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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Oct 22, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors.

                                                I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. The ORBITA Trial of percutaneous coronary intervention and stable single vessel coronary artery disease has to be one of the most hotly discussed in the cardiology world. The featured paper of this week adds important knowledge that will help us understand the physiology stratified results of ORBITA.

                                                Coming right up after these summaries.

                                                The first original paper this week provides novel mechanistic insights that may lead to a new treatment approach for obesity and hypertriglyceridemia. Co-corresponding authors, Drs Xiang and Xia from Central South University of Xiangya in China, looked at Reticulin 3, which is an endoplasmic reticular protein that has previously shown to play a role in neurodegenerative diseases.

                                                In the current paper, the authors show that over-expression of Reticulin 3 in mice induced obesity and a greater accumulation of triglycerides. Remarkably, increased Reticulin 3 expression was also found in patients with obesity and hypertriglyceridemia. They further showed that Reticulin 3 played critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Thus, these results suggest that inhibiting the expression of Reticulin 3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia in the future.

                                                The next study provides insights into the genetic determinates of residual cardiovascular risk in patients already receiving statins. First author Dr Wei, corresponding Dr Denny from Vanderbilt University Medical Center and their colleagues performed a genome-wide association study and identified that a variation at the LPA Locus was associated with coronary heart disease events during statin therapy and independent of the extent of LDL cholesterol lowering. The association of the LPA Locus with coronary heart disease events persisted in individuals with an LDL cholesterol less than 70 milligrams per deciliter. These findings, therefore, provide support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce coronary heart disease events in patients already receiving statins.

                                                The next paper provides important mechanistic results that help us understand pathways in atherosclerotic plague regression. Co first authors, Drs Mueller and Zhu, corresponding author Dr Fazio from Oregon Health and Science University and their colleagues have previously shown that mice lacking an LDL receptor with beta protein 1 in macrophages undergo accelerated atherosclerotic plague formation. However, in the current study they sought to explore the role of macrophage LDL receptor protein 1 during plague regression. They did this by placing EPO E deficient mice on a high fat diet for 12 weeks, then reconstituting their bone marrow using wall type or macrophage LDL receptor protein 1 deficient mice as donors, and finally switching them back to a chow diet for 10 weeks. The authors found that the lack of LDL receptor protein 1 expression in macrophages unexpectedly caused more atherosclerosis regression. Mice with macrophages lacking LDL receptor protein 1 showed less M1 macrophages in the plague and increased CCR7 dependent egress of macrophages from the plague. Thus, loss of macrophage LDL receptor protein 1 has a dual and opposite effect on plague biogenesis, depending on whether the plague is growing or shrinking.

                                                The next paper highlights the intercalated disc, which is a specialized intercellular junction, coupling cardiomyocyte electrical activity in forced transmission as a mechanosensitive signaling hub for causative mutations in cardiomyopathy. First author Dr Trembley, corresponding author Dr Small from University of Rochester School of Medicine and Dentistry and their colleagues showed that myocardin related transcription factors associated with desmosome proteins of their intercalated disc in both murine and human hearts. Genetic deletion of myocardin related transcription factors in cardiomyocytes led to rapid onset of dilated cardiomyopathy in response to pressure overload hypertrophy. Furthermore, myocardin related transcription factors were required for the maintenance of sacromere and intercalated disc integrity under pathological stress. These findings, therefore, provide a unique link between the intercalated disc and mechanosensitive transcriptional regulations. Since myocardin related transcription factors redistribute from intercalated disc in human heart failure, this may represent a novel signaling complex present in cardiomyopathic characterized by desmosome dysfunction.

                                                The next paper investigated the association of blood pressure with peripheral arterial disease events, using data from the ALLHAT Trial. Co first authors Drs Itoga and Tawfik, corresponding author Dr Chang from Stanford University School of Medicine and their colleagues found that both lower systolic blood pressure of less than 120 and higher systolic blood pressure of above 160 millimeters of mercury were both associated with higher rates of peripheral arterial disease events. Diastolic blood pressure less than 70 and a pulse pressure above 65 millimeters mercury were also associated with increased rates of lower extremity peripheral arterial disease events. Given that the recent revised blood pressure guidelines advocate lower systolic blood pressure targets for overall cardiovascular risk reduction, the authors called for future, further refinement of optimal blood pressure targets, specific for peripheral artery disease.

                                                The final original paper this week provides the first integrated atherosclerotic disease risk calculator to incorporate risk factors including high sensitivity C reactive protein, family history, and coronary artery calcium data. First and corresponding author Dr Khera from UT Southwestern Medical Center and colleagues used 3 population-based cohorts to develop Cox Proportional Hazards Models for the outcome of atherosclerotic cardiovascular disease. The derived Astro-CHARM model incorporated factors like age, sex, systolic blood pressure, total and HDL cholesterol, smoking, diabetes, hypertension treatment, family history of myocardial infarction, high sensitivity c reactive protein, and coronary artery calcium scores. The model performance was validated externally in a 4th cohort, and shown to improve risk prediction compared with traditional risk factor equations, and showed good discrimination in calibration in the validation cohort. A mobile application and web based tool was developed to facilitate the clinical application of this tool, and is available at

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

                                                Gosh, I am learning for the first time today that it's terribly inconvenient to lose my voice when I am a podcaster. This is Carolyn Lam and our featured discussion that I am so excited about, but the cool thing is the thing we are talking about is so hot that you don't even need me to say anything. And what we are talking about is the ORBITA Trial. That was greeted with as much hype and hoopla and sensationalism since its publication in 2017. I am so proud to have the first and corresponding author Dr Rasha Al-Lamee from National Heart and Lung Institute Hammersmith Hospital in London. I also have Dr Ajay Kirtane from Columbia University Medical Center in New York Presbyterian Hospital and the Cardiovascular Foundation in New York as the editorialist for the paper. And finally, our associate editor Dr Manos Brilakis from UT Southwestern. Rasha, why don't you just take it away and just tell us, what is your paper focusing on in this week's issue?

Dr Rasha Al-Lamee:         The paper that was published in this issue in circulation is basically our second analysis of the ORBITA Trial, a substudy analysis. Essentially, looking at the primary endpoint and the secondary endpoints of ORBITA, and having a look at those patients from ORBITA and seeing whether there was any association between their invasive physiological assessment using FFR and ISR at the pre-randomization stage and seeing whether the level of ischemia on ISR or FSR was associated or predicted in the way in which they performed in terms of their endpoints. To see whether there was any difference in the placebo control efficacy of angioplasty in those patients who have more or less severe ischemia on their invasive physiological assessment.

Dr Manos Brilakis:            First off, that's a phenomenal paper, and I think she puts things into perspective. I know Ajay put an excellent tutorial. I think all of us were surprised about the findings. You would expect that the more ischemia, that you might see a little more response. Any thoughts as to why there wasn't such an association?

Dr Rasha Al-Lamee:         I think it's so difficult because, of course, as we all know from the primary paper that was published in The Lancet, in terms of the primary endpoint, which would be change in exercise time and the difference between the two groups, the difference is actually much smaller than we expected. And when we have such a small difference in exercise time, the ability to be powered enough to be able to split that endpoint based on stratification of invasive physiology becomes very difficult, and we're perhaps underpowered to be able to do that.

                                                Where we did see a very great effect in terms of the primary assessment in The Lancet paper was in stress echo ischemia. What we saw is those patients who had angioplasty were far more likely to have an improvement, or indeed, a normalization of their ischemia on their stress echo. Where we saw a big difference the two groups we were then clearly powered to be able to stratify those patients based on their invasive physiology, and for that secondary endpoint we saw that, in fact, tied to your stenosis or the lower your ISR or FRR, the more likely you are to have an improvement in stress echo, having had placebo controlled angioplasty.

Dr Manos Brilakis:            Ajay, I know you had a lot of things insight into the vision of the tutorial for the ORBITA Trial. What are your thoughts about the findings?

Dr Ajay Kirtane:                 I would, first of all, congratulate Rasha and the ORBITA team, there are others, for not only doing the main trial, but for conducting these detailed analyses, which were clearly set up ahead of time, and that's been one of the critiques of the trial is why were patients with normal-ish range FFRs included. Well, part of it was to test this hypothesis, and perhaps to show that there would be a correlation between the change in the FFR, if you will, and the endpoints that were measured.

                                                So, I think that that's the first part, that this is actually a scientific experiment, and a thoughtful one in doing so. I think exactly as Rasha said though, if there is a limited signal, with respect to the overall trial, then further subsetting is less likely to show a significant signal. I think that's exactly what the investigators found. The only other comment I would make though is, I would commend Rasha and the team for producing other analyses that are novel in this manuscript including the freedom from angina analysis, as well as responding to some of the earlier critiques of the trial and not using specific methodologies to adjust the baseline differences improves. Those are also included in this analysis.

Dr Manos Brilakis:            Yeah, absolutely, I think that was very enlightening to see, the freedom of angina. And I know there was some questions whether that might change the overall findings from the studies, so there is some quality of life benefit. Rasha, what is your thoughts about this? I mean, you must understand this study better than anyone else. People who have stable angina, should they undergo PCI or not?

Dr Rasha Al-Lamee:         I think the freedom from angina signal was very important, and obviously not something that we had pre-specified, so it wasn't reported in the primary analysis. We're obviously much more able now, since we've published that primary analysis to do secondary analyses and look at things that perhaps we haven't pre specified. And it's interesting to see that 20% more patients are free from angina having had angioplasty vs. placebo. Having said that, to me, it's a fantastic finding, but still a little unexpected. Much less than we might expect looking at unblinded data, or our unblinded clinical experience. I would have expected much higher levels from freedom of angina.

Dr Rasha Al-Lamee:         I think what we know, and what we've seen both from this paper, very importantly, and also the primary manuscript, is that the efficacy of angioplasty is very tightly linked to the improvement in ischemia. We've actually, in fact, got more papers that are coming out from our group recently. And that you can predictably tell your patients that if I sense a lesion that's causing a reduction in ISR or FFR, and potentially symptoms, then I will improve your ischemic burden.

