, as you know is that its rarer than cardiac disease of the aging and additionally, that the population is very heterogenous in terms of the actual defects that are present and the surgeries that are performed. It was relevant to look and see over a wide range of sort of technical complexity surgeries with a wide range of sort of intrinsic preoperative risk of perioperative outcome, whether or not BMI would be associated with an adverse outcome. Either operative mortality in this case, or a composite outcome of mortality, major adverse events, and wound infection.

Dr Carolyn Lam:                Wow, that makes a lot of sense and congratulations. This is not just the first, it's huge and really comprehensive. Could you just tell us a little bit more about what you did and what you found?

Dr Michael O’Byrne:       I think as this point, I'd have to acknowledge that the challenges that we described in terms of both a sample size and in terms of getting a representative sample, is a constant challenge in our field and we have to give credit to my co-authors Marshall and Jeff Jacobs for their work in developing the collaboration that allowed for the STS Congenital Heart Surgery Database to exist. Also, on top of shepherding the database, their research, along with the people at Duke Clinical Research Institute, they've developed a robust risk stratification model for mortality that we utilize as part of this study. Without that, this would be really be very challenging.

                                What we did is performed an observational cohort study using the STS Congenital Heart Surgery Database to look at the risk of perioperative mortality and composite outcome in patients undergoing surgery in the United States between 2010 and 2015. We looked at both the actual events, the sort of observed events, in terms of mortality and adverse events, and then created multivariate models to adjust for the known covariance.

                                We hypothesized that extreme BMI, either very high or very low, would be associated with increased risk of mortality and increased risk of that composite outcome. What we found that operative mortality and that perioperative adverse events occurred more frequently in obese and severely underweight subjects. However, because they have an unequal distribution of potentially important covariance, we used multivariate modeling to adjust for those covariance.

                                Our multivariate models for death, however, the severely underweight subjects had an odds ratio of 1.4 and obese subjects had an odds ratio of 1.3, but neither was specifically significant in that context. We sort of anticipated that with a possibility given the very low event rate. That's the reason we've used a composite outcome, a higher event rate.

                                For that composite outcome, in both different versions of the multivariate model that we used, the severely underweight subjects had an odds ratio of 1.5, underweight subjects had an odds ratio of 1.3, and obese subjects had an odds ratio of 1.2. An increased risk in all three of those populations of interest relative to normal weight or just overweight subjects.

Dr Carolyn Lam:                We're always saying that at circulation we do want to publish papers that have direct and important clinical implications, so Naveed, could you share some thoughts on what this means clinically?

Dr Naveed Sattar:            Yeah, I think they went through the review process and I think the paper was very well written. I think Michael and his colleagues clearly understood the strength and the limitations of the data so that you can only ever itself prove associations here and therefore, clinically when we push them on trying to make clinical inferences, I think clearly they recognize that once they find associations between obesity and adverse outcomes and underweight.

                                What they need to do next, now this is a paper that then leads you to think, "Well actually, I need to do some clinical trials to prove that module ..." You're preventing these outcomes or in very under knowledge where they're actually increasing the BMI but improving their nutrition, cannot also improve outcomes following surgery. Now those are tough things to do. Michael, what do you think from some of the clinical inference? My inferences were the associations were there, particularly for the normal [inaudible 00:12:35] outcomes, but actually to prove that, to make a difference, you probably might need to do some intervention trials or is that how you take it as well?

Dr Michael O’Byrne:       I agree with you 100%. I think that as an epidemiologist, I think that what we see in an observational study like this is an association. The two next levels of research that are necessary at this point are to see whether or not in this population BMI is a modifiable factor in the short run before surgery, or even in the long run. And the second question to answer is whether those adjustments in BMI, if they are achievable, affect outcome with surgery. Absolutely.

                                It's a tremendous challenge, both logistically in organizing a study, and honestly, in terms of capturing a cohort that would be large enough, given that this is almost 100% of the surgeries that occurred over a six year period in the United States.

Dr Naveed Sattar:            I looked at it and thought, "Well, the mortality association once you adjusted were not quite significant but are there any individuals you would not do surgery on based on their BMI based on these results?

Dr Michael O’Byrne:       The motivation for the study is exactly to try to begin to shed light on that kind of question. I think that it might be what I would call a tiebreaker potentially, if you have a situation where a patient is near meeting criteria but isn't quite at a place where you need to do surgery at that point. It might dissuade you from proceeding immediately potentially pursuing a course that might adjust their BMI in the correct direction.

                                At the same time also, in a patient who's underweight particularly to evaluate whether their medical regimen has been optimized and if there are other residual lesions that can be addressed in a non-surgical or medical fashion.

Dr Naveed Sattar:            I suppose the other trick with this type of research research is always trying to make sure that people understand these are the associations and not trying to attribute causality because it's always physical, isn't it? But I think you and your team did that very well and I'm sure we had a back and forth with review but I think your discussion section, your limitation section, is beautifully written and covers those kinds of caveats, which I think is important as well.

Dr Michael O’Byrne:       I thank you for that. That's very complimentary and we certainly strived for that, but I think that you as an editor, and also in terms of the reviewers also, were very helpful in that sort of collaborative process to try to make sure that we're communicating it. It's not always clear in a project that takes months and years to finish when you're writing it necessarily, you may be constantly aware of trying to be clear in your communication but it's also helpful to have a reviewer from the outside carefully read the study.

Dr Carolyn Lam:                That's wonderful and Michael, may I just join Naveed in congratulating you on beautiful paper? And maybe just one other little question, did you have any insights into the mechanisms of increased risk for composite events in the extremes of BMI?

Dr Michael O’Byrne:       I think it's an important question. There's been a tremendous amount of research in adult cardiac disease about whether it is the BMI as a steady state or BMI changes immediately before and after surgery that are relevant in this case. From this kind of observational study, it's very hard and very challenging to try to make any sort of inferences about the causes. It would be an important part of any study moving forward to include ways to investigate that, and honestly, as an interventional cardiologist and epidemiologist, I probably would defer to Naveed, he might have more cogent and logical ideas about that than I do.

Dr Naveed Sattar:            We've had lots of research from a whole variety of researchers. We all understand it's finally serious but recognize it's difficult, so one of the ways moving forward and I think Michael and his colleagues have this is if you have serial BMI data prior to surgery, that could try and inform on reverse causality because of the low BMI, but in terms of the mechanisms, remember these are associations, but I think mechanisms are well covered if you are obese and clearly you have risk factors for death, across the vasculature, across the cardiac functions, across the whole variety of things.

                                We know those mechanisms, question is, to what extent are they actually operating and causing increased risk in the surgical arena and that's a really tough ask. I think people can come up with a multitude of mechanisms. I think the key things, like this particular paper, is that there are potential mechanisms but these are associations ... Look, this is what we found, and clinically now we need to try and address this within the following types of interventions or at least provide some guidance to colleagues and clinicians.

                                Exactly as Michael says, if there is somebody who is approaching surgery whose quite obese, perhaps they should try and intervene to try and lessen their weight for a short period of time prior to [inaudible 00:17:07], you know what happens. It would be nice to do some big trials but I think doing trials in this area is going to be really tough, but with imagination, with good collaboration across centers, trials are not impossible. I think they can be done.

Dr Michael O’Byrne:       Naveed, I think, actually articulated what I think is both the difficulty of doing that trial but also the importance of it. I think that looking at ... In these databases, we don't have a serial BMI and I think that's an important missing piece of information that we tried to address in our discussion and I think it's something that would be really valuable moving forward. And certainly testing interventions, whether they're medical, interventional, or surgical, to help these patients who are obese either lose or maintain an appropriate weight is the next step.

                                On the converse side, this research highlighted to me the prevalence of chachectic or underweight patients in our population and it's something that outside of the infant period, we don't necessarily think about tremendously and we don't think about it as a modifiable factor. I think that's another group of patients who also deserve some attention.

Dr Carolyn Lam:                Listeners, you've been listening to Circulation on the Run. I'm sure you learned a lot as I did. Don't forget to tune in again next week.

 

Aug 14, 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 Center and Duke National University of Singapore. Our podcast today highlights an important perspective piece on charting a future together and turning discovery science into cardiovascular health. You don't want to miss this, coming up right after these summaries. The first original paper tells us about the importance of changes in exercise capacity following transcatheter aortic valve replacement or TAVR.

                                                First author, Dr. Altisent, corresponding author, Dr. Rodés-Cabau, and colleagues from Quebec Heart and Lung Institute in Canada studied a total of 305 patients undergoing TAVR with baseline and six month followup exercise capacity assessments by six minute walk tests. They found that close to one-third of patients undergoing TAVR failed to improve their exercise capacity despite an optimal hemodynamic result post-procedure.

                                                Factors associated with a lesser exercise capacity improvement included patient characteristics such as older age, female sex, non-cardiac comorbidities, such as chronic obstructive lung disease, peripheral artery disease and bleeding episodes resulting in reduced hemoglobin levels. Importantly, the absence of an improvement in physical performance at six months post-TAVR was an independent predictor of mortality and adverse cardiovascular outcomes during the ensuing four years and particularly among patients with a greater impairment of exercise capacity pre-TAVR.

                                                Thus, implementing exercise capacity assessment pre and post-TAVR may help to improve patient risk stratification and augment the accuracy of the prognostic information given to patients, helping to identify those requiring more intensive followup assessment. The next study provides mechanistic insights into the adverse health outcomes associated with particulate matter exposure in the air. First author, Dr. Lee, corresponding author, Dr. Kahn, from Fudan University in Shanghai, China and colleagues conducted a randomized double-blind crossover trial in 55 healthy college students in Shanghai. Real and sham air purifiers were placed in participant's dormitories in random orders for nine days with a 12 day washout period.

                                                Serum metabolites were quantified using gas chromatography mass spec and ultra-high performance liquid chromatography mass spec. They found that higher particulate matter exposure led to a significant increase in cortisol, cortisone, epinephrine and norepinephrine. Between treatment, differences were also observed for glucose, amino acids, fatty acids and lipids. They also found that higher blood pressure, hormones, insulin resistance and biomarkers of oxidative stress and inflammation were present among individuals with higher exposure to particulate matter.

                                                Thus, this study showed that activation of the hypothalamus-pituitary-adrenal and sympathetic-adrenal medullary axis may contribute to the adverse cardiovascular and metabolic effects of particulate matter exposure in the air. In China, indoor air purification may be a practical way to reduce personal exposure to particulate matter. The next study shows that N-acetylcysteine may be new effective thrombolytic treatment. First author, Dr. Lizarrondo, corresponding author, Dr. Gauberti and colleagues from Inserm, France hypothesized that N-acetylcysteine might cleave the von Willebrand factor multimers inside occlusive thrombi, thereby leading to their disillusion and arterial recanalization.

                                                To test this hypothesis, the authors used experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of Laser Doppler Flowmetry and magnetic resonance imaging. They showed that intravenous and acetylcysteine administration promoted lysis of arterial thrombi that were resistant to conventional approaches such as recombinant TPA, direct thrombin inhibitors and anti-platelet treatments. Furthermore, through in vitro and in vivo experiments, they provided evidence that the molecular target underlying the thrombolytic effects of N-acetylcysteine were principally the von Willebrand factor that crosslinked platelets in arterial thrombi.

                                                Co-administration of N-acetylcysteine and a non-peptidic GP2B3A inhibitor further improved its thrombolytic efficacy essentially by accelerating thrombus disillusion and preventing rethrombosis. In a new large vessel thromboembolic stroke model in mice, this co-treatment significantly improved ischemic lesion size and neurological outcomes. Importantly, N-acetylcysteine did not worsen hemorrhagic stroke outcome suggesting that exerted thrombolytic effects without significantly impairing normal hemostasis. Thus, in summary, N-acetylcysteine was shown to be an effective and safe alternative to currently available anti-thrombotic agents to restore vessel patency after arterial occlusion.

                                                The clinical implications of the study are wide reaching considering the very wide availability, low cost and apparent safety of N-acetylcysteine. This is discussed in an accompanying editorial by Dr. Lillicrap from Queens University, Kingston, Canada. The final study identifies a novel mechanism for regulation of cardiac fibrosis that revolves around plasminogen activator inhibitor type 1 or PAI-1. First, author, Dr. Flevaris, corresponding author, Dr. Vaughan and colleagues of Northwestern University, Feinberg School of Medicine in Chicago, Illinois showed that cardiac fibrosis was detected by late gadolinium enhancement cardiac MRI in two otherwise healthy humans with complete PAI-1 deficiency due to a homozygous frameshift mutation in serpene 1.

                                                They further performed a series of mouse experiments to show that treatment of young PAI-1 deficient mice with angiotensin 2 induced extensive hypertrophy and fibrotic cardiomyopathy. Ventricular myocytes were found to be the important source of cardiac transforming growth factor beta or TGF beta and PAI-1 regulated TGF beta synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. PAI-1 deficiency significantly enhanced multiple TGF beta signaling elements and transcriptional targets. Thus, in summary, this study show that PAI-1 is an essential repressor or cardiac fibrosis and access a molecular switch that controls the cardiac TGF beta access and its early transcriptional effects that lead to myocardial fibrosis.

                                                Modulation of the cardiomyocytes TGF beta access represents a unique therapeutic strategy that may abrogate fibrotic signaling and cardiac fibrosis. Well, that wraps it up for your summaries. Now for our featured discussion. We are incredibly privileged today to have the director of the National Heart, Lung and Blood Institute, Dr. Gary Gibbonss with us on the podcast, as he talks about his perspective piece entitled "Charting Our Future Together: Turning Discovery Science into Cardiovascular Health." Also, joining me today is our editor in chief, Dr. Joseph Hill from UT Southwestern. Joe, I know you share my incredible excitement and enthusiasm at having Dr. Gibbonss on this podcast with us.

                                                Maybe could I invite you to say a few words to frame just how important this perspective piece is for Circulation?

Dr. Joseph Hill:                   We all know that cardiovascular medicine and science are evolving at an unprecedented pace. The challenges we face are evolving and yet the opportunities and the tools and the resources at our disposal are unprecedented in their scope and vision. We're very pleased that Gary has provided strong leadership at NHLBI now for several years and has laid out in this perspective piece here where he thinks the next steps are specifically around this strategic vision that focuses on precision medicine and data science. I would love to hear Gary provide additional perspective on that vision.

Dr. Gary Gibbons:            Well, thank you, Joe. As the director of NHLBI, clearly we're public servants and we're accountable stewards of the nation's investment in heart, lung and blood and sleep disorders. This piece gave us an opportunity to outline some of the opportunities that lay ahead in a strategic visioning process. First, I should note that a key part of the legacy of the NHLBI is to make strategic investment with enduring principles in mind to really support investigator initiated discovery science as really the core foundational element of our research portfolio, as well as to maintain a balance portfolio to really expands to spectrum of basic translation clinical population and implementation science.

                                                In this piece, we particularly want to highlight our strategic visioning process in which we encourage the broad input of the NHLBI community that actually included over 4,000 participants in this process from every state in the country. Indeed, 42 countries around the world to provide the most compelling questions and critical challenges that the field faces around strategic goals of understanding normal human biology, reducing disease, accelerating translation and preparing a biomedical workforce and resources for the discovery science of the 21st century.

                                                Out of that strategic vision, we focus in on two elements that emerged that relate it to precision medicine and data science for this piece and really that was the central core of what we wanted to share with the Circulation readership about how these two areas we think are going to be transformative in the years ahead.

Dr. Carolyn Lam:               Dr. Gibbons, you know, when the term precision medicine is used, sometimes it's a bit fuzzy I think in the minds of a lot of people. Could you maybe give a few examples or perhaps a specific idea that comes to mind?

Dr. Gary Gibbons:            You're right. There's often a lot said about it than probably a bit of hype about it. In some ways you could see this as a legacy of cardiovascular medicine and science. It could be argued that the definition of cardiovascular risk factors that came out of the Framingham Heart Study many years ago was the first sort of forerunner of precision medicine. It helped us indeed define those individuals who are at the greatest risk of having a heart attack and that to this day has played a role in directing targeted preventive treatments of the highest risk individuals in order to prevent heart attacks. That has continued to evolve.

                                                I think what's new now is that we have, as Dr. Hill mentioned, new modalities of both imaging and analytics of computational science, as well as novel biomarkers and genetic markers that can help us be even more precise in that risk assessment. That's really I think the greater opportunity to further subcategorize patient populations to get the right drug to the right patient at the right time with a more strategic treatment approach.

Dr. Joseph Hill:                   Gary, that's very exciting. I think your vision is absolutely compelling. I like how you categorize the NHLBI as a catalyst for the future. I'd like to think that the Biomedical Journals, the AHA Portfolio of Journals and Circulation are also catalysts that will partner with NHLBI and other entities to chart the course for the future. That again the challenges that we face now are different than they were back in the era when Framingham first got started after World War II. The tools that we have are also evolving rapidly and certainly our perspective from Circulation is that we are stewards of helping chart that course, helping identify and bring forth the best science around the world. In many ways we look to you as a partner.

Dr. Gary Gibbons:            Oh, absolutely. The NHLBI really can't fulfill our mission of turning discovery science into the health of the nation and indeed around the world without a circle of partners and that certainly includes the platforms of disseminating new knowledge like Circulation, as well as partner organizations such as American Heart Association. We definitely appreciate the value that your organ brings to really enhancing our efforts to not only take discovery science, but make that knowledge available to practitioners and researchers and patients.

                                                I think a key part of the 21st century is how we not only can discover and generate new knowledge, but how we can facilitate that movement of data to knowledge and from knowledge to action that actually enhances the lives of patients in the real world context. Again I believe your journal plays an important role in helping to do that.

Dr. Carolyn Lam:               You both mentioned critical challenges that we're facing and will face. The Chinese for these challenges or crisis, the word is actually wéijī. Okay? Wéi is actually meaning danger, whereas jī is for jīhuey which is opportunity. In every challenge, there's always this new opportunity and I just really would like to ask what are the greatest challenge and perhaps the greatest opportunity?

Dr. Gary Gibbons:            I think the challenge that we probably face is the emerging epidemic of non-communicable diseases typically cardiovascular disease throughout the world. Not only in the most industrialized nations, but indeed mainly the developing nations. This will quickly surpass communicable infectious diseases as the major burden and causes of mortality worldwide. We're dealing with a global challenge. Increasingly, we recognize that scientific discovery and analysis is often siloed in various packets. Our vision for the future is really to promote the creation of a global reach of what we're calling a Data Commons. That is that a disease has no borders. Science should not be limited to national states.

                                                It is part of the commonwealth if you will of information and knowledge that really should transcend national borders. We say this is a global community of data and information and knowledge exchange and collaboration. As part of this global community, it's that we think this diverse and inclusive approach will be critical to the best minds and best practitioners of the world learning from each other and contributing to this commonwealth of knowledge. We're excited because the opportunity on the other side of that challenge is that it's an unprecedented capability of power to communicate now. We I think are communicating with you from Singapore and we're in a digital age in which this notion of communication and knowledge exchange should be more fast than it's ever been before.

                                                Indeed, we can create computer platforms that are similar to what exist for a Facebook or a Google that are global in scope. The vision is really to say what would happen if we could turn that toward biomedicine and make biomedicine part of this data science such that we have global contributions to our understanding, knowledge exchange and really create that sort of global sandbox if you will of knowledge exchange and discovery. That's part of this notion of creating a Data Commons and really advancing data science as an element of a strategic vision.

As we move forward with precision medicine and data science, our most sacrosanct stewardship is for the next generations. A critical element is to ensure that we're providing them with the tools and training to really lead the charge of advancing these exciting areas of science and that indeed will be a global enterprise.

Dr. Joseph Hill:                   That's very exciting, Gary. I take my hat off to you for the leadership that you have maintained at the NHLBI during these times that are once very challenging and at the same time exhilarating. I look forward to working with you through our journal and partnering with you to bring to fruition much of what you had laid out in your vision.

Dr. Gary Gibbons:            Thank you, Joe. We look forward to our ongoing partnership.

Dr. Carolyn Lam:               Thank you, listeners, for joining us today. Do join us again next week.

Aug 7, 2017

Carolyn:               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.

                                Later on in this podcast, we will be meeting Dr. Nancy Schweitzer, Editor-in-Chief of the new Circulation Heart Failure. We will be discussing today's feature paper on acute myocarditis as well as hearing about her visions for the journal. All that coming right up after these summaries.

                                The first original paper this week suggests that day-to-day blood pressure variability may be a significant risk factor for dementia. First author Dr. Oishi, corresponding author Dr. Ohara, and colleagues of Kyushu University from Fukuoka, Japan, studied a total of 1,674 community-dwelling Japanese elderly without dementia, who were followed up for five years, and had home blood pressure measured three times every morning for a median of 28 days.

                                They found that the age and sex adjusted incidences of all-cause dementia, vascular dementia, and Alzheimer's disease increased significantly with increasing day-to-day variability of home systolic blood pressure. These associations remained unchanged after adjusting for potential confounding factors, including average home systolic blood pressure. The study, therefore, suggests that the measurement of day-to-day blood pressure variability, using home blood pressure monitoring, may be a useful way to assess future risk of dementia, irrespective of dementia subtype.

                                The next paper is one of the first studies to directly target a gene within the fibroblast of a mammalian heart and show a direct role in regulating cardiac fibrosis. Co-corresponding authors Dr. Molkentin from Howard Hughes Medical Center and Cincinnati Children's Hospital Medical Center and Dr. Davis from University of Washington and colleagues performed an elegant series of mouse experiments to show that the gene-encoding p38 alpha mitogen-activated protein kinase was required to mediate fibroblast activation in the mouse heart following injury.

                                They also showed that forced activation of p38 within fibroblasts, using a transgenic approach, was sufficient to drive fibrosis in multiple tissues of the mouse, including the heart.

                                In totality, their findings indicated that p38 mitogen-activated protein kinase was a nodal signaling effector within the cardiac fibroblast that drove both wound healing and long term fibrosis in heart failure. In other words, it appears to play a crucial role in the control of both physiological and pathological processes. The clinical implications are that pharmacologic inhibition of p38 mitogen-activated protein kinase in heart failure could reduce progressive fibrosis. However, the same inhibition during acute myocardial infarction injury may inhibit wound healing and be detrimental. These issues are discussed in an accompanying editorial by doctors, Stratton, Koch and McKinsey.

                                Receptors, well known for their roles in angiogenesis and cancer, may play a role in atherosclerosis, as shown in the next paper, which looked at the Eph-family of receptor tyrosine kinases. These are the largest family in the mammalian genome, which interact with ephrin ligands on adjacent cells to mediate cell adhesion repulsion signaling.

                                First author, Dr. Finney, corresponding author, Dr. Orr, from LSU Health Sciences Center, Shreveport, and colleagues assessed the role of EPHA2 in atherosclerosis by deleting the EPHA2 in a mouse model of atherosclerosis and by assessing EPHA2 function in multiple vascular cell culture models.

                                The authors identified a novel role for EPHA2 in atherosclerosis by regulating both plaque inflammation and progression to advance atherosclerotic lesions. Cell culture studies suggested that endothelial EPHA2 contributed to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas, smooth muscle EPHA2 expression regulated the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition.

                                The clinical implications are that blunting EPHA2 ligation may selectively reduce plaque-associated inflammation. Since the effect of EPHA2 on smooth muscle proliferation appears to be largely ligand independent, unlike its effect on inflammation, the blunting of EPHA2 ligation may limit inflammation while leaving smooth muscle fibroproliferative remodeling intact.