                                                What I think is more tricky is how much I will relieve your symptoms, or make you feel better. That may be because symptom assessment itself is very tricky, and perhaps that actually just diagnosing cardiac angina is actually a very difficult thing. The easiest way to piece out improvement in symptoms is to find those patients who become free of angina because, of course, that's the binary end point. When we look at grades of symptoms, and whether their angina frequency improves, or whether the level of angina improves in terms of PCI, then I think it becomes much harder, especially in a blinded trial where, of course, when people come back, even with atypical chest pain, it will still be recorded as potentially angina because, of course, both the investigators and the patients have no idea what they've had done, which is quite different from real life where, of course, you are able to think more about whether this chest pain might indeed be from the heart or from other causes.

Dr Manos Brilakis:            Perfect, thank you very much. And I would completely agree with you that, the study was perfect. And, as Ajay said, it is something that we needed, and more of them should be done. And I think you are right that this is the best way to piece out the symptom improvement.

                                                Ajay, any final comments?

Dr Ajay Kirtane:                 I think that the toughest challenge with trials like this is to really enroll the patients that many of us as interventionists feel would really improve in terms of their symptom class. Even despite these efforts, if one looks at the baseline of anginal frequency in the trial, the means are relatively high, which suggest that the anginal burden, at least in terms of measurements through the anginal questionnaire is not that severe. One could argue that somebody has severe angina that is occurring all the time, that those are types of patients that are hard to randomize in a clinical trial.

                                                I think, at least my overview stepping back perspective of the context of ORBITA within clinical practice, is exactly that. The trial is an important scientific advance, but this does not encompass the answer for every single patient that comes to see us in the office that have a range of symptoms, very severe to less severe. That was something Rasha has been saying all along as well. It's not something that we could over extrapolate this to every patient that we see. So, I think that when the hype dies down, these types of scientific analyses will stand out. They emphasize the need for regular clinical research, and in that way, I think has generated a lot of attention not only to the clinical field here, but also the scientific pursuit of evidence. That's a really magical thing.

Dr Rasha Al-Lamee:         I think, if I can add to that Ajay, I think it's probably also sort of the assessment of symptoms is incredibly important. I think many of us, and I'll include myself in this, when we see a very tight stenosis, are happy to essentially correlate any level of symptoms to that tight stenosis. One thing I've learned from all this, I want to see reproducible angina that very much is textbook, cardiac caused chest pain, and the atypical anginas we see, perhaps some of that pain is not from that stenosis, but from somewhere else. Therefore, by fixing that stenosis, we don't necessarily make that pain go away.

Dr Manos Brilakis:            Absolutely, and I think you are absolutely, if it is something simple vessel disease, if it's something a little more straightforward, then I think you are right Ajay, that this is much harder, multiple vessel disease especially in people with reduced ejection fraction.

Dr Carolyn Lam:                You've been listening to Circulation on the Run! Don't forget to tune in again next week!


Oct 15, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Will artificial intelligence replace the human echocardiographer? Aha, well to find out the answer, you have to wait for the incredibly exciting discussion of today's feature paper coming right up after these summaries.

                                                The clinical benefits of the cholesterol ester transfer protein, or CETP inhibitor dalcetrapib depends on adenylate cyclase type 9, or ADCY9 genotype. However, what are the underlying mechanism responsible for the interactions between ADCY9 and CETP activity? In the first paper from today's journal first author Dr Rautureau, corresponding author Dr Tardif from Montreal Heart Institute, and colleagues used a mouse atherosclerosis model inactivated for ADCY9 and demonstrated that loss of ADCY9 protected from atherosclerosis and was associated with improved endothelial function, but only in the absence of CETP. ADCY9 in activation increased weight gain, adipose tissue volume, and feed efficiency, but only in the absence of CETP.

                                                This mouse model reproduced the interactions between ADCY9 and CETP activity observed in patients, and offers new mechanistic insights for the importance of ADCY9 in determining the responses to CETP inhibition. For example, the dal-GenE clinical trial is currently testing prospectively whether patients with coronary disease and the favorable ADCY9 genotype will benefit from dalcetrapib.

                                                The next study addresses the controversy around the cardioprotective effects of Omega-3 polyunsaturated fatty acids, and uncovers signaling pathways associated with eicosapentaenoic acid, or EPA supplementation that may mediate protective effects in atherosclerosis. First author Dr Laguna-Fernandez, corresponding author Dr Bäck from Karolinska Institute, and their colleagues showed that EPA supplementation significantly attenuated atherosclerotic lesion growth. They performed a systematic plasma lipidomic analysis and identified that 18 monohydroxy eicosapentaenoic acid was a central molecule formed during EPA supplementation. 18 monohydroxy eicosapentaenoic acid was a precursor for the plural resolving lipid mediator called resolvent E1.

                                                In the present study, a resolve in E1 was shown to regulate critical atherosclerosis related functions in macrophages through its downstream signaling receptor to transfuse protective effects in atherosclerosis.

                                                Are there racial differences and long-term outcomes among survivors of in-hospital cardiac arrest? In the next paper first and corresponding officer Dr Chen from University of Michigan and her colleagues performed a longitudinal study of patients more than 65 years of age who had an in-hospital cardiac arrest and survived until hospital discharge between 2000 and 2011 from the National Get With The Guidelines Resuscitation Registry whose data could be linked to Medicare claims data. They found that compared with white survivors of in-hospital cardiac arrest, black survivors had a more than 10% lower absolute rate of long-term survival after hospital discharge. This translated to a 28% lower relative likelihood of living to one year, and a 33% lower relative likelihood of living to five years after hospital discharge for black versus white survivors.

                                                Nearly one-third of the racial difference in one-year survival was dependent on measured patient factors. Only a small proportion was explained by racial differences in hospital care, and approximately one-half was the result of differences in care after discharge, or unmeasured confounding. Thus, further investigation is warranted to understand to what degree unmeasured, but modifiable factors, such as post-discharge care may account for the unexplained disparities.

                                                The next study provides insights into a novel mechanism of atherogenesis that involves protease-activated receptor 2, a major receptor of activated factor 10, which is expressed in both vascular cells and leukocytes. Co-first authors Dr Hara and Phuong, corresponding author Dr Fukuda from Tokushima University Graduate School of Biomedical Sciences, and their colleagues showed that in ApoE-Deficient deficient mice, protease-activated receptor 2 signaling activated macrophages and promoted vascular inflammation, increasing atherosclerosis.

                                                Furthermore, they showed that in humans, plasma-activated factor 10 levels positively correlated with the severity of coronary artery disease, suggesting that the signaling pathway may also participate in atherogenesis in humans. Thus, the protease-activated receptor 2 signaling pathway may provide a novel mechanism of atherogenesis and serve as a potential therapeutic target in atherosclerosis.

                                                The next paper tells us that biomarkers may help to predict specific causes of death in patients with atrial fibrillation. First and corresponding author Dr Sharma and colleagues from Duke Clinical Research Institute evaluated the role of biomarkers in prognosticating specific causes of death among patients with atrial fibrillation and cardiovascular risk factors in the ARISTOTLE trial.

                                                They looked at the following biomarkers: high sensitivity troponin T, growth differentiating factor 15, N-terminal pro-B-type natriuretic peptide, and interleukin 6. They found that sudden cardiac death was the most commonly adjudicated cause of cardiovascular death, followed by heart failure and stroke or systemic embolism deaths. Biomarkers were some of the strongest predictors of cause-specific death, and may improve the ability to discriminate among patients' risks for different causes of death.

                                                How do the complement and coagulation systems interact in cardiovascular disease? Well in the final original paper this week, first author Dr Sauter, corresponding author Dr Langer from Eberhard Karls University Tübingen, and their colleagues used several in vitro, ex vivo, and in vivo approaches as well as different genetic mouse models to identify the anaphylatoxin receptor C3AR and its corresponding ligand C3A as platelet activators that acted via intra -platelet signaling, and resulted in activated platelet fibrinogen receptor GP2B3A. This in turn mediated intravascular thrombosis, stroke, and myocardial infarction. This paper, therefore, identifies a novel point of intersection between the innate immunity and thrombosis with relevance for the thrombolic disease of stroke and myocardial infarction.

                                                That wraps up with week's summary. Now for our featured discussion.

                                                Can we teach a machine to read echocardiograms? Well today's feature paper is going to be all about that. I am so excited to have with us the corresponding author of an amazing, and I think, landmark paper, Dr Rahul Deo from the One Brave Idea Science Innovation Center and Brigham and Women's Hospital in Boston, as well as our associate editor Dr Victoria Delgado from Leiden University Medical Center in The Netherlands. Now let me set the scene here. We know that echocardiography is one of the most common investigations that we do in cardiology, and in fact even outside of cardiology, and it is hands down the most accessible, convenient tool to image the heart.

                                                Now let's set this up by remembering that echocardiograms are performed with machines, but led by echocardiologists like me. Now this is really scary Rahul because I think your paper is trying to say ... Are you trying to put people like me out of business?

Dr Rahul Deo:                    Definitely not. I think what I'm hoping to do is actually two things. One of them is, despite the fact that it's an accessible and safe tool, because it needs people like us, it's probably not used as often as ideally it could be. So part of our hope was to democratize echocardiography by being able to take out some of the expenses from the process so that we can hopefully get more simpler studies done at an earlier stage in the disease process. Because in many ways, at least from my experiences being an attending, it feels like if we could just have gotten to these patients earlier we may have been able to start therapy that could've changed the disease course, but our system can't really afford to do huge numbers of echoes on asymptomatic patients. Really we were trying to find some way of facilitating this by at least helping out on trying to quantify some of the simple things that we do with echocardiography.

Dr Carolyn Lam:                I love that phrase, democratizing echo. And you're absolutely right, if we could put it in the hands of non-experts and help them interpret them, we could really lead to detecting disease earlier, and so on and so forth. Wow. But everyone's wondering, how in the world do you go about doing that?

Dr Rahul Deo:                    One of the things that's really been amazing in these last five years or so is that the field of computer vision, so the field by which computers are trained to mimic humans in terms of visualizing, recognizing, identifying images, has really advanced, and incredibly rapidly. And one of the reasons for that is that the video game type of computing system, the same things that go into Playstations and such, have resulted in much, much more rapid computing. And that's allowed us to train more complex models.

                                                So that's one of the things that's changed, and also, it's just much easier to get our hands-on training data. So machines can be trained to do things, but they need lots of examples. And the harder the task, the more examples they need. So the widespread availability of digital data has made that easier, though I would say that it wasn't that easy to get our hands on enough echocardiography data to be able to train. But in general, almost any task where there's enough data has been solved on the computer vision side. So this has really been an exciting advance in these last few years. So we thought we could very well just used these same technologies on a clinical problem.

Dr Carolyn Lam:                Okay, but Rahul what are you talking about here? Like the machine's actually going to recognize different views, or make automated measurements? That's the cool thing, frankly, that you've written about because we know that the machines can already kind of do EF, ejection fraction, but you're talking about something way bigger. So tell us about that.

Dr Rahul Deo:                    Yeah, so there are many cute examples in the popular press about machines being able to recognize the differences between cats and dogs, or some breeds of dogs. And so if you think about things that way, it really shouldn't be that much more difficult to imagine recognizing between different views, which probably are much more dramatically different than different breeds of dogs. So you could really just take the same models, or the same approaches, give enough examples, label them, and then say figure out what the differences are.

                                                And I think one of the challenges with these systems is they're often black boxes. They can't tell us exactly what it is that they're using, but when it comes to something like recognizing whether something is an apical four chamber view or a parasternal long axis view, we actually don't care that much as to how it is that the computer gets there. We just wanted them to do it accurately, and that's one of the places for some of these computer vision models. It's a field broadly called deep learning, and it's just great at achieving complex tasks.

                                                So, once you recognize views, then the other thing that computers have been shown to be able to do is recognize specific objects within an image. For example, you could give an entire football field and you could find a single player within it. You could recognize where the players are, where the ball is, where the grass is. So computers can distinguish all those things too. And then once you know where something is, you can trace it and you can measure it. So in that sense it's very similar to what a human reader would do, it's just broken down into individual steps, and each one of those needs to be trained.

Dr Carolyn Lam:                You put that so simply so that everyone could understand that. That's so cool. You mentioned, though, accuracy. I could imagine that a machine would likely interpret one image the same way again and again, and that addresses something that we really struggle with in echo doesn't it? Because, frankly, one reader against another, we always know. Ejection fraction has got a plus minus seven or something, and then even within the same reader you could read the same thing and say something one day, and say something the other. So this is more than just automating it, is it?

Dr Rahul Deo:                    Yeah, so it's certainly making it more consistent, and the other thing that we were able to do, I mean once you can teach it to identify and traces the contours of the heart in one image you can have it do it in every single image within the video, and every single video within the study. So now, I mean it's quite painful. I know this from my own experience in terms of tracing these things, so a typical reader can't trace 150, 200, 300, 500 different hearts, that's not going to happen. So instead, they'll sort of sift through manually, pick one or two, and if there's variability from one part of the study to the other, that really won't be captured.

                                                And in this case, the computer will very happily do exactly what you ask it to do, which is to repeat the same thing again and again and again, and then be able to average over that, capture variability. So that's one of the tasks that is much more easy to imagine, setting a computer who won't talk back to you and won't resist and won't refuse to actually taking on the mundane aspect of just getting many, many, many more measurements. And that could happen not only in a single study, but also could happen more frequently. So you could imagine that, again, there's just not that resistance that's coming from having to have an individual do these things.

Dr Carolyn Lam:                Oh, my goodness, and not only does he not ... well he, machine, not say no, I mean they don't need to take time off or weekends off. We could get immediate reports directly. Oh my goodness. Victoria I have to bring you in on this. We knew as editors when we found this paper that this is something we just have to publish in Circulation that's going to be groundbreaking. Could you tell us a little bit more about what you think the implications of this is?

Victoria Delgado:              I think that this is a very important paper because it's a very large study and it's sets, I would say, three important questions that we deal every day in clinical practice. One is how to reduce burden in very busy echo labs by facilitating the reporting of the echoes and the interpretation of the echoes. Second: to have an accurate measurement and quantification of the images that we are acquiring, and third: this is recognition of the pattern.

                                                And I think that this very important, particularly in primary care because, for example in Europe here, echocardiography is not really in the primary care and the patients are being referred to secondary level hospitals or third level hospitals. That means that the waiting days sometimes is too long. If we train the general practitioners, for example, to do simple echocardiograms with the handheld systems which are also the technologies that are coming and are really available in your iPhone, for example, on your phone, you can get an echocardiographic evaluation of a patient that comes to a general practitioner.

                                                And if you don't have too much knowledge on interpretation, these tools that can have recognition of the pattern of the disease can trace a red flag and say, okay this patient may have this disease or may have this problem, you should consider sending or referring this patient to us at Leiden Hospital where he's going to have a regular check-up and a complete echocardiogram. That could lead to less burden in very busy labs and only refer the patients in a timely manner to the centers when they have to be referred, when the others can wait of can be referred much later.

                                                I think that that's important, and next two technologies that are coming now and it will be very important, some groundbreaking technologies. One is the handheld systems, the ones that you can have in your phone, the ones that you can have in your tablet for example. And the other one is going to be the artificial intelligence to, if not diagnose completely, at least to recognize the pattern that there is a pathology where we need to focus, and we need to act earlier.

Dr Rahul Deo:                    I think that one place we would like to see this used is in a primary care setting where you have individuals who have risk factors that we know would be risk factors, for example, for let's say heart failure with preserved ejection fraction. But really, my experience in that phase of clinical practice is there's a lot of resistance from patients to get on the medications. So hypertension is, at that point, often, I just got worked up because I had a hard time finding parking, and so on, and so on, where there's just a natural resistance.

                                                So if you could imagine having objective measures describing, let's say how their left atrium is doing at that point, how it looks the next year, what the change in therapy is doing, all these things, you actually can bring in that quantification at a low enough cost that makes it actually practical, then that would be one place we could imagine motivating or intensifying therapies on the basis of something like this.

                                                And I think one area we have to admit we didn't solve is we haven't solved the ability to facilitate getting the data in the first place. We do know that there are these focused workshops around trying to get some simple views, and more and more of our internal medicine residents are able to get some of these, but we can't dismiss that this is still an important challenge in terms of being able to get the images. What we want to do is say, well you can get some images and we can help you interpret them and quantify in an effort to try to motivate therapies being initiated or intensified in a way that's sometimes difficult to do in the current system.

Dr Carolyn Lam:                So, Rahul and Victoria, you both mentioned that one of the key aspects is the acquisition of the echo. Not just the machine that does it, but also who takes the images that will then be automatically analyzed. So, Rahul, do you think that sometimes you're going to invent something that will replace even the acquisition, or maybe even simplify it so that we may not need Doppler anymore?

Dr Rahul Deo:                    One of the things that we thought about was, we wanted to limit ourselves to views that might be easier to acquire, in part because we wanted to reduce the complexity of the study and yet still try to capture as much information as possible. And getting back to the first part of your question, you could imagine that recognizing a view is not that different from recognizing that a view is 10 degrees off from where it should be. You could imagine training a computer to do just that very same thing too. It could recognize a slightly off axis apical four chamber view and guide you into correctly positioning the probe, and you could even imagine a robotic system that does this and just takes the person out of it all together. In part because a very skilled sonographer can quickly look at something and say, oh I just need to tilt my wrist this way and move it this way. I was always humbled by that because I never could quite do that myself.

                                                But in the same way, and in the way, that's happening is that an image is recognized, and then the reference image is held in one's brain, and then they just know from experience what needs to be done to turn one into the other. But that very well-oiled machine could very well be taught to do that exact same thing too.

Dr Carolyn Lam:                Oh wow. That is just totally amazing. I know the listeners are being blown away by this just as I am. Let me just end by asking for any last words, Victoria and Rahul, of the clinical application of this. When are we going to have this primetime? What do you think?

Victoria Delgado:              I think that this is coming. This is one, for example, of the first studies showing the feasibility of this technology. In terms of accuracy, probably we need improvement, but that depends very much on the quality of the echocardiographic data that we obtain. And in the future, I think that we are going to rely more and more on this technology, and we will have the expert view for those cases that are ambiguous or where the technology has limitations. But in terms of accuracy, for example, I can imagine one of the clinical scenarios that we face in everyday clinical practice is the evaluation of the effect of the treatment in heart failure patients for ejection fraction, and in patients, for example, treated with chemotherapy to see changes in ejection fraction.

                                                That, if we do it manually as we do now, we know that we have limitations in terms of the own viability of the observer. If you leave it for artificial intelligence, maybe that viability may be reduced, and you may be better in terms of adjusting the medication if needed. Because you removed completely what would be the individual viability. So these are the fields that probably I see more and more application of this technology in order to improve the reproducibility of the measurements and accuracy. But yeah, for that we need probably very good image quality, and I see in echocardiography we always tend to say, yeah the image quality is not that good. I'm sure that echocardiography can give you much more than just using through the echocardiography. You can use contrast, you can use many other techniques in order to improve the image quality. And artificial intelligence, the better the image quality is, probably the better it's going to be as well, the accuracy of the measurements and the recognition of disease.

Dr Carolyn Lam:                Wow, and Rahul?

Dr Rahul Deo:                    I completely agree with Victoria. I think that we're going to have to be clever about where we incorporate something like this into the current clinical workflow. You have to choose your problem carefully, you have to understand it. Any system like this is going to make some mistakes. To figure out how to minimize the impact of those mistakes, and at the same time add benefit and potentially enable things that wouldn't even be done. So I think that the fun stuff is yet to come here in terms of really incorporating this in a way that can really change clinical practice.