                                Well, that wraps it up for our summaries. Now, let's go to our feature discussion.

                                Our feature paper today may cause us to think a little bit differently about fulminant versus non-fulminant acute myocarditis because the findings are actually in contrast with previous studies and are extremely insightful.

                                And, to discuss this, I am so pleased to have the corresponding author, Dr. Enrico Ammirati from Niguarda Hospital in Milan, Italy, as well as Dr. Nancy Sweitzer, Associate Editor of Circulation from University of Arizona, who managed this paper. But importantly, also, the Editor In Chief of Circulation Heart Failure. Welcome, Enrico and Nancy.

Enrico:                  Hello.

Nancy:                  Thank you, Carolyn.

Carolyn:               Enrico, could I ask you to start by clarifying the conditions that we're talking about here? When we say acute myocarditis or fulminant myocarditis, and non-fulminant myocarditis, what exactly are we referring to?

Enrico:                  We refer to an acute condition and fulminant myocarditis is a myocarditis inflammation of the myocardium that's a media anatomic or mechanical support due to an anatomic instability, while non-fulminant myocarditis it's a condition where the patient remains hemodynamically stable. Previous records have suggested that despite their dramatic presentation of patient with a fulminant myocarditis might have better outcome than those with acute fulminant myocarditis.

                                Now in this study we have over 55 patients with fulminant myocarditis and in particular, 34 patients with fulminant myocarditis with viral genomes within two weeks from the onset of symptoms, whereas in the previous record, in particular from [inaudible 00:07:38] we have shown in 15 occasions of fulminant myocarditis, that fulminant myocarditis as quite a good prognosis.

                                But what we believe it is that gives disparity between our results that connected all acute patients admitted to the emergency department with [inaudible 00:08:01] and symptoms onset within one month to two weeks before. Is the main difference comparing [inaudible 00:08:11] this study [inaudible 00:08:13] patient with onset of symptoms since one year before the onset of symptoms. And we believe that we enroll acute patients.

                                Whereas in the other study, there was sort of selection by us. It was true that in those previous studies, they have all just patients who we were endomyocardia biopsied performed whereas in our study we did not perform endomyocardia biopsies in that case. But we feel that we have a snapshot of the acute stage of a fulminant myocarditis, so we connected all the patients, whereas in previous study, maybe some of the patients they had acute symptoms died before evaluation from the other researchers.

Carolyn:               Indeed, it makes a lot of sense that there may be some survival bias involved. For example, if the sickest patient didn't get a biopsy, for example.

                                Nancy, when you were managing this paper, what were the kind of the discussions that occurred at the editorial discussions?

Nancy:                  I think that Dr. Ammirati pointed it out really well. The editors felt that this was a very important paper because it really looked inclusively at myocarditis in the modern era, and showed us where perhaps bias in prior studies had led us astray in terms of our beliefs about, particularly the outcomes in this syndrome. Not only the outcomes in the fulminant patients, who have a very profound and important early mortality risk, but also the outcomes in the non-fulminant patients, who in this study, really do extremely well and do not progress to LV dysfunction, which has been a long-held belief, I think. So understanding much better the full spectrum of myocarditis was made much easier because of the comprehensive look Dr. Ammirati and his colleagues took.

Carolyn:               Enrico, I do congratulate you on a beautiful paper. As I said, as a heart failure cardiologist myself, it has changed my thinking. Could you maybe share just a bit more details of what your study found and how this is important clinically?

Enrico:                  What we have found it is that hospital deaths or heart transplantation was about 25 percent in fulminant myocarditis compared to ten percent in non-fulminant myocarditis and despite greater improvement in the left ventricle injection fraction [inaudible 00:10:56] in fulminant myocarditis compared to non-fulminant forms. The proportion of patients with the left ventricle injection fraction below 55% [inaudible 00:11:09] was higher in fulminant myocarditis comparing it to non-fulminant myocarditis. So we have to pay great attention to do this form of myocarditis not thinking that this is a condition that can simply recover with time but we have to aggressively manage this condition, and we have to see about trials designed [inaudible 00:11:39] in this specific setting to improve the [inaudible 00:11:50] outcome and to reduce myocardial injury during the acute phase.

Carolyn:               True. And Nancy, I mean you see tons of these patients too. How has this impacted you?

Nancy:                  It's interesting, it definitely has impacted me. I like everyone, taught and taught on my teaching rounds for many years that the fulminant patients we were seeing, despite how ill they were, would have better outcomes than those who were non-fulminant. And also, many patients who present with dilated cardiomyopathy who are non-ischemic are told after searching for some viral illness in the year prior to their presentation that probably they had a virus attack the heart or an inflammation of the heart. I've stopped saying those things, and I continue to see review of papers that I'm handling about myocarditis refer to these misconceptions. So I think this is going to be a really important paper, and clarifying our understanding of how this disease evolves over time.

Enrico:                  I fully agree, I fully agree with this message, and [inaudible 00:12:54] but I believe that the traditions that are involved in [inaudible 00:13:00] maybe can be misleading for other cardiologists.

Carolyn:               Nancy, I'm gonna switch tracks a little bit, I mean your explanation of that already gets me so excited about the kinds of papers that are gonna get to be seen at the new Circulation Heart Failure under your leadership. So could you just tell us a little bit more about your vision as editor-in-chief.

Nancy:                  Well Carolyn, Circulation Heart Failure is an excellent journal Dr. [inaudible 00:13:33] has stewarded it beautifully in its first decade of life. In many ways I don't want to change the journal, I want the very best science that's helping us have a deeper understanding of the disease processes and therapies that affect our patients. That said, I would say we have a couple new initiatives, or sort of slight differences in how we're going to manage the journal going forward. I must say, the content we get is spectacular, and we're so fortunate to be able to look through the papers we get, and try to choose the very best science. It's an amazing privilege for me and the new team.

                                We're really interested in young investigators and those people who are starting out in their career. The emerging scientists who are producing the best heart failure science. Early in your career you might not have the weight of data behind you to merit publication and circulation proper, but we hope that with good science well thought out excellent hypotheses, Circulation Heart Failure will be an appropriate target for those emerging investigators.

                                We found some great pleasure in approaching young scientists at meetings, and discussing their work, and asking them to send it to our journal. And that's been great fun and we've seen wonderful yield from that. We've been getting submissions from people we've spoken to whose work we admire, and we really hope to build that part of the journal up. Hand in hand with that is an effort at building our social media presence. We're an entirely online journal. We're very interested in visually appealing content. We do have an images in case report section. And we're going to work to try to build an online community for our young investigators who may not have the money to travel internationally, but who really needed global community of heart failure research colleagues, and we hope to be a place to build that.

                                And finally, we're interested in some areas that maybe, are emerging or underrepresented in other journals. Areas like ... the way technology is transforming heart failure mechanical circulatory support devices, wearable devices, the other technologies we're using increasingly in our patients. And the world of pulmonary hypertension, and right ventricular dysfunction, which is sort of searching for a journal home, and we hope that we can be that journal home. And of course representing the full spectrum of therapies for heart failures including transplantation. I already mentioned mechanical circulatory support, you know, all the richness that is the evolving field of heart failure, and how we ... I think as professionals in that field think about and treat our patients a little differently than other people caring for heart failure.

Carolyn:               Listeners, you just heard it right here, on Circulation on the Run.

                                Thank you so much for joining us this week. Tune in again next week for even more exciting news.

Jul 31, 2017

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

                                                Our feature paper this week provides important mechanistic insights into oxidative stress and inflammation with aging. More of that soon right after the summary of this week's journal.

                                                The first paper contributes to our understanding of the genetic and functional relevance of soluble guanylyl cyclase activity for coronary artery disease. As background, a chromosomal locus at 4q32.1 has been associated with coronary artery disease risk with genome wide significance. The locus encompasses GUCY1A3, which encodes the alpha one subunit of the soluble guanylyl cyclase, a key enzyme of the nitric oxide cyclic GMP signaling pathway.

                                                In today's study from co-corresponding authors Dr. Kessler, and Dr. Schunkert from Munich, Germany and colleagues the authors showed that the GUCY1A3 locus has regulatory properties with the risk allele leading to reduced expression of GUCY1A3. The lead snip modulated finding of the transcription factor ZEB1 resulting in reduced expression of GUCY1A3 in carriers of the risk allele. As a consequence risk allele carriers demonstrated impaired inhibition of vascular smooth muscle cell migration and platelet aggregation after stimulation of the soluble guanylyl cyclase.

                                                In summary, this study suggest that modulating soluble guanylyl cyclase activity or inhibiting the effects of reduced expression of GUCY1A3 may be promising therapeutic strategies for individuals with the high risk alleles of GUCY1A3.

                                                The next paper reports the outcome associations between adding a radial arterial graft to single and bilateral internal thoracic artery grafts in the arterial revascularization trial or ART. As a reminder, ART was designed to compare survival after bilateral internal thoracic artery over single left internal thoracic artery bypass with about 20% also receiving a radial artery graft instead of a saphenous vein graft.

                                                In the current paper, first author Dr. Taggert from University of Oxford and corresponding author Dr. Benedetto from University of Bristol in the United Kingdom and colleagues showed that the primary endpoint of ART which was a composite of myocardial infarction, cardiovascular death and repeat revascularization at five years was significantly lower in the radial artery group when compared to the saphenous vein graft group. This association was present when the radial artery graft was used to supplement both the single internal thoracic artery as well as the bilateral internal thoracic artery grafts.

                                                In summary this post-hoc ART analysis showed that an additional radial artery was associated with lower risk for mid-term major adverse cardiac events when used to supplement single or bilateral internal thoracic artery grafts.

                                                The next study addresses the questions of whether intensive blood pressure lowering beyond usual targets recommended by guidelines would lead to more lowering of left ventricular hypertrophy in patients with hypertension and whether reducing the risk of left ventricular hypertrophy explains the reported cardiovascular benefits of intensive blood pressure lowering.

                                                To answer this question Dr. Soliman from Wake Forest School of Medicine in North Carolina and colleagues studied the 8,164 participants with hypertension but no diabetes from the Systolic Blood Pressure Intervention or SPRINT Trial. They showed that among SPRINT participants without baseline left ventricular hypertrophy, intensive blood pressure lowering was associated with a 46% lower risk of developing left ventricular hypertrophy compared to standard therapy. Similarly, among SPRINT participants with baseline left ventricular hypertrophy blood pressure lowering intensively was associated with a 66% greater likelihood for regression or improvement of their left ventricular hypertrophy. Furthermore, adjusting for left ventricular hypertrophy as a time-varying covariate did not substantially attenuate the effect of intensive blood pressure therapy on cardiovascular disease events.

                                                In summary these findings add further evidence of the benefits of the intensive blood pressure lowering in patients with hypertension and suggest that these benefits go beyond reducing the hemodynamic stress on the cardiac structure. Further research is needed to understand the mediating factors and mechanisms by which intensive blood pressure lowering impacts the cardiovascular system.

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

                                                We are going to talking about aging, oxidative stress and inflammation today and really taking a deep dive into potential mechanisms. I am so pleased to be here with the corresponding author of our feature paper in this week's issue. And that is Dr. Mustapha Rouis from INSERM University Paris six in France as well associate editor from University of Rochester Dr. Charlie Lowenstein.

                                                Welcome gentlemen.

Dr. Charlie Lowenstein: Thank you for having us.

Dr. Mustapha Rouis:       Thank you very much.

Dr. Carolyn Lam:               Mustapha, what inspired you to actually look at the Thioredoxin system in looking at this aging question? What were your hypotheses?

Dr. Mustapha Rouis:       Actually our laboratories working on cardiovascular diseases for several years. We have been trying to understand why oxidative stress and inflammation increase with age despite the presence of a variety of antioxidant proteins in the body. So among the antioxidant proteins the Thioredoxin-1, isoform one which is a small ubiquitous incytocylic protein called our attention because it's a multi functional protein. It can exert an antioxidant role, anti-inflammatory and anti-apositic role. So therefore we wanted to know whether the increase in the oxidative stress and inflammation with age is it due or at least in part to a deficiency of Thioredoxin-1. If so is there increases due to a decrease in protein synthesis or to increase in its degradation.