                                                I want to add one thing that I really haven't mentioned. And we, at this point, really just focused on trying to mimic the stuff that we're already doing. Part of the motivation of this work is to try to potentially see things that we can't even see right now and try to potentially predict onset of disease or early latent forms of something that would really be difficult to detect by the human eye. And we've seen examples of that in some of the other fields around radiology, and I think that's going to be a place that would be augmenting beyond what we're even doing currently.

                                                But of course, the challenge is that the system has to be interpretable enough that we understand what it is that it's seeing, because otherwise I'm sure we'll be reluctant to embrace something clinically that we don't understand.

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


Oct 8, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.

                                                The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.

                                                The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.

                                                In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"

                                                Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.

                                                In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.

                                                Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.

                                                They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.

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

                                                Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?

                                                Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.

                                                Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings?

Dr Richard Haynes:          So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.

                                                It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan.

Dr Carolyn Lam:                Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan?

Dr Richard Haynes:          That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way.

Dr Carolyn Lam:                Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that?

Matthew James:              Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease.

Dr Carolyn Lam:                Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right?

Dr Richard Haynes:          Eligibility was actually determined by the EGFR, the estimated GFR.

                                                Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm.

Dr Carolyn Lam:                Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm?

Dr Richard Haynes:          I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial.

Dr Carolyn Lam:                Justin, I mean you come from the heart failure world too just like me. What was your take?

Dr Justin Ezekowitz:        I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.

                                                Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well.

Matthew James:              Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.

                                                I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction.

Dr Richard Haynes:          I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients.

Dr Justin Ezekowitz         I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.

                                                I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.

                                                The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.

                                                The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published.

Dr Carolyn Lam:                You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages?

Braden Manns:                 Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes.

Matthew James:              I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population.

Dr Justin Ezekowitz:        So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely.

Dr Richard Haynes:          I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has.

Dr Carolyn Lam:                Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.

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

Oct 1, 2018

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

                                                FDG-PET CT was recently introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, can we improve on its diagnostic performance? Well, to learn more you have to listen to the upcoming featured discussion, right after these summaries.

                                                Our first original paper this week describes a potential novel therapy for hypertension. In this study from first author Dr Hu, corresponding author Dr Soong, from Yong Loo Lin School of Medicine National University of Singapore, authors showed that galectin-1 is a key regulator for proteasomal degradation of CaV 1.2 channels. L-type CaV 1.2 channels are known to play crucial roles in the regulation of blood pressure. In a series of elegant in vitro and in vivo experiments, the authors showed that galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and thereby, exposing specific glycines for polyubiquitination. This mechanistic understanding provided the basis for targeting CaV 1.2 galectin-1 interaction and demonstrated the modulatory role that galectin plays in regulating blood pressure. The study, therefore, offers a potential novel approach for the therapeutic management of hypertension.

                                                Direct oral anticoagulants or DOACs, are surpassing warfarin as the anticoagulant of choice for stroke prevention in non-valvular atrial fibrillation. However, DOACs outcomes in elective peri-procedural settings have not been well elucidated and remain a source of concern for clinicians.

                                                The next paper in today's issue was a meta-analysis designed to evaluate the peri-procedural safety and ethicacy of DOACs versus warfarin. For author Dr Nazha, corresponding author Dr Spyropoulos, from the Feinstein Institute for Medical Research in Northwell Health at Lenox Hill Hospital in New York, reviewed the literature for data from phase three randomized controlled trials comparing DOACs with warfarin in the peri-procedural period among patients with non-valvular atrial fibrillation. Sub study from four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF. The short-term safety and ethicacy of DOACs and warfarin were not different in patients with non-valvular atrial fibrillation peri-procedurally. Under an uninterrupted anticoagulation strategy, DOACs were associated with a 38% lower risk of major bleeds compared to warfarin.

                                                The next paper presents results from the Sarcomeric Human Cardiomyopathy Registry or SHARE, which combined longitudinal data sets curated by eight international hypertrophic cardiomyopathy specialty centers to provide a better understanding of the factors that contribute to heterogeneous outcomes in lifetime disease burden in patients with hypertrophic cardiomyopathy. First and corresponding author Dr Ho from Brigham and Women's Hospital and colleagues analyzed longitudinal clinical information on 4,591 patients with hypertrophic cardiomyopathy. By examining the data set spanning more than 24,000 patient-years, the mortality of patients with hypertrophic cardiomyopathy was shown to be 3-fold higher than the general population at similar ages. The lifetime cumulative morbidity of hypertrophic cardiomyopathy was considerable, particularly for patients diagnosed before age 40 years and patients with sarcomere mutations. Atrial fibrillation and heart failure were the dominant components of disease burden. Thus, young age of diagnosis and the presence of sarcomere mutations are powerful predictors of adverse outcomes in hypertrophic cardiomyopathy. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.

                                                The final original paper this week provides molecular insights into atherosclerosis and it shows that defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Now, we know that atherosclerotic blocks demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine lesions. In today's paper, first author Dr Shah, corresponding author Dr Bennett from University of Cambridge and colleagues studied levels of 8-oxoguanine and its regulatory enzymes in human atherosclerosis. They found that human plaque vascular smooth muscle cells showed defective nuclear 8-oxoguanine repair, associated with reduced acetylation of the base excision repair enzyme 8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base excision repair defect in vascular smooth muscle cells alone markedly reduced plaque formation, thus indicating that endogenous levels of oxidative DNA damage in vascular smooth muscle cells promoted plaque development.

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

                                                Prosthetic valve endocarditis is a life-threatening complication. However, making a timely diagnosis of prosthetic valve endocarditis before the occurrence of severe complications is really difficult. Now, FDG-PET CT has recently been introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, previous studies reported only modest diagnostic accuracy and may have been hampered by confounders. But today's study, our feature study in Circulation, addresses this issue. We have none other than the corresponding author, Dr Ricardo Budde from Erasmus Medical Center in Rotterdam, the Netherlands, and our dear associate editor, Dr Victoria Delgado, who is in Leiden University Medical Center, also in the Netherlands.

                                                So please tell us, how does your study help us address this issue of the accuracy of FDG-PET CT

Dr Ricardo Budde:           What we actually did is that of course endocarditis is a relatively rare disease, so we had six hospitals in the Netherlands that collaborated on this study and in each of the hospitals we searched for PET CT scans that were performed in patients with a prosthetic heart valve, either because they were suspected of having endocarditis, or if they were meant for other purposes, for example oncological follow-up. Then we grouped all those CT scans together, interpreted the PET CTs anew by dedicated interpreters, and then compared the findings with the actual diagnosis in the patient, which of course is always difficult in endocarditis because to make the diagnosis is difficult. So, also, one year follow-up period was included in that to be absolutely certain whether the patient had endocarditis or not. By taking this whole cohort of patients, we were able to determine the diagnostic accuracy of PET CT, as well as by using a logistics model, identify confounders which influence the diagnostic accuracy of PET CT.

                                                I think the study that we did addresses several important aspects and the way it helps physicians in actually interpreting and implementing PET CT to diagnose endocarditis is two-fold. First of all, we identified confounders that have to be taken into account when interpreting and using the PET CT. For instance, low inflammatory activity at the time of imaging and the use of surgical adhesive during a prosthetic heart valve implantation are confounders which should be taken into account when interpreting the PET CT. Furthermore, the guidelines have always insisted on not to use or use it very cautiously PET CT within the first three months after prosthetic heart valve implantation. However, we showed that actually this period after implantation does not necessarily have to be taken into account as also a good diagnostic accuracy can be obtained within the first three months after implantation.

Dr Carolyn Lam:                Ricardo, that's wonderfully put. I don't do a CT, PET CT, routinely. In fact, I am echocardiologist and it used to be that infective endocarditis was diagnosed with echo. So Victoria, tell us, how does echo stand now with this information?

Dr Victoria Delgado:        That's a very good question but I think the guidelines set a very clear figure of how the diagnostic workup of patients with prosthetic valve endocarditis should be performed. An echocardiography is the first imaging technique. The point is that transthoracic echocardiography in patients with suspicion of prosthetic valve endocarditis is very challenging. In terms of ideal, echocardiography is probably the best imaging technique to do first to evaluate whether it is endocarditis or not. It's difficult, we have to take into account that for a specific prosthetic valve, particularly mechanical, the shadowing can make that we don't see the [inaudible 00:10:22] and sometimes it's difficult, particularly in the early phase immediately after implantation, all the inflammation can be confounder for presence of endocarditis. In those cases, I think that this study provides additional and important data highlighting which are the confounders when you use PET CT to evaluate depressions of endocarditis. I think that, when you take into account those confounders, the accuracy of this technique is very good in order to make or help in the diagnosis of these patients. So, echocardiography, I think that will remain as our first imaging technique to rule out [inaudible 00:11:10] we can see but in those cases where the diagnosis is not confirm or rule out with transthoracic and transesophageal echocardiography this study provides additional data and important data showing that PET CT is a valuable complementary imaging diagnostic test for these patients.

Dr Carolyn Lam:                Ricardo, would you agree with that because I think your study also emphasized that perhaps FDG-PET CT should be implemented early in the diagnostic workup to prevent the negative confounding effect of the low inflammatory activity? So how do we put this all together?

Dr Ricardo Budde:           Well actually, I agree with Dr Delgado that echocardiography is and should be the first-line test that you do if you have a patient that has a suspicion of endocarditis. I mean, the advantages of echocardiography are many and it's non-invasive, it's bedside-available if needed, it's patient-friendly, and it provides a huge amount of information so you should always start with echocardiography. However, sometimes it can be difficult by echocardiography, for the reasons just explained by Dr Delgado, and I think then PET CT should be considered. And when you want to do a PET CT, then you should do it early within the diagnostic workup.

                                                Actually, in the article, one of the figures is a flow chart which we provide, and it provides information on how we think PET CT can best be implemented in the workup of endocarditis. In this flow chart we also start with doing an echocardiography and also, importantly, consult the endocarditis time to make initial classification of whether it's a rejected, possible, or definite prosthetic heart valve endocarditis. After that, you can follow the flow chart and see when you can best implement PET CT, in our opinion.

Dr Carolyn Lam:                Indeed Ricardo, I am so glad you brought up this figure and listeners, you have to take a look at it. I can imagine that everybody will be using this and discussing it and how to incorporate this in the workflow. And indeed you do start with either transthoracic or transesophageal echo and blood cultures, so thank you for clarifying that.

                                                Now, for our clinicians out there, are there any situations you may be telling us to be a little more careful? Could you put it simply for us when it comes to the FDG-PET?

Dr Ricardo Budde:           You mean when not to perform a PET CT?

Dr Carolyn Lam:                Yeah, or when we have to be really careful about inaccuracies.

Dr Ricardo Budde:           I think, of course, the confounders that we indicate in the article, especially if bioglue has been used by the surgeon during the initial surgery. We know that bioglue can be seen on a PET CT as a false positive uptake of FDG and it's also important to note that this is a phenomenon that can persist for a very long time after a valve implantation. It could be for years, so especially that I think is a very important confounder to take into account and be careful when you interpret PET CT or use the PET CT and always read the original surgical report if it is available to obtain this information.

Dr Carolyn Lam:                That's wonderful advice. Victoria, do you have anything to add?

Dr Victoria Delgado:        No, I think that Dr Budde explained perfectly this figure that is key in the article and also how to evaluate patients with suspected endocarditis of prosthetic valve. One thing that sometimes we forget is starting from the first step that is a good clinical history which includes also a good evaluation of previous history and, if possible, what has been done in the patient. I think that this key information to understand the findings on the echocardiography, transthoracic or transesophageal, and the subsequent investigations that you are going to perform. Either CT which is considered, for example, when you have a definitive prosthetic valve endocarditis and you want to rule out potential complications such as abscess, for example, and if you perform a PET CT or other imaging modalities that then also indicate the presence of infection like, for example, [inaudible 00:15:26] leukocytes with PET, for example.

Dr Carolyn Lam:                And I just want to end up with one little point. Ricardo, how about the fact that part of your results don't corroborate the ESC guideline recommendations that they say you have to avoid FDG-PET in the recently implanted prosthetic valve. How do you feel it's going to play out for clinicians?

Dr Ricardo Budde:           Well, I think the 2015 ESC guidelines on endocarditis are a very important document. One must take into account that the inclusion of PET CT in the ESC guidelines was a major step, and some might say that it was a little premature to include the use of PET CT because the number of data that was out there were still relatively limited. I think it's something that we are learning along the way. Now that we are using PET CT more often we are more aware of what we do to findings that we get and also the findings that we have within specific timeframes after the implantation of a prosthetic heart valve. One of the things that I think is desperately needed also at the moment is to have a prospective study where we would do PET CT in patients after implantation of a prosthetic heart valve that do not show any signs of endocarditis where we do PET CT just to determine these normal uptake values. I think that would be a major contribution to the whole learning experience that we're currently having with implementing PET CT within prosthetic heart valve endocarditis.

Dr Carolyn Lam:                Indeed, and Ricardo your paper has added significantly to our understanding. Readers, remember, it's Figure 6 of our feature paper this week. It is a beautiful figure. Pick it up, take a look. In the meantime just thank you so much Ricardo and Victoria for joining me today.

                                                Listeners, don't forget to tune in again next week.


Sep 24, 2018

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

                                                Ticagrelor has shown superior efficacy to clopidogrel in the management of acute coronary syndromes. But what about in patients undergoing PCI for stable coronary artery disease? Well, our feature paper this week gives us answers to this question but you're going to have to wait to the feature discussion to hear these answers. That's coming up right after these summaries.

                                                Our first original paper this week shows that RBM20 mutation carriers have an increased risk of arrhythmias. You may recognize RBM20 as that splicing factor which targets multiple pivotal cardiac genes such as Titin and Calcium/Calmodulin-Dependent Kinase 2 Delta or CAMK2D. In today's paper first author Dr van den Hoogenhof and co-corresponding authors Dr Pinto and Creemers from Academic Medical Center Amsterdam, compared the clinical characteristics of RBM20 and Titin mutation carriers and used RBM20 knock out mice to investigate the downstream effects of RBM20 dependent splicing. They showed that loss of RBM20 disturbed calcium handling and led to more pro-arrhythmic calcium releases from the sarcoplasmic reticulum. Patients that carried a pathogenic RBM20 mutation had more ventricular arrhythmias despite a similarly depressed left ventricular function compared to patients with a Titin mutation.

                                                Targets of RBM20 splicing were enriched for calcium and ion handling genes, most notably CAMK2D and type 2 Ryanodine receptor. Loss of RMB20 induced an increased L-Type Calcium current density, intracellular calcium overload, increased sarcoplasmic reticulum calcium content and increased spontaneous calcium releases which all could be attenuated with treatment with an L-type calcium channel blocker. Furthermore, these results suggest that RBM20 mutation carriers should be closely monitored for potential electrical disturbances and cardiac arrhythmias even in the early stages of disease.

                                                Echocardiographic quantitation of degenerated mitral regurgitation is recommended in clinical guidelines but is it really scalable to routine clinical practice? First author Antoine, corresponding author Sorano from Mayo Clinic Rochester Minnesota and their colleagues looked at more than 3900 patients diagnosed with isolated mitral valve prolapse between 2003 and 2011 and to any degree of mitral regurgitation quantified by any physician or sonographer in routine clinical practice. They found that in multi-variable analysis routinely measured effective regurgitant orifice area was associated with mortality independent of left ventricular ejection fraction and systolic diameter symptoms or age and comorbidities. Furthermore, compared with general population mortality excess mortality appeared for moderate mitral regurgitation with an effective regurgitant orifice area above 20 squared millimeters and became notable with an effective regurgitant orifice area above 30 squared millimeters which then steadily increased with even higher levels of above 40. Thus, quantitation of degenerative mitral regurgitation is scalable to routine clinical practice with strong independent prognostic power when performed routinely by multiple practitioners.

                                                The next study identifies a novel mechanism of lipid homeostasis that is linked to a pseudo gene associated with the recently discovered apolipoprotein known as APOO. Co-first authors Montasser and O'Hare, corresponding author Dr Mitchell from University of Maryland School of Medicine in Baltimore, performed an array based association analysis in more than 1100 Amish subjects and identified a variant strongly associated with LDL cholesterol levels. They identified a founder haplotype on chromosome 5 which was associated with a 15 mg/dl increase in LDL cholesterol after recombination mapping, the associated region contained eight candidate genes. Using a zebra fish model to evaluate the relevance of these genes to cholesterol metabolism they found that the expression of the transcribed pseudo gene APOOP1 increased LDL cholesterol and vascular plaque formation. Thus, based on these data the authors proposed that APOOP1  regulates levels of LDL cholesterol in humans and represents a novel mechanism of lipid homeostasis.

                                                The Orion-1 trial demonstrated that inclisiran which is a small interfering RNA therapeutic that targets PCSK9 MRNA with [inaudible 00:05:42] produces significant LDL reduction. In today's study from Dr Ray from Imperial College London and colleagues, the authors described in detail the effect of inclisiran on prespecified secondary lipid and lipoprotein outcomes over time for up to 210 days and also described the individual variation and response in these measures. They found that a single 300 milligram dose of inclisiran  lowered non-HDL cholesterol at day 180 by 35% and a second dose at day 90 resulted in a 46% reduction at day 180. Similarly a single dose of 300 milligrams of inclisiran  reduced apolipoprotein B by 31% at day 180 and a second dose of 300 milligrams administered in day 90 reduced apolipoprotein B by 41%. Significant reductions in all atherogenic lipoproteins measured were sustained through today 210. Furthermore, every individual had a reduction of apolipoprotein B and non-HDL cholesterol at 180 days with the 300 milligram two-dose regimen of inclisiran. Thus, inhibiting the synthesis of PCSK9 through small interfering RNA may be a viable alternative to monoclonal antibodies with respect to effects on atherogenic lipoproteins and that brings us to the end of our summaries. Now for our feature discussion.

                                                Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndrome but it has not really been assessed in patients undergoing PCI for stable coronary artery disease. For our feature paper today it's going to shed some light and help us with this question and these are the results of the STEEL-PC trial. I'm so pleased to have with me right now the corresponding author Dr Robert Storey from University of Sheffield in the UK as well as our associate editor who managed this none other than Dr Stefan James from Uppsala University. Thank you.

                                                Rob, could you tell us what is the issue you tried to address and because your study is not that simple, we're not used to thinking about these pharmacodynamic and kinetic studies so could you explain a bit of what you did?

Rob Storey:                        Well it's quite a few concepts that we assessed in this study. We've got data from a number of studies showing that Ticagrelor both at doses of 90 mg twice daily and 60 mg twice daily is more reliable and superior P2Y12 inhibitor compared to clopidogrel. We've got this issue of very variable response to clopidogrel with some poor responders and some high responders and a range in between. That's fairly well established and part of this study was to get more data on the 60 mg dose of Ticagrelor in these stable CAD patients undergoing PCI and get some pilot data on clinical efficacy obviously this study was not part of clinical outcomes.

                                                But, there's another issue in terms of adenosine uptake so Ticagrelor has a relatively weak effect on adenosine uptake into red cells and other cells and this may or may not explain some of its clinical effects including some adverse effects such as dyspnea. We wanted to get a better idea of the impact of Ticagrelor at both these doses on adenosine uptake.

Dr Carolyn Lam:                Could I ask ... Okay this may be naïve. I'm not an interventional cardiologist but why would you expect something different in an acute coronary syndrome compared to stable coronary artery disease? Is there an underlying hypothesis there?

Rob Storey:                        Well there can be changes to their differences in platelet reactivity although those aren't particularly great and overwhelmed really by P2Y12 inhibitor like Ticagrelor which gives such reliable inhibition of the P2Y12 receptor. But, there have been a limited number of groups that have looked at adenosine uptake and so we wanted to get independent confirmation or not of whether Ticagrelor therapeutic concentrations impacting on adenosine uptake and get some ideas of whether it's affecting circulating adenosine levels. That's an important question in terms of understanding the mechanisms and actions of Ticagrelor.