                                                For this purpose we have constituted a cohort of young and old subject, male and female. They want to focus on this particular point because this is very important point it has not been easy to achieve and we took a lot of time to sort and to keep only subject meeting our criteria. Those who we wanted to enroll consisting of people free from any history of diseases such as cardiovascular diseases, diabetes, obesity, inflammation, any kind of inflammation, cancer et cetera. In addition we wanted subject without any risk factor for cardiovascular disease except of course the age. No smoking, no hyperlipidemia and no taking any medication.

                                                This really very hard to achieve. Then once we have enough subject we evaluate the Thioredoxin-1 using commercially available very specific kit, ELISA kit and showed that the plasma level of Thioredoxin-1 decreased significantly with age. Since it has been described for several years that Thioredoxin-1 can be cleaved at the C terminal level, the cleavage has been described to be occur after lysine at position eight. This will generate a truncated called Thioredoxin-80. We measured the plasma concentration of Thioredoxin-80 in this sample, in this same sample of the selected subject using an ELISA method developed in our laboratory because there is no commercially kit for Thioredoxin-80.

                                                The result showed that Thioredoxin-80 increased with age therefore the decrease in the plasma concentration of the full length Thioredoxin-1 observed in the old, in the elderly is probably due to an increase in its cleavage and not to a decrease in its synthesis. Of note we observed an increase of the expression and activity of two alpha secretases ADAM-10 and ADAM-17 two enzyme responsible for the cleavage process in the peripheral blood mononuclear cells of the old subject. Our results consolidate our interpretation.

Dr. Carolyn Lam:               Wow, what a beautiful set of studies that included human samples and then also included some very elegant mouse experiments. I remember the excitement among the editors when we discussed this paper. Charlie could you just share a little bit of what went on when we looked at this?

Dr. Charlie Lowenstein: First I'd like to put this study into context which is that oxidants increase during aging and it's been known for a long time that animals that have high metabolic rates have short life spans and one of the things that goes along with high metabolic rate is a lot of radical production. And since the 1950's there's been this theory, the free radical theory of aging that radicals damage cells. And so the question is, are radicals bad? What do they do in aging? And what defenses do we have against them? So that's one of the contexts of this article.

                                                Secondly we also know that oxidants are associated with diseases. Increased oxidants during cancer, during inflammatory diseases and during atherosclerosis so that's why this study is important. It's important for two reasons. First of all there's a theory that as you age there's more radicals and radicals might actually cause part of the problem in aging. Secondly radicals are also associated with inflammatory diseases like atherosclerosis.

                                                When the editors got this article, it was very exciting for several reasons. First of all, the short form of Thioredoxin, TRX-80 might explain why older people have more oxidative stress. Secondly this short form TRX, TRX-80 might be a new bio-marker for aging. And thirdly, the short form of Thioredoxin might help us monitor different antioxidant therapies when people have too many radicals. So for a number of important clinical reasons our editors were very excited when we received this important manuscript.

Dr. Carolyn Lam:               Mustapha, what are your next steps when it comes to this?

Dr. Mustapha Rouis:       Well several studies have shown that Thioredoxin-1 can reduce inflammation and can protect the body against several pathologies which has an increased interest in its use for therapeutic purpose. However its cleavage in the generation of the Thioredoxin-80, limited research work in this direction so I just remember you that the Thioredoxin-80, the truncated form in contrast to the full length Thioredoxin-1 exerts a pro-oxidant, pro-inflammatory angiogenic and carcinogenic effect. So nevertheless in order to counter these difficulties we plan to synthesize some Thioredoxin limited peptides such as catalytic site containing peptides and these peptide used it in therapy could show significant biologic activity. This peptide could lose constitute maybe an alternative to the full length Thioredoxin.

Dr. Carolyn Lam:               Wow, that is exciting. Charlie, what do think is the take home message for clinicians listening to this?

Dr. Charlie Lowenstein: Scientists and clinicians all agree that an excess of radicals is bad. But there's an antioxidant paradox which is when patients take antioxidants like vitamin E, those antioxidants don't help. In a large clinical trial suggesting that vitamin E and other antioxidants don't help. So the question is, maybe antioxidant therapy helps some patients but doesn't help others. One of the interesting aspects of this study that maybe the presence or absence of TRX-80 might determine whether antioxidant therapies will help. Furthermore, maybe TRX-80 levels might be able to guide patients as to whether or not they should take antioxidant therapy. There are many important aspects of this study that point toward future studies.

Dr. Mustapha Rouis:       We thought about inhibiting the ADAM-10, ADAM-17 alpha secretase enzyme to prevent the cleavage process and I know that many drug companies are trying to find the specific inhibitors but the problem is these two enzyme are benefit in brain for enzymatic disease. So waiting to have a specific inhibitor for this enzyme that do not cross the hematoencephalic barrier to use it in humans but until that we may be the use or conceive the peptides it's better approach.

Dr. Carolyn Lam:               I'm just loving this discussion because it's really bringing out a lot more to this paper than I realized as a clinician. Charlie could you end by just saying a few words about how we look at basic science papers in Circulation and the importance of the clinical translation element that we keep saying is our primary focus.

Dr. Charlie Lowenstein: Circulation is a great journal that covers important clinical topics. There's a lot of basic science that underlies some of these clinical topics so whenever we get a paper that gives us insight into a disease or reveals a new therapy and it's at the basic level we look very carefully at it. We want to know, will it help our readers understand something about the clinical process, clinical disease, diagnostics [inaudible 00:16:00] So when we get a paper we look at it very carefully and emphasize it has to be a basic paper that reveals a mechanism that's important to clinicians. That clinicians can understand and appreciate and gain insight about what's going on with their patients. I'm both a clinician and a scientist, I am charged with trying to figure out what basic concepts are relevant to our clinical audience.

Dr. Carolyn Lam:               Thank you Mustapha, thank you Charlie and thank you listeners for tuning in this week. Don't forget to tune in again next week.

 

Jul 24, 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 Center and Duke National University of Singapore. Our journal this week features an in-depth review on transcatheter therapy for mitral regurgitation, a very, very hot and interesting topic. You have to listen on, coming up right after these summaries.

                                                Our first original paper this week sheds light on the influence of aging on aldosterone secretion and physiology. First author Dr. Nanba, corresponding author Dr. Rainey and colleagues from the University of Michigan in United States, examine the relationship between age and adrenal aldosterone synthase in 127 normal adrenals from deceased kidney donors. The donors' ages ranged from nine months to 68 years. The authors found that adrenals from older individuals displayed less normal aldosterone synthase expression and zona glomerulosa, and greater content of abnormal foci of aldosterone synthase expressing cells.

                                                Furthermore, older age was independently associated with dysregulated and autonomous aldosterone physiology, in an ancillary clinical study of subjects without primary aldosteronism. This study therefore suggests that aging may be associated with a sub-clinical form of aldosterone excess and provides at least one potential explanation for age related cardiovascular risk.

                                                The next study shows, for the first time, that the chemokine receptor, CXCR4, in vascular cells, limits atherosclerosis. The CXCL12 and CXCR4 chemokine ligand receptor axis is known to control cell homeostasis and trafficking. However, its specific in atheroprotection has thus far been unclear. This is addressed in today's study by first author Dr. During, corresponding author Dr. Weber, and colleagues of The Institute for Cardiovascular Prevention in Munich, Germany. In hyperlipidemic mice, the authors showed that cell-specific deletion of CXCR4 in arterial endothelial cells, or smooth muscle cells, marked the increase atherosclerotic lesion formation. Mechanistically, CXCR4 axis promoted endothelial barrier function through VE-cadherin expression and a stabilization of junctional VE-cadherin complexes. In arterial smooth muscle cells, CXCR4 sustained vascular reactivity responses, and a contractile smooth muscle cell phenotype. Whereas, CXCR4 deficiency favored the occurrence of macrophage-like smooth muscle cells in atherosclerotic plaques and impaired cholesterol efflux.

                                                Finally, in humans, the authors identified a common allele variant within the CXCR4 locus that was associated with reduced CXCR4 expression in carotid RG plaques, and increased risk for coronary heart disease. Thus, the study suggests that enhancing the atheroprotective effect of arterial CXCR4 by selective modulators may open normal therapeutic options in atherosclerosis.

                                                The next paper is the first to study the effects of rosuvastatin on carotid intima-media thickness in children, with heterozygous familial hypercholesterolemia. First author Dr. Braamskamp, corresponding author Dr. Hutten, and colleagues from Academic Medical Center Amsterdam in the Netherlands, study children with heterozygous familial hypercholesterolemia aged 6 to less than 18 years, with LDL cholesterol more than 4.9, or more than 4.1 millimoles per liter in combination with other risk factors, who received rosuvastatin for 2 years, starting at 5 milligrams once daily, with uptitration to 10 milligrams for children aged 6 to 10 years old, or 20 milligrams daily for those aged 10 to 18 years old.

                                                Carotid intima-media thickness was assessed by ultrasonography at baseline, 12 months and 24 months in all patients and in age-matched, unaffected siblings. Carotid intima-media thickness was measured at 3 locations, the common carotid artery, the carotid ball, and the internal carotid artery in both the left and right carotid arteries. At baseline, the mean carotid intima-media thickness was significantly greater for the 197 children with heterozygous familial hypercholesterolemia compared with the 65 unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid intima-media thickness in children with heterozygous familial hypercholesterolemia than in the untreated, or unaffected siblings. As a result, there was no difference in carotid intima-media thickness between the two groups after two years of rosuvastatin. These findings, therefore, support the value of early initiation of statin treatment for LDL cholesterol reduction in children with heterozygous familial hypercholesterolemia.

                                                The final study highlights the therapeutic potential of a novel alpha calcitonin gene-related peptide for the treatment of heart failure. First author Dr. Aubdool, corresponding author Dr. Brain, and colleagues from King's College London in United Kingdom, tested the stable alpha analog of calcitonin gene-related peptide in 2 models ... First, an angiotensin 2 infused mouse, and secondly, pressure overload cardiac hypertrophy mouse model using suprarenal aortic ligation. They showed that systemic colon injection of the alpha analog blunted the angiotensin 2 induced rise in blood pressure, as well as the vascular and cardiac remodeling, changes in water consumption, and renal injury, that are normally associated with angiotensin 2 infusion. Furthermore, protective effects were also seen when starting the alpha analog treatment, only during the last week of the 2-week angiotensin 2 infusion, in other words, when hypertension was already established. Finally, the alpha analog preserved heart function, and diminished the degree of hypertrophy and fibrosis in the aortic ligation model.

                                                Thus, these results demonstrate the therapeutic potential of the alpha calcitonin gene-related peptide pathway, and the possibility that this injectable alpha analog may be effective in cardiac disease.

                                                Well, that wraps it up for this week's summaries! Now, for our featured discussion.

                                                For our feature discussion this week, we're talking about trans-catheter therapy for mitral regurgitation, a very hot field and a field in which there have been a lot of advances. To help us break it down, and get right into the insights, the challenges, and potential solutions, I am so pleased to have the first author of this in-depth review paper, Dr. Paul Sorajja from Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital, as well as Dr. Manos Brilakis, associate editor from UT Southwestern, here with us today!

                                                Paul, could I start with you, and just ask you first to give us an idea of what we're talking about here when we talk about mitral regurgitation ... There are different kinds, which are we referring to, and what are the challenges involved in a trans-catheter therapy for mitral regurgitation?