Dr Carolyn Lam:                Got it. Thanks for breaking it down so nicely. So what did you find?

Rob Storey:                        What we found was surprisingly that we saw no impact of Ticagrelor at either dose and at any time point within a month after PCI on adenosine uptake. That is the circulating levels of adenosine and the rate at which adenosine is taken up by cells in the blood mainly red blood cells. The explanation for that really is that the therapeutic levels of Ticagrelor that you see are not sufficient to impact on adenosine uptake because it's a very weak inhibitor of the adenosine uptake pathway known as the MT1. The therapeutic levels are just not getting up to a high enough concentration to have a significant impact on that.

Dr Carolyn Lam:                Stefan, you've thought a lot about this. What did you think of the findings?

Stefan James:                    I think it's very interesting. Of course, the pharmacodynamic effects that you can measure by pretty simple means, the level of platelet inhibition, it should be similar in ACS and stable coronary artery disease and I think it's sort of confirming what Rob has been showing in other populations with ACS ... we have been very interested in trying to understand the additional mechanisms of action of Ticagrelor... try to understand the mortality rate without the benefit for Plato, for example. Was it only -- platelet  inhibition or were there other mechanisms? And, there is a specific Ticagrelor related side effect, dyspnea, which we would have been interested in understanding... is this a  mechanism of action? We can't really explain that.  There are other mechanisms and other effects that we have seen can also be explained by adenosine, so I thought it was very interesting and important to understand more about these mechanisms.  

Dr Carolyn Lam:                Yeah.

Stefan James:                    But I would like to ask you, Rob. Do you think this adenosine hypothesis now, is dead, or should we still try to explore this?

Rob Storey:                        Well of course in this study what we didn't look at was the adenosine kinetics in the tissue level which is where we hypothesize the dyspnea may arise from stimulation of C5 is in the lung tissue so we're missing that piece of information. It's still conceivable that very weak levels of ENT-1 inhibition may impact from adenosine levels in the tissue. We're not seeing a strong ENT-1 inhibition sufficient to raise circulating levels or something that we can pick up on this in vitro assay.

                                                I think it still remains an open question. We've got this sort of contradictory information from drugs like cangrelor and other drugs in development like Elinogrel  where we don't see an impact on adenosine but they still may cause dyspnea.  So I think it's a very open question still.

Stefan James:                    Do you think that your paper gives us additional strength to the hypothesis that the mortality benefit for ticagrelor as seen in Plato is explained by the platelet inhibition and the balance between the reduction in ...

Rob Storey:                        Well I think what we see really in all these studies is that Ticagrelor is a fantastically effective PTY12 inhibitor. It gives you the best level of platelet inhibition during maintenance therapy out of all the available PTY12 inhibitors. And clearly having such more reliable PTY12 inhibition than clopidogrel could still be driving a mortality benefit in high risk patients so we can't exclude the adenosine pathway contributing to some of the clinical effects but I think this sways me a little bit more to the position of thinking this is most of the benefits through platelet inhibition.

Dr Carolyn Lam:                Interesting. So you're on the cutting edge of this. What's the next step then?

Rob Storey:                        Clearly we can see that very effective and reliable P2Y12 inhibition is important and leads to clinical benefits and I think we need to implement that wherever we're using P2Y12 inhibitors. We need to take that message and use a more consistent therapy rather among those with associated with variable response which doesn't seem to make sense. I think this stable PCI population, their risk has fallen. And we see that in this study, quite a number of patients report a response to clopidogrel but no stent thrombosis.

                                                That really reflects, I think improvements in stent design and implantation techniques, so the implication is that maybe aspirin alone is enough to prevent stent thrombosis with modern techniques if you get a good result but in the higher risk patients particularly the ACS patients it's likely you need much more reliable platelet inhibition and that's why Ticagrelor really provides this security.

Dr Carolyn Lam:                So, Rob there is one thing you tested two doses and they seemed to be equivalent at least in antiplatelet inhibition, right? So what does this mean? Should we maybe preferentially use the lower dose from now on, is there still room for the higher dose? Could you share some insights there?

Rob Storey:                        Well I think one has to be cautious in not jumping to adopt a dose just on the basis of pharmacodynamic data but clearly what we show is that the 60 mg dose of Ticagrelor offers a very reliable and consistent level of PTY12 inhibition and that's likely to be very effective in preventing stent thrombosis in combination with aspirin. We also show signals that were also shown in the Pegasus study that the 60 mg dose may be better tolerated such as with lower levels of dyspnea.

                                                So, there is the option for off label use of the lower dose of Ticagrelor in those who cannot tolerate the high dose due to dyspnea because certainly they'll have better platelet inhibition down titrating from 90 to 60 and if they were to switch to Clopidogrel. So I think our study offers some comfort in terms of that aspect. The only caveat is that you have to be careful not to use strong CYP3A inducers such as some epilepsy drugs with Ticagrelor cause that can increase the metabolism and we did have one case of high platelet reactivity with strong CYP3A inducers so using a higher dose initially I think is a good idea. The label says 90 mg for 1 year following ACS and the 6 is licensed beyond one year as a down titration predominantly.

                                                Our study certainly gives some comfort that down titrating earlier if a patient can't tolerate the 90 for whatever reason, seems to be a justifiable thing. And the other thing is the European guidelines support the use of Ticagrelor off label in elective PCI and our study certainly gives some comfort that off label use and the low risk elective PCI patients of the 60 mg dose can be justified at least from a pharmacodynamic point of view.

Dr Carolyn Lam:                Well, thank you because that's exactly what our audience is loving to hear. How do these findings translate into the clinical practice - Would you have any other take home messages for the clinicians listening in?

Rob Storey:                        Well I think one thing we looked at also was troponin release which is very common after PCI. We didn't see an impact of PTY12 inhibition high levels on troponin  release and I think that sort of caveat in terms of that's not going to be the best measure in terms of surrogate for efficacy in the PCI population. The other question really is, how much of the platelet inhibition and how much of the adenosine effects of Ticagrelor influence the clinical outcomes and clearly the studies sways towards the platelet inhibition very consistent high level of platelet inhibition explaining most of the benefits.

Carolyn Lam:                      You've been listening to circulation on the run, don't forget to tune in again next week.


Sep 18, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's journal features two papers that deal with genetic testing in young athletes and for sudden arrhythmic death, and with findings that may surprise you. They really show the complexities of this era of genetic testing and cardiovascular medicine, and in fact are discussed as growing pains in cardiovascular genetics. You must listen to our feature discussion, which is coming right up after these summaries.

                                                The first original paper this week suggests that targeting fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis. Fibronectin polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblast following cardiac injury. In today's paper, first author Dr Valiente-Alandi, corresponding author Dr Blaxall from University of Cincinnati College of Medicine and Heart Institute, and their colleagues hypothesized that interfering with fibronectin polymerization, or its genetic ablation and fibroblasts, would attenuate myocardial fibrosis and improve cardiac function following ischemia reperfusion injury. Using mouse and human cardiac myofibroblasts, authors found that the fibronectin polymerization inhibitor pUR4 attenuated the pathological phenotype exhibited by mouse and human myofibroblasts by decreasing fibronectin polymerization and collagen deposition into the extracellular matrix as well as by myofibroblast proliferation and migration.

                                                Inhibiting fibronectin matrix deposition by pUR4 treatment or by deleting fibronectin gene expression in cardiac fibroblasts confirmed cardioprotection against ischemia reperfusion-induced injury by attenuating at first left ventricular remodeling and cardiac fibrosis, thus preserving cardiac function. In summary, interfering with fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure.

                                                The Insulin Resistance Intervention after Stroke, or IRIS trial, demonstrated that pioglitazone reduced the risk of both cardiovascular events and diabetes in insulin-resistant patients. However, concern remains that pioglitazone may increase the risk of heart failure in susceptible individuals. To address this, Dr Young from Yale Cardiovascular Research Center and the IRIS investigators performed a secondary analysis of the IRIS trial. They found that older age, atrial fibrillation, hypertension, obesity, edema, high CRP, and smoking were risk factors for heart failure.

                                                Pioglitazone did not increase the risk of incident heart failure, and the effect of pioglitazone did not differ across levels of baseline risk. It should however be noted that in the IRIS trial, the study drug dose could be reduced for symptoms of edema or excessive weight gain, which occurred more often in the pioglitazone arm. Overall, pioglitazone reduced the composite outcome of stroke, MI, or hospitalized heart failure in the IRIS trial.

                                                The next study highlights the importance of genetic variation in cardiac fibrosis and suggests that while fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In this paper from co-first authors Dr Park and Ranjbarvaziri, corresponding author Dr Ardehali, from David Geffen School of Medicine, University of California, Los Angeles, the authors utilized a novel multiple-strain approach known as the Hybrid Mouse Diversity Panel to characterize the contributions of cardiac fibroblasts to the formation of isoproterenol-induced cardiac fibrosis in three strains of mice.

                                                They found that isolated cardiac fibroblasts treated with isoproterenol exhibited strain-specific increases in the levels of activation, but showed comparable levels of proliferation. Similar results were found in vivo with fibroblast activation but not proliferation correlating with the differential levels of cardiac fibrosis after isoproterenol treatment. RNA sequencing revealed that cardiac fibroblasts from each strain exhibited unique gene expression changes in response to isoproterenol.

                                                The authors further identified LTBP2 as a commonly upregulated gene after isoproterenol treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure, suggesting that it may be a potential therapeutic target. That brings us to the end of our summaries. Now for our feature discussion.

                                                We all know that t-wave inversion is common in patients with cardiomyopathy, however up to a quarter of athletes of African descent, and five percent of white athletes also have t-wave inversion on ECG, but with unclear clinical significance despite comprehensive clinical evaluation. Now, what is the role in diagnostic use of genetic testing beyond clinical evaluation when we investigate these athletes with t-wave inversion? Well we're about to get some answers in today's feature paper, and I'm so pleased to have the corresponding author of the paper, Dr Sanjay Sharma from St. George's University of London, as well as our associate editor Dr Mark Link from UT Southwestern.