Dr. Paul Sorajja:                I think there are a number of challenges, I think the first thing is that MR is often thought of as one disease, but it's really an incredibly heterogeneous disease ... Broadly, we talk about primary versus secondary MR, but the mitral valve is so complex, with multiple different components, any one of which can disrupt and cause MR. When we're talking about trans-catheter therapy, it's often very easy, again, to think we could have one therapy that could treat a simply insufficient valve, but it's way more complex than that, and as a result, there have been many different approaches that have been developed, adding to the complexity of how we manage these patients.

Dr. Carolyn Lam:               Right, and in your paper, I loved the way you grouped them, very logically, under those from mitral valve repair, and that for mitral valve replacement ... And then, under repair, you grouped it into leaflet versus targeting the LV ... Could you maybe give us some top-line insights on these techniques?

Dr. Paul Sorajja:                Yeah, there are a number of different approaches that have mechanistically gone after the different components through the pathophysiology of MR, where there is leaflets, where there's analysts, cords, or ventricular approach ... I think it's somewhat simplistic to think of it that way, but as catheter-based technology, we are technically limited by what we can do from a catheter standpoint. I think it's inevitable to think about these catheter technologies as eventually being combined, rather than singular, in order to approach what surgeons do in the OR.

Dr. Carolyn Lam:               Right, but then even going further, you spent quite a bit of the paper talking about trans-catheter mitral valve implantation ... So, replacing the mitral valve, that's really cool, could you tell us a bit about that, and about that important issue brought up about patient selection.

Dr. Paul Sorajja:                Yes, it's a very good point, I think in terms of trans-catheter mitral replacement, I think that that's really where the future is going to go ... The simple analogy is that people think that it will follow the route of TAVR, but I think it will follow the route of TAVR more quickly so, because when you look at how the mitral valve is currently treated in the OR, sometimes, a lot of the times, patients can end up worse. Whereas, a trans-catheter solution actually, I think in terms of the safety margin, actually will equate a degree of safety relative to surgery, if it's done and developed correctly, as opposed to how TAVR's done. I think for TAVR, it's been a number of years for our field to be equivalent or superior to surgery, whereas I think with mitral, I think there's a lot of potential for mitral to have equated a degree of safety. As an example, in the Tendine Feasibility Study, it was published this past January ... A high-risk population, there was not a single procedure death, out of 30 patients ... And for these patients who would go to the OR with an eject fraction of 30 to 40 percent, I think that's quite remarkable.

Dr. Carolyn Lam:               Wow, that's really exciting indeed! Manos, you handled this paper, and it's just so beautifully laid out ... That flow chart, I just want to refer all our listeners to the flow chart in Figure 7, that talks about maybe an approach that can be considered. Manos, could you share some thoughts on how this developed?

Dr. Manos Brilakis:           Yeah, absolutely, and obviously Paul is the expert on this, but I think it's very important about this paper, and through discussions with Paul and through the development of the paper, is that there's more of a collaboration between the surgeons and the interventionists. So instead, if it's additional style of ... Or the interventionists are doing one thing and the surgeon is doing another, I think the key to success in the mitral field is working very closely together ... Many of those valves right now, the percutaneous valves, are done through a cut down and a typical approach, so working very closely to addressing the anatomic components of the mitral valve problem is a big plus.

                                                The other thing I think that is very important is the new emergence of imaging, trying to understand whether the new mitral valve is going to create issues with LVOT obstruction or not. I think that's leading to a whole new understanding of when and how patients are even candidates for this approach, and I think Paul can elaborate more on this, but as things evolve, fewer and fewer patients are going to be excluded from these new technologies.

Dr. Carolyn Lam:               Paul, would you like to take that? What do you think is happening and will happen with patient selection?

Dr. Paul Sorajja:                There has been a challenge in current feasibility studies, in terms of getting patients in, the anatomical restraints are exactly what Dr. Brilakis has outlined. There's a certain bulkiness and size to the valve, which essentially poses risk for LVOT obstruction if the valve is too big ... As a feasibility study that's still early, or a field that's still early in its development, there's been a really conservative approach in terms of patient selection to ensure that LVOT obstruction doesn't happen. I think we're pushing the boundaries for that, and I think we've learned a lot from CT imaging, in terms of predicting LVOT obstruction, and I think the valves are also getting to be shorter in profile, which makes it less likely ... But that is definitely one of the limitations, and it's a limitation that exists, not just for trans-cat therapy but also for surgical therapy.

Dr. Carolyn Lam:               Right, and then maybe a question for both of you ... What do you think the future is going to hold? What do we need to make this more mainstream, and where do you think this will leave surgical approaches? I know you said a combined approach, but maybe you could elaborate a little bit more?

Dr. Paul Sorajja:                I do think, and I agree, I think Manos' point is spot on about that ... This will have to be multidisciplinary, the surgeons and cardiologists absolutely need to continue to work together, that's what's led to the successful development of TAVR, and I think that will be even more so for mitral, because the mitral valve is just infinitely more complex, and we have a lot to learn from the surgeons. But I think going forward, the collaboration is going to be a requirement, and then the training is also going to be a significant portion ... Putting in a mitral valve is much more complex than putting in an aortic valve ... I think if there's a safety margin that's demonstrated, I still think that it will be more appealing and more rapidly adopted than aortic disease.

Dr. Carolyn Lam:               Well, Manos?

Dr. Manos Brilakis:           No, I completely agree with Paul on that respect. I think, in my mind, at least, an again, this is from an early standpoint, the next big step would be to make it completely percutaneous, right now, you still have to do the cut down, and it's a little more invasive, although still safer than the completely open surgery, but maybe having a complete percutaneous system would be the next big step ... There's no question in my mind, as well ... And watching very closely how Paul and the surgical team are handling this, I think this is definitely the way for the future. Sometimes, in TAVR, it's not as technically demanding, and you don't really need to have too many people in the room, but for this procedure, it's definitely more important to have everyone in the room, and benefit from everyone's expertise.

Dr. Carolyn Lam:               Manos, could I switch tracks for a moment now, and ask you to comment on the question that I get a lot ... You're an Interventionist, you handle a lot of the interventional papers for Circulation, and a lot of people are wondering, what makes papers like Paul's ... What makes interventional papers something that we would want to publish in Circulation? Could you share some thoughts?

Dr. Manos Brilakis:           Absolutely, thanks Carolyn ... That's a big part, I think, of the appeal of Circulation right now. We're really trying to communicate to people that cutting-edge, clinical science is actually at the heart and the core of Circulation, and clinical content is what drives a lot of editorial ... Especially in intervention, where particularly interesting and new, cutting-edge technologies, new trials, observational studies ... But essentially, things that are cutting-edge, and are going to have a specific implication and impact in the way the field is going ... And this is part of Dr. Sorajja's paper, showing where the future lies in terms of trans-catheter mitral technologies, but along the same lines, we love to have cutting-edge papers on various aspects ... Coronary, peripheral, all aspects of interventional cardiologies, as well as interventional imaging ... The goal, again is to make the submission easy, there are not many honors requirements for submitting the papers, it's very simple to submit, and there's an answer going out very quick, so we're looking forward to receiving more and more interventional papers on cutting-edge science.

Dr. Carolyn Lam:               Thank you so much for joining us today, and don't forget to tune in again next week.

 

Jul 17, 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 Center and Duke-National University of Singapore.

                                                Now, the SGLT2 inhibitor, empagliflozin, has been shown to improve outcomes in the EMPA-REG OUTCOMES trial. But do these benefits also apply in the real world, and to other SGLT2 inhibitors as a class? Well, we may just have some answers this week in the CVD-REAL study. More soon right after these summaries.

                                                The first original paper this week uncovers the mechanism of beneficial action of T-cells for proper healing after myocardial infarction. Now, the pro-inflammatory danger signal, adenosine triphosphate or ATP, is released from damaged cells, and degraded by the ectonucleotidase CD73 to the anti-inflammatory mediator, adenosine.

                                                Using newly-generated CD4-CD73 null mice, first author, Dr. Borg, corresponding author, Dr. Schrader, and colleagues from Heinrich Heine University of Düsseldorf in Germany, showed that a lack of CD73 on T-cells enhanced tissue fibrosis and worsened myocardial function in the remodeling phase after myocardial infarction.

                                                T-cells migrated into the injured heart and upregulated their enzymatic machinery to enhance the extracellular degradation of ATP to adenosine. T-cells lacking CD73 showed accelerated production of pro-inflammatory and profibrotic cytokines. Finally, the adenosine 2B receptor was upregulated on cardiac immune cells in the remodeling phase.

                                                In summary, therefore, local adenosine formation by CD73 on T-cells appears to be the body's own defense mechanism to control inflammation induced by myocardial infarction. This is a mechanism that might be exploited to promote healing or remodeling by specifically targeting the adenosine 2B receptor in the infarcted heart.

                                                The next paper provides insights on genetic determinants of susceptibility to peripheral artery disease, and specifically puts the spotlight on Bcl-2-associated athanogene-3, or Bag3, which is a cell chaperone protein previously identified in a genetic screen for determinants of tissue loss with hindlimb ischemia.

                                                In the current study, Dr. McClung from East Carolina University, Brody School of Medicine in Greenville, North Carolina, and colleagues, used adeno-associated viruses to show that an isoleucine to methionine variant at position 81 in Bag3 was sufficient to confer susceptibility to ischemic tissue necrosis in BALB/c mice.

                                                In a series of elegant experiments, they demonstrated that Bag3 was a modulator of ischemic muscle necrosis and blood flow. In summary, this study provides evidence that genetic variation in Bag3 plays an important role in the prevention of ischemic tissue necrosis, and highlights a pathway that preserves tissue survival and muscle function in the setting of ischemia.

                                                The next study provides insights into inflammatory atherogenesis by studying psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction. First author, Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI, National Institutes of Health in Bethesda, United States, and colleagues, hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of non-calcified plaques with high-risk features.

                                                To test this hypothesis, they compared total coronary plaque burden, non-calcified coronary plaque burden, and high-risk plaque prevalence between 105 psoriasis patients, 100 older hypolipidemic patients eligible for statin therapy, and 25 non-psoriasis healthy volunteers. All patients underwent CT coronary angiography, and a sample of the first 50 psoriasis patients were scanned again at one year following therapy.

                                                The authors found that patients with psoriasis had greater non-coronary burden and increased high-risk plaque prevalence compared to healthy volunteers. Furthermore, compared to older hypolipidemic patients, patients with psoriasis had elevated non-calcified burden, and equivalent high-risk plaque prevalence. Finally, improvement in skin disease severity was associated with an improvement in non-calcified coronary burden at one year.

                                                The clinical implications are that patients with psoriasis have similar coronary artery disease risk as hyperlipidemic patients one decade older, and these patients with psoriasis should be screened earlier for cardiovascular disease and educated about their elevated risks. Further investigations focus on the longitudinal impact of psoriasis treatment on high-risk plaque morphology, as well as on the extent of cardiovascular risk mitigation in randomized trials.

                                                Well, those were your summaries. Now for our feature discussion. Now, we've heard of the EMPA-REG OUTCOME trial, that prospective randomized, controlled trial, showing a substantial reduction in cardiovascular death and hospitalization for heart failure with the sodium-glucose cotransporter 2, or SGLT2 inhibitor, empagliflozin, and that's, remember, that was in patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

                                                Well, our paper today really extends our knowledge and tells us a bit more about the role of SGLT2 inhibitors in real-world clinical care. And I'm so please to have with us the first and corresponding author, Dr. Mikhail Kosiborod from Saint Luke's, Mid America Heart Institute, as well as Dr. Gabriel Steg, associate editor from Paris, France, joining us today. Hello, gentlemen.

Dr. Gabriel Steg:               Hello.

Dr. Mikhail Kosiborod:   Hi. Good morning, Carolyn.

Dr. Carolyn Lam:               Mikhail, I am going to say what I said to you at the ACC and at the ESC Heart Failure: Congratulations on CVD-REAL. Please tell us about CVD-REAL.