                                                Sanjay, please let us know what you did and what you found.

Dr Sanjay Sharma:            Well as you rightly say, that up to 25% of black athletes have t-wave inversion, as do three to five percent of white athletes. And these t-wave inversions often overlap with the sort of patterns that you see in patients with hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. For example, 80% of people with hypertrophic cardiomyopathy have t-wave inversion as do 60% of patients with ARVC. Now we know that some ECG patterns, t-wave inversions in V1 to V4 are benign in black patients, but the significance of other ECG patterns is unknown. Cascade screening in family members with cardiomyopathy have shown that t-wave inversion may be the only manifestation of gene inheritance, and there are reports to suggest that some athletes with t-wave inversion do go on to develop overt cardiomyopathy. Now when we investigate the vast majority of our patients with t-wave inversion, these are our athlete patients, we don't actually find anything. But over the past decade, also, these has been major advance in next generation sequencing that allows us to perform genetic testing in a large number of genes that can cause diseases, capable of causing sudden death.

                                                And so, we thought we'd investigate the role of this gene testing in athletes with t-wave inversion. We looked at a hundred, 50 black athletes and 50 white athletes who had t-wave inversion, and we investigated them comprehensively with clinical tests. But we also added in a gene panel looking at 311 genes implicated in six cardiac diseases, notably hypertrophic cardiac myopathy, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, long QT syndrome, and the brugada syndrome. We found that 21% of our athletes were then diagnosed with a cardiac disorder capable of causing sudden death, and the vast majority of these people had hypertrophic cardiomyopathy. And this diagnosis was based on clinical evaluation. When we looked at gene testing, we found that gene testing only picked up a problem in 10%. So, the diagnostic yield of gene testing was half that of comprehensive clinical investigation.

                                                When we actually looked at athletes who had nothing wrong with them in clinical investigation, and actually had a gene mutation, we found that only 2.5% of athletes who had t-wave inversion but clinically normal tests, actually had something wrong with them. And our conclusions were that gene testing picks up only half the athletes that clinical testing does, and gene testing is only responsible for identifying 2.5% of athletes with t-wave inversion, where clinical tests are negative. That was the summary of our study in short. We did find that black athletes were less likely to have a positive diagnosis of cardiac myopathy than white athletes, and black athletes are also less likely to have a genetic mutation capable of causing a cardiomyopathy than white athletes.

Dr Carolyn Lam:                First and foremost, congratulations on such a beautiful paper, and so wonderfully summarized as well. It really seems to fly in the face, doesn't it? Of the way we've been discussing personalized medicine and saying that we're going to start whole genome sequencing everyone and that's going to provide all the answers for future disease risks. I mean, if I'm not wrong, what your paper is trying to tell us is that at this moment we don't have good examples where genetic testing may trump clinical diagnoses, and in fact we should be still focusing on a comprehensive clinical evaluation of patients and in the absence of a genotype we should learn to question what we're doing in genetic testing. Do you agree with that?

Dr Sanjay Sharma:            You couldn't have said that more precisely. As I've said, the diagnostic yield of clinical testing was 21% versus only 10% with genetic testing. The diagnostic yield of pure genetic testing in people with otherwise completely normal findings clinically was only 2.5%. And the other thing that I forgot to tell you was that genetic testing, if we included genetic testing in addition to comprehensive assessment, cost us three times as much as clinical investigation on its own, and had we relied solely on genetics, and nothing else, it would have cost us ten times more than clinical testing. So our cost per making a diagnosis using genetics only would have amounted to $30,000 per condition.

Dr Carolyn Lam:                Wow, what a great wake up call. Mark, you've thought a lot about this and in fact there was another paper in this week’s journal that has very complimentary messages. In fact you invited an editorial by Dan Roden, and I really loved his title of it, "Growing Pains in Cardiovascular Genetics." Would you maybe add your thoughts in relation to the other paper, as well as overall?

Dr Mark Link:                     Sure. Circulation was very interested in these papers. These are really  ... Now, as Dan Roden says, "Growing pains." Twenty years ago when genetics came out it was looked upon as it was going to completely change our clinical medicine and precision medicine is really relying a lot on genetics. And while ultimately that may be the case, we are in a stage now where the honeymoon is over. And the other paper that was in this same issue was a paper by Hosseini  and colleagues, and it was the Clin Gen paper looking at the Brugada Syndrome abnormalities. Now the Clin Gen is an NIH sponsored group that takes individuals from a number of different institutions and actually gene testing, and tries to provide an independent assessment of the abnormality of genes. Previously is was companies that did this. A company would gene test ... They would look for gene abnormalities, try to link it with clinical disease, and they could basically then do just on their patients. But Clin Gen now is trying to tie all those companies together to get a broad consortion and to look at genetic abnormalities and whether they're truly pathologic, where there's areas of unknown significance, or whether they're truly not pathologic.

                                                So as an example, they took Brugada Syndrome, and they took the different gene abnormalities that have been described from basically different companies and different labs and different institutions, and they looked at the evidence behind the fact that they were truly pathologic, 'cause all 21 genes were defined as pathologic. They found in their independent assessment that only one ended up to be truly pathologic, and the others ones were disputed. And sort of another wakeup call that just because a single company calls a gene pathologic or Brugada Syndrome, does not make it pathologic necessarily. So we all thought these were two very important papers that looked at some of the limitations of genetic testing. We asked Dan Roden, who is really a very accomplished scholar in this field, to provide perspective on this. And I agree, I loved his title, "Growing Pains in Cardiovascular Genetics." And what he did is reviewed the history of genetic testing, and he actually starts before genetic testing and starts with Mendelian genetics, and [inaudible] genetics. And then 23 years ago they started linking that Mendelian genetics to gene abnormalities, especially in diseases such as long QT syndrome and hypertrophic cardiomyopathy.

                                                We've come a tremendous way in diagnosing gene abnormalities and associating them with these underlying cardiac myopathies and hind channel abnormalities. So no one doubts we've come a tremendous way, but there's a long way to go in terms of getting better diagnostic accuracy and really defining where these genetic testing are ultimately going to play out in clinical medicine. So everyone's excited about it, but I think these two papers are two cautionary tales that we do have to remember that genetic testing in 2018 is not the end all and be all.

Dr Carolyn Lam:                I love that, cautionary tales. So important. But where do we go from here? What's the take home message for clinicians listening to this today in 2018? I mean is it that perhaps when we do these things we now need to include medical geneticists and genetic counselors as vital partners as we look at this all? Perhaps we need to not forget the primacy of clinical evaluation. What do you think, Sanjay?

Dr Sanjay Shar:                  Well, there are guidelines from the American Medical Genetics side as to what one defines as a disease-causing mutation. But I agree that we need to be using certified laboratories that can actually interpret the genetic mutations. For example, in our study of athletes, 63% actually had variance of undetermined significance. So they had spinning mistakes in their genes which probably didn't account to anything at all, but had these mutations, or these so called variance of undetermined mutations been interpreted by someone who didn't really know much about this, these could have resulted in false positive results which could cause absolute chaos for an athletes career. So I do think this type of testing has to be governed very, very carefully and needs to be performed in very specialized and certified laboratories.

Dr Carolyn Lam:                Indeed. Not just to the athlete, but to their families too, isn't it? Mark, what do you think is the take home message [inaudible 00:16:18]?

Dr Mark Link:                     I think one of the big take home messages that I took away from these papers is that clinical medicine is not dead. In fact, clinical medicine in this day and age is still the prime way of taking care of patients. Genetic testing is still in its infancy. It doesn't help clinically in too many situations yet. It will in the future. It helps in the diagnosis, it's not as useful in the treatment. So we have a long ways to go with genetics. I like your comment that going forward we're going to need more genetic counselors to make sense of these results. Clinicians are going to have a hard time making sense of these results. I do think that there is plenty of role once a disease causing mutation has been defined, and in that situation it's invaluable in cascade screening in identifying other family members who may be affected, but outside that I do believe and I agree completely with both of you, that clinical medicine is not dead. And clinical evaluation should be number one and should enjoy it's prime time because that's where we still are at. And genetics is still in its infancy and so is cardiology.

Dr Carolyn Lam:                Perhaps in selective settings ... We're not talking here about, for example, hypercholesteremia variance, we're not talking about cancer gene variance for which screening may be a little bit more advanced, and we may understand the gene phenotype associations that are perhaps-

Dr Mark Link:                     I think that understanding gene phenotype associations are going to be critically important in the future. I think, as Sanjay said, the real use of genetic screening now is cascade screening for the family, and there it's invaluable. That you can tell if you've got a co-band with the disease, and with a defined pathological mutation. You can test siblings, sons and daughters, parents to see if any of them have the gene. I think that's where it should be used for sure in 2018.

Dr Carolyn Lam:                Thank you so much Mark and Sanjay. So some precautions, some hope. Very, very balanced discussion. So much more we could discuss, so I really want to highly encourage our audience. Pick up this issue. You have to read these amazing papers and the editorials.

Dr Carolyn Lam:                So, here's a podcast with all your colleagues, and don't forget to tune in next week.


Sep 10, 2018

Dr Carolyn Lam:                We start today's podcast with a few words from our Editor-in-Chief, Dr Joe Hill.

Dr Joe Hill:                           I speak with you today with a heavy heart as we recently lost an esteemed and beloved colleague, Professor Bongani Mayosi. Bongani was a pioneering leader, a renowned investigator, Dean of the Medical School at the University of Cape Town, and an important member of our Circulation editorial leadership team.

                                                Bongani had an abiding passion for the under-served, especially those in his native Africa. He died tragically and suddenly at the early age of 51, just 10 days after recording the podcast you're about to hear.

                                                We mourn the loss of this colleague and our hearts go out to his family. It is a very poignant moment, as we hear his voice once again. We grieve deeply, and are reminded of Bongani's towering achievements and contributions to the betterment of our world.

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.