Dr. Mikhail Kosiborod:   Right, well, we know, as you just mentioned, that the EMPA-REG OUTCOME trial showed substantial reduction in cardiovascular death, and hospitalizations for heart failure in patients with type 2 diabetes and established cardiovascular disease. We were all very excited once that data got presented in September of 2015 in Stockholm, but there were several very important questions that weren't really addressed, and truly, could not be addressed, in EMPA-REG's trial.

                                                The first, actually, and probably the most important is, we all know that clinical trials, while we regard them as the gold standard of evidence, as we should, they do have their own set of limitations, the most important of which is that they examine a relatively small sliver of patients; and many patients we see in the clinic, in the hospital, don't look like patients in clinical trials. I think the most important questions we tried to address was, "Will this translate to real-world clinical practice?"

                                                The second was, as you recall, again, all patients on EMPA-REG had established cardiovascular disease, so we wanted to know whether the benefits associated with the use of SGLT2 inhibitors could potentially extend to lower-risk patients with type 2 diabetes without established cardiovascular disease, a much broader spectrum of patients.

                                                And finally, and also very importantly, I think, the third question was, "Is it an empagliflozin-specific effect or is it a class effect?" These are all the critical questions we tried to address in the CVD-REAL study.

Dr. Carolyn Lam:               Great. Could you give us the topline results, please?

Dr. Mikhail Kosiborod:   Right. So, just as a reminder, we collected data from well-established registries in six countries, so the United States and some five countries in Europe, Sweden, Norway, and Denmark, and also, the United Kingdom and Germany. And really, the inclusion/exclusion criteria for the study were quite broad, you just had to have type 2 diabetes and be newly started on either an SGLT2 inhibitor or any other glucose-lowering medications, which was the comparative group.

                                                And after we did the one-to-one propensity match to make sure, comparable samples, we ended up with about 154,000 patients, and each treatment group, over 300,000 patients overall. What we actually observed was a marked and highly significant reduction in the risk of hospitalization for heart failure that was associated with use of SGLT2 inhibitors versus other glucose-lowering drugs.

                                                In fact, the magnitude of reduction in risk that was associated with SGLT2 inhibitors, so that outcome was quite similar, about 39% relative risk reduction, quite similar to what we see in the EMPA-REG OUTCOME trial. But this, of course, was for the entire class of SGLT2 inhibitors, so patients in the study were treated primarily with canagliflozin and dapagliflozin, with a small proportion being treated with empagliflozin.

                                                We also saw dramatic and highly significant associated reduction in the risk of all-cause death with SGLT2 inhibitors versus other glucose-lowering drugs, about a 51% relative risk reduction, and the composite of those two outcomes, obviously, there was significant associated reduction in risk as well.

                                                So, again, the hazard ratio estimate that we saw for these outcomes were quite similar, and in some cases, almost identical to what we've seen in EMPA-REG, but for a patient population that was much broader, in fact, about 90% of patients, close to 90% of patients in our study did not have established, documented cardiovascular disease. And, of course, as I mentioned before, important implications to these findings, in my opinion.

Dr. Carolyn Lam:               Yeah, that is just remarkable. Gabriel, could you share some of the discussions that happened among the editors about this paper?

Dr. Gabriel Steg:               We were really excited by this paper. I think this is truly a landmark paper for a number of reasons. It's a very large, multinational study, but even more than the size, I think what's interesting here are a couple of key aspects. First of all is data on all-cause mortality, which is a highly reliable outcome when you look at many of the observational studies.

                                                Non-fatal outcomes can easily be skewed or biased in ascertainment or assessment, but this is relatively reliable. And here, we have a very large multinational cohort that finds benefits on death, heart failure, and their composite, which are remarkably consistent internally, consistent across countries, and consistent with the randomized trial data evidence from the EMPA-REG OUTCOME trial.

                                                So that is striking, and this is consistent across six countries using a very large sample size. But again, the size of the sample is not the most important thing, because in observational studies, you often have very large sample sizes, but if you have bias in your observational study, the bias is just replicated times the size of the study.

                                                The consistency here between the treatment effects across the various countries, the consistency with the efficacy assessed in randomized clinical trials is really a crux in the quality of the data and how believable the results are. Another key aspect that got us really excited is the fact that only a minute fraction of the data is related to use of empagliflozin.

                                                Most of the data was acquired using other SGLT2, and we still only have results now with empagliflozin, we don't have outcome trial data with the other agents. They are pending, but pending the availability of these trials, the fact that this large study sees a consistent benefit, in terms of heart failure and mortality, of the other agents in the class suggests that this is a class effect.

                                                And likewise, the fact that we're seeing these benefits in a population that is much, much broader than the population of EMPA-REG OUTCOMES is also very, very intriguing, and exciting, and makes us really want to see more data not only from the randomized trials that are upcoming, but also from this study.

                                                Because now, what we would like to see is, see the detailed cardiovascular outcomes in these cohorts, and I know that Mikhail and his colleagues are working very, very actively on preparing these analyses. I think this is going to be exciting. This is the first of a series of landmark papers from a model observational study.

                                                There are many issues with observational studies. This is almost as good as it can ever get, and I want to compliment Mikhail and the consortium that's with him, because this is a tremendous effort, across several countries, on achieving this. I think it's very exciting for our readership and for clinicians around the world.

Dr. Carolyn Lam:               I couldn't agree more, and I share your compliments for Mikhail. Perhaps, Mikhail, could you give us a sneak peek at the future and the ongoing work?

Dr. Mikhail Kosiborod:   We frequently think of, and I think perhaps mistakenly at times, think of clinical trials and observational real-world data as competing with one another. In many cases, they're really complementary, and I think if you really, kind of, think of interventions that we consider as those gold standards enshrined in clinical guidelines, or something we absolutely should be doing for our patients.

                                                Just to pick one example, statins for secondary prevention after a cardiovascular event, for example, there is data from both sources suggesting that these drugs are highly beneficial, right? So it is very important to have data from both sides, and I think, as Gabriel mentioned, I look at CVD-REAL as a model, in many ways, of how compelling the data from non-randomized, large, real-world observational studies can be when done well.

                                                In terms of a sneak peek for the future, there are many, many things going on. We are carefully examining the outcomes that we are reporting in circulation, including heart failure and all-cause mortality in various subgroups. We are, of course, as Gabriel mentioned, intently looking at other outcomes, including myocardial infarction, stroke, cardiovascular death, and a composite of major adverse cardiac events.

                                                We're also examining some of the diabetes, one could argue, maybe, diabetes-specific outcomes, such as hypoglycemia rates. We, of course, as cardiologists tend to concentrate on cardiovascular outcomes, but it's also important to remember that there are other important outcomes that could be associated benefits.

                                                So these medications may be associated with marked reduction of cardiovascular events, such as death and heart failure, but they may also reduce hypoglycemia rates and, of course, that's important from a quality-of-life standpoint for patients with diabetes, so some of that work is ongoing.

                                                And I would say, importantly, one of the other things that we're hoping to be able to do in the future is to go beyond cardiovascular outcomes, and perhaps blood glucose-specific outcomes, such as hypoglycemia, and start looking at events such as renal disease events, which I think are very important, of course. Interact quite a bit with, I suspect, in many ways, with some of the cardiovascular benefits that we're observing with those agents, both in the clinical trials and, now, in large observational studies.

                                                And that's just the beginning. I mean, I think it's fair to say that, as Gabriel mentioned, a huge amount of work went into putting this together, right? And we're actually not only expanding things from a standpoint of outcomes. We're also expanding things from a standpoint of countries that will be participating in CVD-REAL consortium.

                                                So we're actually planning to add at least two or three more countries from Europe, Middle East, and Asia in the coming months, and more so in the future. And of course, once you have a resource like this, there are additional questions that can be addressed, actually, both with SGLT2 inhibitors as a class, but also with other classes of type 2 diabetes medication. So that's, I think, as much of a sneak peek as I can give you right now. Just definitely promise you that there is a lot more coming.

                                                In addition to ADA, we're going to have abstracts being presented at ESC in August, and also the European Association for the Study of Diabetes meeting in Lisbon, in September, and there's going to be a lot more afterwards as well. So just stay tuned, I would say. This is definitely just the beginning. There's going to be a lot more coming.

Dr. Carolyn Lam:               You took the words right out of my mouth. Listeners, stay tuned, and don't forget to tune in next week as well.

 

Jul 10, 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 Center and Youth National University of Singapore. Coming right up, we will be discussing fascinating new data on the prevalence of subclinical coronary artery disease in masters endurance athletes but first, here's your summary of this week's journal. The first paper provides insight into ischemic cellular post conditioning. Now, we know that cardiosphere derived cell therapy has been utilized as a strategy to treat ischemic heart disease and reduce chronic scar burden when administered months after myocardial infarction. In the current study, by first author Dr. de Couto, corresponding authors Dr. Marban and Berman from Cedars-Sinai Heart Institute in Los Angeles, California, the authors used rat and pig models of myocardial infarction to show that exosomes, which are nanosize lipid bi-layer vesicles, actually mediate the cardio protective effects of cardiosphere derived cells when administered after reperfusion of myocardial infarction.

                                                They further show that treatment with either cardiosphere-derived cells or their secreted exosomes reduce infarct size and improved functional recovery. Using RNA sequencing to determine exosome content and alterations in gene expression profiles on macrophages from cardiac tissue or bone marrow, they found that a specific micro RNA species miR 181-B within the exosomes, acted on macrophages and was implicated as a key mediator of the cardio-protective benefits. Thus, this study gives new reason to test the idea that allogeneic cardiosphere-derived cells may be efficacious in preventing scar formation and improving cardiac function, when given in the earlier reperfusion period. The data further support that exosomal transfer of miR 181-B from these cardiospheric-derived cells into macrophages underlie the cardio-protective effects after reperfusion.

                                                The next study describes a potential new therapeutic strategy for vasoproliferative retinopathy which can underlie age-related macular degeneration, the leading cause of blindness in industrialized nations. First author, Dr. Bucher, corresponding authors Dr. Yea and Friedlander, from the Scripps Research Institute in La Jolla, California used rodent models of retinal neo-vascular disease to show that Tspan-12, beta-catenin signaling plays an important role in the development of vasoproliferative retinopathy. As background, Tspan-12 belongs to the Tetraspanin family, which mainly includes cell surface proteins characterized by four transmembrane domains and two extra cellular domains.

                                                Members of the Tspan family participate in a diverse cellular processes and act as signaling platforms by forming Tspan-enriched micro domains in plasma membranes. The authors went further to use a novel phage display combinatorial antibody library to specifically design a Tspan-12 blocking antibody which is capable of interacting with human and mouse Tspan-12 antigen. They then provided strong evidence that the Tspan-12 blocking antibody prevents developmental pathological neovascularization in  murine models of vasoproliferative retinopathy. Combination therapy with a known anti-VEGF agent demonstrated significant synergy supporting the potential clinical use of the anti-Tspan-12 antibody as a novel angiomodulatory agent.

                                                The next study addresses the paradox that blacks have higher coronary heart disease mortality compared with whites, but non-fatal coronary heart disease risks may be lower for black versus white men. To address this paradox, first author Dr. Colantonio, corresponding author, Dr. Safford and colleagues from Weill Cornell Medical College in New York, compared fatal and non-fatal coronary heart disease incidents and case fatality among blacks and whites in three studies. The Atherosclerosis Risk in Communities or ARIC study, cardiovascular health study, and reasons for geographic and racial differences in stroke or regards study, all stratified by gender.

                                                They found that the incidents of non-fatal coronary heart disease was consistently lower among black versus white men, although black men have a higher burden of unfavorable social determinants of health and cardiovascular risk factors and a higher fatal coronary heart disease incidents. Following adjustment for social determinants of health and cardiovascular risk factors, black men and women had a similar risk of fatal coronary heart disease, but a lower risk of non-fatal coronary heart disease compared with white men and women respectively. Finally, blacks with incident coronary heart disease had a higher case fatality compared with whites and the difference remained similar after adjustment for social determinants of health and risk factors. Thus, there is an apparent lower risk for non-fatal coronary heart disease among black versus white men and women, which needs to be further studied. Blacks have a higher risk of their initial coronary heart disease event being fatal compared with whites, highlighting the need for reinforcing primary prevention in this population.

                                                The next study provides important information on the burden of re-admissions after hospitalization for critical limb ischemia. First author, Dr. Kolte, corresponding Dr. Aronow and colleagues from Brown University in Providence, Rhode Island, used the 2013/2014 nationwide re-admissions databases to identify almost 61,0000 hospitalizations for primary diagnosis of critical limb ischemia during which patients underwent endovascular or surgical therapy. They found a 30-day re-admission rate of 20.4%. Independent predictors of 30-day re-admission included presentation with an ulcer or gangrene, age above 65 years, females, large hospital size teaching hospital status, known coronary artery disease, heart failure, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis. Interestingly, mode of revascularization was not independently associated with re-admissions.

                                                The most common reasons for re-admissions included infections, persistent or recurrent manifestations of peripheral artery disease, cardiac conditions, procedural complications, and endocrine issues. Finally, the costs of 30-day re-admissions for critical limb ischemia during the study period were 624 million U.S. dollars. Thus, this study provide knowledge of independent predictors and reasons for re-admissions that will help clinicians and hospitals to identify, develop, and implement strategies to reduce re-hospitalizations and healthcare costs associated with critical limb ischemia.

The final study tells us that there may be a direct relationship between life-long exercise volume, and coronary atherosclerosis in athletes. Dr. Aengevaeren and colleagues from Radboud University Medical Center in the Netherlands, studied 284 middle-aged men engaged in competitive or recreational leisure supports, using contrast enhanced CT to assess coronary artery calcification and plaque characteristics.

                                                Participants also reported life-long exercise history patterns and exercise volumes were quantified as metabolic equivalent of task or met minutes per week. They found that participants in the more than 2,000 met minutes per week group had a higher prevalence of coronary artery calcification and atherosclerotic plaques. The most active group did, however, have a more benign composition of plaques with fewer mixed plaques and more often, only calcified plaques. These observations may explain the increased longevity typical of endurance athletes, despite the presence of more coronary atherosclerotic plaques in the most active participants. Well, that wraps it up for your summaries. Now for our featured discussion.

                                                Our current physical activity guidelines recommend 150 minutes of moderate exercise and that's supposed to protect against cardiovascular disease and increase longevity. However, what do we really know about the dose response relationships and the effects of exercises doses that exceed current recommendations. Well, recent data, including a paper in this week's issue, suggests that long-term, high volume endurance exercise may actually accelerate, rather than reduce coronary atherosclerosis. To discuss this exciting paper, we have the corresponding author, Dr. Sanjay Sharma, from Saint George's University of London, as well as editor of digital strategies and associate editor at UT Southwestern who handled this paper, Dr. Amit Khera. Welcome, gentleman.

Dr. Amit Khera:                 Good morning.

Dr. Sanjay Sharma:          Thanks for having us.

Dr. Carolyn Lam:               First, Sanjay, oh yikes! As a runner and as a person who strongly advocates regular exercise, please, please, put us out of our misery. Tell us what you've found and what you think are the possible explanations.

Dr. Sanjay Sharma:          I'm a runner too, and I don't think anyone would argue that the benefits of exercise on the cardiovascular system are unrivaled. People who exercise regularly do reduce their risk of an adverse event from a heart attack by 50% when they're in their 5th and 6th decade and they live around three years longer than people who don't exercise at all. Now as you rightly point out, the current recommendation suggests 2 1/2 hours of moderate physical activity per week and by that I would mean, at maximum, a 15-minute mile pace. Clearly, our endurance athletes exercise much, much more than that. They exercise 10 to 20 times greater than that volume and in parallel with this has been the emergence of a large number of people participating in marathon runs. For example, in Europe, there were two million marathon runs per annum and that figure's going up by about 5%.

                                                Coinciding with this burgeoning increase in endurance exercise, is the development of several reports that show that exercise may cause release of biomarkers of cardiac damage. Animal experiments have shown that exercise may cause scaring in the heart and human studies have shown that some marathon runners have more calcium in their coronary arteries compared to relatively sedentary individuals. One of the problems with these studies is firstly, the biomarker release is very transient, it goes away after about two days. Animal experiments cannot really reflect what goes on in human beings because they're artificial and animals are forced to exercise with electrical shocks, et cetera. The studies in human beings have been conducted in runners who have been former smokers.

                                                In fact, the most commonly reported study or cited study, contained individuals of whom 50% had risk factors for coronary artery disease. What we decided to do was to do a clean study, where we took 150 individuals who had none of the risk factors for coronary artery disease and 92 relatively sedentary controls who exercise within the normal limits. We have to exclude a lot of people because we have to exclude anyone that had ever smoked, anyone that had high blood pressure, high cholesterol, or a family history of permanent cardiac disease. We actually subjected them to all sorts of investigations and we found that a small number of male runners had more calcium in their arteries compared to sedentary individuals.

Dr. Carolyn Lam:               Wow! Please tell us that there's something good that you can say about that. First of all, I really want to congratulate you on this most elegant study and Amit, I'm sure you put in what the editor's thought but we're just so proud to be publishing such a high quality study here. Amit, is there anything you might want to add of what the editors thought?

Dr. Amit Khera:                 Sure, I first want to congratulate Dr. Sharma and his colleagues. This was a carefully done study and we've talked a bit about the coronary calcium but there was extensive investigation and I really think this advanced the field. Sounds like all three of us are runners, so this hit home to all of us and as he mentioned, this has been a very hot area and one that's been very controversial. I think here what we have is a manuscript that really helped move the field forward, helped us better understand the biology. The one thing I'll comment on that we found very interesting was the observation that those that were the masters athletes actually had more of a calcific phenotype, where as those that were not looked like a soft plaque phenotype, if you will. Actually, if you look, we have a companion article in circulation looking at sort of dose dependent finding a similar finding. My question, now turned back to Dr. Sharma is, what do you counsel your patients now with these findings? Has it changed now how you recommend exercise or your thoughts on how you counsel them?

Dr. Sanjay Sharma:          Well, we examined 152 different athletes, or masters athletes in 92 controls. These athletes were aged 56 years old, who'd been training for 36 years and had immediate marathon number of 13. Now, what we've found in these individuals is that a small number of males, that's 11%, had a coronary artery calcium score of more than 300. Some men had more plaques than sedentary individuals and these plaques were distributed throughout all three coronary arteries. When we looked at the pathology of the plaques very carefully, we found that the plaques in the athletes were calcified. Indeed, 72% of athletes had very calcified plaques. We know that such calcified plaques are stable, they're less likely to fissure and are less likely to cause coronary thrombosis and therefore, acute myocardial infarction.

                                                This led us to propose that although exercise may be causing some atherosclerosis through the sheering and stressful source during exercise of the bending and kicking of vessels, we believe that the repair mechanism here is different to that seen in people who smoke or who have high cholesterol or high blood pressure. The repair mechanism results in very calcified and stable plaques in athletes and this may actually mitigate the risk of acute myocardial infarction and may explain why the number of people who actually suffer an acute myocardial infarction during a marathon run is very small, around 1 in 50,000, and no different to the number of people who suffer a sudden cardiac arrest playing football or basketball, due to congenital or inherited abnormalities of the heart. 

Dr. Carolyn Lam:               Sanjay, those are just such important points to keep in mind as we read your paper. It did strike me as a significant minority, actually, of these long term endurance athletes who develop significant coronary artery calcification and it could potentially be a clinically benign phenotype. At the end of the day, this is a cross-sectional study, isn't it? We can't, I suppose, extrapolate into the clinical events. What are your postulations there and what could be future work that you're planning?

Dr. Sanjay Sharma:          Well, you make a good point. This is a cross-sectional study and the demonstration of an increased cardiopathy calcium does not necessarily reflect future cardiac events. We have followed these individuals up for the last 18 months. These masters athletes and have not demonstrated a single one to develop an acute event that would last 18 months. We really don't know what the meaning of these plaques is. I think the only thing to do now, being we've got the liberty of having so many people that do marathon runs and so many people who've been exercising for three or four decades, we can actually do a prolonged follow up study, so the answers will be a while coming. To follow these people up with high calcium, just to see whether they do go on to develop adverse events in the future. All our study has shown is that some male athletes who've exercised lifelong get an increasing number of plaques. These plaques appear to be calcified and stable and the long term effects of such  plaques is unknown.

Dr. Carolyn Lam:               Sanjay, just circling back to Amit's question earlier and maybe Amit, you could take it to after this. What do we recommend to our athletes who come in and have a high coronary artery calcium score? Do we tell them to stop?

Dr. Sanjay Sharma:          I certainly wouldn't and I'm much less worried about an increase coronary calcium score in a lifelong runner or cyclist than I was 10 years ago. It appears that these plaques are there in some individuals, they are calcified, they appear stable. Given the fact that we know that coronary events during marathon running in experienced runners are very, very low indeed. I don't think I would be keen to do anything about it, not even consider stacking therapy based on our findings at present. As I said before, we do need longitudinal follow up to really identify all ascertain the precise implications of these plaques in masters athletes.

Dr. Carolyn Lam:               Right, and this is again recognizing that your particular population was free of traditional cardiovascular disease. Of course, if we were to find these risk factors in our athletes, we would most certainly treat the traditional risk factors. Amit, anything to add there?

Dr. Amit Khera:                 I think that was an excellent point about his approach to counseling patients. I will mention on the editorial staff, we felt like this was such an interesting area with emerging data and fast moving, that it was warranting of an editorial. I recommend people to look at the one by Aaron Baggish and Ben Levine. I think they had a very similar conclusion and that was that they don't necessarily proscribe exercise in patients with high coronary calcium but rather, focus on risk mitigation strategy, focusing on risk factors as we normally would do. I think the conclusions are similar and the thoughts in that editorial were insightful, pairing both of these papers and helping us make sense out of this really evolving field.

Dr. Carolyn Lam:               Well, thank you Sanjay and Amit for this wonderful discussion. I learned so much as I'm sure our listeners did. You've been listening to Circulation On The Run. Tune in next week. 

Jul 3, 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 Center and Duke National University of Singapore. What is the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy? We will be discussing new data in this area in just a moment, following these summaries.

                                                The first paper describes the effect of long-term metformin and lifestyle measures on coronary artery calcium. This is a paper from Dr. Goldberg of George Washington University Biostatistics Center and colleagues of the Diabetes Prevention Program Research Group. The Diabetes Prevention Program and its outcome study is a long-term intervention study in subjects with prediabetes, which showed reduced diabetes risk with lifestyle and metformin compared to placebo.

                                                In the current study, the authors looked at subclinical atherosclerosis, which was assessed in 2,029 participants using coronary artery calcium measurements after 14 years of average follow-up. They found that men but not women with prediabetes treated with metformin for an average duration of 14 years had lower coronary calcium scores than their placebo counterparts. No difference in coronary calcium scores was observed in the group receiving a lifestyle intervention as compared to the placebo group.

                                                These findings provide the first evidence that metformin may protect against coronary atherosclerosis in men with prediabetes, although demonstration that metformin reduces cardiovascular disease events in these subjects is still needed before firm therapeutic implications of these findings can be made. The reason for an absence of an effect in women is unclear and deserves further study.

                                                The next study provides insights on the physiology of angina from invasive catheter laboratory measurements during exercise. Dr. Asrress of Royal North Shore Hospital in Sydney, Australia, and colleagues, studied 40 patients with exertional angina and coronary artery disease who underwent cardiac catheterization via radial axis and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual GTN was administered to half the patients and all patients continued to exercise for two minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity, and central aortic pressure were recorded using sensor wires.

                                                Using this novel invasive approach, the authors showed that administration of GTN ameliorated angina by reducing myocardial oxygen demand as well as increasing supply with a key component being the reversal of exercise-induced coronary lesion vasoconstriction. This was evidenced by the fact that there was a relationship between the diastolic velocity pressure gradient with significant increase in relative stenosis severity. In keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilation of normal segments, with trends towards reversal with GTN.

                                                Thus, this study describes the development of a paradigm where patients with coronary artery disease can exercise while simultaneously having coronary and central aortic hemodynamics measured invasively, and has shown that this provides a unique opportunity to study mechanisms underlying the physiology of angina. In treating patients with exercise-induced angina, the results highlight the importance of after-load reduction and the use of agents that reduce arterial wave reflection and promote coronary artery vasodilation.

                                                The next study provides mechanistic insights into reverse cholesterol transport, where excess cholesterol is removed from macrophage-derived foam cells in atherosclerotic plaques. It suggests that melanocortin receptor-1, or MC1-R, may play a role. As background, the melanocortin system, consisting of melanocyte-stimulating hormones and their receptors, regulate a variety of physiological functions, ranging from skin pigmentation to centrally-mediated energy balance control. At the cellular level, the biological actions are mediated by G protein-coupled melanocortin receptors, such as MC1-R. MC1-R not only affects melanogenesis in the skin but also has immunomodulatory effects through its wide expression in the cells of the immune system.

                                                In the current study from Dr. Rinne of University of Turku in Finland, and colleagues, human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was further assessed in apolipoprotein E deficient mice. Their findings identified a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R conferred protection against macrophage foam cell formation through a dual mechanism. It prevented cholesterol uptake while it concomitantly promoted reverse cholesterol transport by increasing the expression of ATP-binding cassette transporters, ABCA1 and ABCG1.

                                                Thus, the identification of MC1-R in lesional macrophages, demonstration of its role in regulating reverse cholesterol transport, combined with its established anti-inflammatory effects, suggests that MC1-R could be a novel new therapeutic target for preventing atherosclerosis.

                                                The next study suggests that obesity-related heart failure with preserved ejection fraction, or HFpEF, is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments. First author, Dr. Obokata, corresponding author, Dr. Borlaug, and colleagues from Mayo Clinic Rochester and Minnesota studied 99 patients with obese HFpEF with a BMI above 35, with 96 non-obese HFpEF with a BMI less than 30, and 71 non-obese controls without heart failure. All subjects underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.

                                                The authors found that, compared to non-obese HFpEF, obese HFpEF patients displayed greater volume overload, more biventricular remodeling, greater right ventricular dysfunction, worse exercise capacity, more impaired pulmonary vasodilation, and more profound hemodynamic arrangements, despite a lower NT-proBNP level. Obese HFpEF patients displayed other important contributors to high left ventricular filling pressures, including greater dependence on plasma volume expansion, increased pericardial restraint, and enhanced ventricular interaction, which was exaggerated as pulmonary pressure load increased.

                                                These data provide compelling evidence that patients with the obese HFpEF phenotype have real heart failure and display several pathophysiological mechanisms that differ from non-obese patients with HFpEF. These and other issues are discussed in an accompanying editorial by Dr. Dalane Kitzman and myself. We hope you enjoy it.

                                                The final study identifies a novel long noncoding RNA that regulates angiogenesis. As background, although we know that the mammalian genome is pervasively transcribed, a large proportion of the transcripts do not encode a protein, and are thus regarded as noncoding RNAs. Based on their length, they can be divided into small or long noncoding RNAs, long being described as more than 200 nucleotides. Although their function is not fully understood, long noncoding RNAs have been increasingly reported to mediate the expression of other genes, affect the organization of the nucleus, and modify other RNAs.

                                                In the current study by first author, Dr. Leisegang, corresponding author, Dr. Brandes, and colleagues of Goethe University in Frankfurt, Germany, epigenetically controlled long noncoding RNAs in human umbilical vein endothelial cells were searched by axon array analysis following knockdown of the histone demethylase JARID1B. The authors discovered a novel noncoding RNA named MANTIS to be strongly upregulated. MANTIS is located in the antisense strand of an intronic region of the gene for annexin A4, calcium- and phospholipid-binding protein. MANTIS is a nuclear long noncoding RNA that is enriched in endothelial cells but also expressed in other cell types. Reducing MANTIS levels led to impaired endothelial sprouting, tube formation, attenuated endothelial migration, and inhibition of the alignment of endothelial cells in response to shear stress.

                                                Brahma-like gene 1, or BRG-1, was identified as a direct interaction partner of MANTIS, implying a role of MANTIS in the formation of the switch/sucrose non-fermentable chromatin remodeling complex. MANTIS binding to BRG-1 was shown to stabilize the BRG-1 interaction, hence by inducing an open chromatin conformation, MANTIS was proposed to maintain the endothelial angiogenic potential. The implications of these findings are discussed in an accompanying editorial by Dr. Zampetaki and Mayr from Kings College London.

                                                That brings us to the end of our summaries. Now for our feature discussion.

                                                Today, we are going to be discussing the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. To discuss this, I have the first and corresponding author of our feature paper, Dr. Heather Boyd, from Statens Serum Institut in Copenhagen, and our familiar Dr. Sharon Reimold, content editor for special populations from UT Southwestern. Welcome, Heather and Sharon.

Dr. Heather Boyd:            Thank you.

Dr. Sharon Reimold:        Thank you.

Dr. Carolyn Lam:               Heather, it's a topic that I can't say I'm very familiar with, association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. Could you start by sharing why would we think there would be a link? What was the hypothesis you were testing?

Dr. Heather Boyd:            A couple years ago, there was a paper published in the European Heart Journal that reported evidence of angiogenic imbalance in women with fetuses with major congenital heart defects, so women who were pregnant with babies that had heart defects, and then in fetuses that were terminated because of this kind of defect. My research group focuses a lot of attention on preeclampsia. In the last decade or so, angiogenic imbalance in preeclampsia has been a really hot topic. Women with preeclampsia, particularly women with early-onset preeclampsia, have big angiogenic imbalances. When we saw the European Heart Journal paper, we immediately thought, "What's the connection between preeclampsia and heart defects in the offspring?"

Dr. Carolyn Lam:               Oh!

Dr. Heather Boyd:            Exactly. That was our entry point to it, was the term "angiogenic imbalance" in that paper sort of was a flag for us. It wasn't a completely new idea, but we in Denmark have one big advantage when considering research questions that involve either rare exposures and/or rare outcomes, and that's our National Health Registry. We have the ability to assemble these huge cohorts and study conditions like heart defects with good power, so we decided just to go for it.

Dr. Carolyn Lam:               That makes a lot of sense now. Please, tell us what you did and what you found.

Dr. Heather Boyd:            The first thing we did was look at the association between carrying a baby with a heart defect and then whether the mom had preeclampsia later in the same pregnancy. We had information on almost 2 million pregnancies for this part of the study. We found that women carrying a baby with a heart defect were seven times as likely as women with structurally normal babies to develop early preterm preeclampsia. We defined that as preeclampsia where the baby has to be delivered before 34 weeks, so the really severe form of preeclampsia. Then, women carrying a baby with a heart defect were almost three times as likely to develop late preterm preeclampsia as well. That's where they managed to carry it until 34 weeks but it has to be delivered some time before 37 weeks.

                                                These findings were similar to those of other studies, but we were able to go a step further and look at individual heart defect subtypes. What we found there waws that these strong associations were similar across defect categories. Then we decided to see if we could shed any light on the origin of the problem, whether it was coming from the mom's side or the baby's side. To do this, we looked at women with at least two pregnancies in our study period to see whether preeclampsia in one pregnancy had any bearing on the chance of having a baby with a heart defect in another pregnancy or vice versa.

                                                This part of the study included 700,000 women. We found very similar findings. We found that women with early preterm preeclampsia in one pregnancy had eight times the risk of having a baby with a heart defect in a subsequent pregnancy. Late-term preeclampsia in one pregnancy was associated with almost three times the risk of offspring heart defects in later pregnancies. Then, we found that it worked the other way around too. Women who had a baby with a heart defect were twice as likely to have preterm preeclampsia in subsequent pregnancies.

                                                Those results were really, really exciting, because whatever mechanisms underlie the associations between preterm preeclampsia in moms and heart defects in the babies, they operate across pregnancies. Therefore, that pointed towards something maternal in origin.

Dr. Carolyn Lam:               That is so fascinating. Sharon, please, share some of the thoughts, your own as well as those of the editors when we saw this paper.

Dr. Sharon Reimold:        I think that there's a growing data about the links between hypertensive disorders of pregnancy and preeclampsia with subsequent abnormal maternal outcome. But this paper, I think, has implications for how we look at moms who are going to have offspring with congenital heart defects as well as those with preeclampsia. For instance, I would look at a patient now that has preeclampsia, especially in more than one pregnancy, to identify that they may be at risk to have offspring with congenital defects in the future if they have additional children. But the mom is also at risk based on other data for developing other cardiovascular risk factors and disease as she gets older. It was really the link going back and forth with the hypertensive disorders and the congenital defects that we found the most interesting.

Dr. Carolyn Lam:               That struck me too, especially when you can look at multiple pregnancies and outcomes. That's amazing. You know what, Heather, could you share a little bit about what it's like working with these huge Danish databases? I think there must be a lot more than meets the eye.

Dr. Heather Boyd:            It's an interesting question, because I'm a Canadian and I was trained in the US. I did my PhD in epidemiology at Emery, and then I moved to Copenhagen. When I first got here, I was absolutely floored at the possibility of doing studies with millions of women in them. It opens some amazing possibilities, like I said earlier, for certain outcomes and certain exposures. You just need to have a question where the information you want is registered.

Dr. Carolyn Lam:               Yeah. But I think what I also want to put across is, having worked with big databases, and certainly not as big as that one, it's actually a lot of work. People might think, "Oh, it's just all sitting there." But, for example, how long did it take you to come to these observations and conclusions?

Dr. Heather Boyd:            I have a fabulous statistician. I think she's the second author there, Saima Basit. She spends a lot of her time pulling together data from different registers. But yes, you're right. The data don't always just mesh nicely. The statisticians we have working with us are real pros at this sort of data slinging.

Dr. Carolyn Lam:               Could I just pose one last question to both of you. What do you think are the remaining gaps?

Dr. Sharon Reimold:        I think that this is a clinical link. Then, going back to figure more about what's going on biologically to set up this difference? Because right now there's really no intervention that's going to make a difference, it's just a risk going forward. This is sort of like medicine done backwards, that there's this association and now we need to figure out exactly why.

Dr. Heather Boyd:            I can piggyback on what Sharon said a little bit, because I think one of the things we need to remember is that not all women with preeclampsia have babies with heart defects. Not by a long shot. What we need to do now is to figure out what distinguishes the women who do get this double whammy from the vast majority who don't.

                                                One of the things that Denmark does really nicely is that there are large bio banks. One of the things we want to do is go back to bank first trimester maternal blood samples and see if we can identify biomarkers that are unique to the women with both preterm preeclampsia and babies with heart defects. That's one of the things we're thinking about to address this gap. Because, as Sharon says, we've got to figure out what the mechanism is.

                                                The other thing we want to do is to see whether the association between preeclampsia and heart defects extends, for example, to other things, to cardiac functional deficits, for example, because it's probably not just severe structural defects. If there's an association, it's probably on a continuum. Are babies born to preeclamptic moms, do their cardiac outputs differ? Do their electrical parameters differ? Do they just have different hearts?

                                                We're really lucky because right now the Copenhagen Baby Heart Study is offering to scan the hearts of all infants born at one of the three major university hospitals in the Copenhagen area. We're about to have echocardiography data on 30,000 newborn hearts to help us look at this. I'm really excited about that possibility.

Dr. Carolyn Lam:               I've learnt so much from this conversation. I'm sure the listeners will agree with me. Thank you both very, very much.

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