                                                CD4-positive T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Today's paper describes the first study to detect apolipoprotein B peptide 18 specific CD4 T cells in mice and humans. First author Dr Kimura, corresponding author Dr Ley from La Jolla Institute of Allergy and Immunology and their colleagues constructed novel P18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotypes by flow cytometry. They found that these P18 specific T cells were mainly anti-inflammatory regulatory T cells in healthy donors, but co-expressed other CD4 lineage transcription factors in patients with sub-clinical cardiovascular disease.

                                                Immunization with P18 reduced atherosclerotic burden in APOE deficient mice and induced antigen specific T regulatory cells. This study therefore, identifies APOB peptide 18 as the first T regulatory APOtope in human atherosclerosis.

                                                The next study suggests that testing intracellular calcium handling in circulating B lymphocytes may be a novel biomarker for monitoring patients with heart failure. During [inaudible 00:02:47] intracellular calcium is released from sarcoplasmic reticulum into the cytoplasm through Type II ryanodine receptor calcium release channels. In heart failure chronically elevated, circulating catecholamine levels cause pathologic remodeling of these Type II receptors, resulting in diastolic sarcoplasmic reticulum calcium leak, thus decreasing myocardial contract [inaudible 00:03:09]. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum calcium release and this occurs through Type I ryanodine receptors. Chronically elevated catecholamine levels in heart failure cause Type I mediated sarcoplasmic reticulum calcium leak, thus contributing to skeletal myopathy and weakness.

                                                In today's paper, first author Dr Kushner. Co-corresponding authors Dr Kitsis from Albert Einstein College of Medicine and Dr Marx from Columbia University, New York hypothesized, that since circulating B lymphocytes express Type I ryanodine receptors, they may be a potential surrogate for defects in intracellular calcium handling due to leaky ryanodine channels in heart failure. Indeed, they found that circulating B lymphocytes from humans and mice with heart failure exhibited remodeled Type I ryanodine receptors and decreased endoplasmic reticulum calcium stores, consistent with chronic intracellular calcium leak. This calcium leak correlated with circulating catecholamine levels. The intracellular calcium leak was significantly reduced in mice treated with S107, which is a drug that specifically reduces ryanodine receptor calcium leak.

                                                Furthermore, heart failure patients treated with LVADs exhibited a heterogenous response. Thus, Type I ryanodine receptor mediated calcium leak in B lymphocytes assessed using flow cytometry may provide a surrogate measure of intracellular calcium handling and systemic sympathetic burden and therefore represent a novel biomarker strategy for monitoring the responses in heart failure therapy.

                                                Hypouricemia and gout are known to be associated with increased risk of cardiovascular disease. And xanthine oxidize inhibitors such as allopurinol and febuxostat are the mainstay of urate lowering treatment of gout, but do they have different effects on cardiovascular risk? First author, Dr Jong, corresponding author, Dr Min from Brigham and Women's Hospital Harvard Medical School in Boston, Massachusetts, studied a cohort of almost 100,000 older Medicare patients with gout and found that there was, overall, no difference in the risk of MI, stroke, new onset heart failure, coronary revascularization are all cause mortality between patients initiating febuxostat compared to those initiating allopurinol. However, there did seem to be a trend toward an increased opiate not statistically significant risk for all-cause mortality in patients who use febuxostat for over three years compared to allopurinol use for over three years. The risk of heart failure exasperation was slightly lower in febuxostat initiators.

                                                The final original paper this week provides important contemporary data on the clinical characteristics in hospital management and long-term outcomes of patients with acute myocarditis. Co-corresponding authors, Dr Ammirati and Kamichi, both from Milan, Italy and their colleagues screened 684 patients with suspected acute myocarditis and recent onset of symptoms within 30 days between May 2001 and February 2017 and included 443 patients with acute myocarditis diagnosed either by endomyocardial biopsy or by increased troponin and edema and late gadolinium enhancement on cardiac magnetic resonance imaging. They showed that among these 443 patients, 118 patients or 26.6% had either left ventricular ejection fraction less than 50% sustained ventricular arrhythmias or a low cardiac output syndrome. While, the 73.4% had no such complications.

                                                Cardiac mortality and heart transplantation at five years was 4.1%, but went up to 14.7% in the patients with complicated presentation and contrast down to zero percent in the uncomplicated cases. Similarly, major acute myocarditis related cardiac events after the acute phase, such as post discharge death and transplantation, sustained ventricular arrhythmias, symptomatic heart failure needing device implantation all occurred in 2.8% at five years, but was much higher in patients with a complicated presentations at 10.8% versus zero percent in the uncomplicated presentations. Thus, the authors concluded that patients with acute myocarditis can be effectively stratified based on their initial clinical presentation. Patients with left ventricular ejection fraction less than 50% at the first echo. Those with sustained ventricular arrhythmias or those with low cardiac output syndrome are at higher risk of cardiac events compared to those without these manifestations.

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

                                                With advances in therapy most deaths in people with HIV are now due to noncommunicable diseases, especially cardiovascular disease. What does the global burden of HIV associated cardiovascular disease really look like? Well we're going to get some answers in today's feature paper. I have with us today the first and corresponding author of the paper, Dr Anubshaw from University of Edinburgh, as well as our associate editor, Dr Bongani Mayosi from University of Cape Town in South Africa.

Dr Carolyn Lam:                Welcome to you both. And Anub, what an important question to examine. Could you tell us how you looked into this question and what you found?

Dr Anubshaw:                   Sure. So, this is a very interesting question from our end and we had in short idea looking at the risk of cardiovascular disease in patients with HIV. And there are many studies of it, varying results. I'm looking at the risk of heart disease and stroke in patients with HIV. So, what we did was a big systematic review to extract all the data out there looking at the risk of heart disease in patients with HIV, we then developed a model that looked at what the overall risk was and then tried to calculate the actual burden of cardiovascular disease attributable to patients with HIV. In some of the work we found, well, primarily we found that the majority of the burden, as expected in Sub-Saharan Africa and that is primarily the cause, in prevalence of HIV is the highest in Sub-Saharan Africa, accounting for about two thirds of all people living with HIV.

Dr Anubshaw:                   The risk of cardiovascular disease with patients with HIV is twofold higher compared to patients not infected by virus. And there was not [inaudible 00:10:12] variations in the actual burden. The majority of the burden in Sub-Saharan Africa and Southeast Asia.

Dr Carolyn Lam:                Wow, Sub-Saharan Africa and Asia Pacific, isn't it? Oh my goodness, Bongani, your views please on these standing results from Africa.

Dr Bongani Mayosi:         Yes. I think these results are actually very important in the Sub-Saharan African region, reaching the, at the center of the HIV/AIDs epidemic in the world. And particularly important now that we are finding people and are on treatment and that they are growing older and there's a thriving proportion of people above the age of 60, they are on HIV infection and therefore the whole question of cardiovascular disease in these patients has become very important and clearly now these data suggest that HIV [inaudible 00:11:08] for cardiovascular disease, but what is more important [inaudible 00:11:14] they are important [inaudible 00:11:17] for cardiovascular disease, but also a [inaudible 00:11:22]. [inaudible 00:11:23] such as another vascular condition, which is pulmonary hypertension associated with HIV detection. [inaudible 00:11:35] with the increase of the number of people on treatment, these particular conditions are becoming [inaudible 00:11:43] in the context of how to [inaudible 00:11:48], but is an important condition in the African continent. So that the overall burden of cardiovascular disease is likely to be greater than is estimated here because the study is only estimating atherosclerotic cardiovascular disease.

Dr Anubshaw:                   That brings up a very intriguing question, Anub. Could you at all distinguish between atherosclerotic risk factors and the role that played versus more HIV specific risk factors, such as the medication, the degree of HIV control, level of inflammation, for example? Now, of course in a meta-analysis this may be difficult, but just your thought.

                                                You're absolutely right from a meta-analysis point of view it's very difficult for a couple of reasons. Firstly, we do not have individual patient level data, so we couldn't really see a [inaudible 00:12:45] level which patients are on [inaudible 00:12:47] therapy and what their personalized risk factors are. Varying schools of thought estimated around the candidates that they need, which kind of portrays a risk of heart disease in the [inaudible 00:12:59] artery in patients with HIV. And what we think may be happening there, one that HIV represents a degree of sub-clinical inflammation that leads to vascular inflammation, which then leads to accelerated atherosclerosis and there's some fantastic mechanistic evidence looking at this where, workers have looked at vascular inflammation in the arteries in patient HIV can go through control and you do get much more vascular inflammation. There is some evidence about the fact that the [inaudible 00:13:31] therapy itself can cause [inaudible 00:13:34] and therefore increase the risk of atherosclerotic heart disease.

                                                And finally, some risky behavior is probably much more, have a look at HIV for example, smoking entered the [inaudible 00:13:46] etc., etc. and there may be a degree of overlap in terms of or correlation in terms of risk factors being much more common in HIV patients, which are more conditional for atherosclerotic heart disease. I think a combination of all those three things probably explain the increase risk of atherosclerotic heart disease and strokes in these patients.

Dr Carolyn Lam:                Indeed. Your paper is so important to raise awareness of that very risk. I mean, if I could please re-iterate, you show very clearly that people with HIV are the two fold increase risks of cardiovascular disease and that that global burden had tripled over the last two decades. I think that your paper really shines a bright light in this area, that we have to study further because the clinical implications are enormous aren't they? Because we're using guidelines developed in non-HIV patients to perhaps treat these cardiovascular diseases in HIV patients and there may be other pathophysiologic mechanisms like you just mentioned. What do you think are the main clinical implications of your paper?

Dr Anubshaw:                   The clinical implication is quite important because what the burden estimate show is that the majority of burden is in no or little information and therefore the resource of those innovations are quite limited, but there's one condition that has been treated so well in these countries. One of the main success stories of medicine, over the last two or three decades and how they've tackled HIV, who runs PEP for has made intrical virals available so widely in the Sub-Saharan African regions, while there's other highly prevalent regions. And they set up logistically clinics to deliver and scare for persons with HIV and if you and I will see that the survival in these patients [inaudible 00:15:39] just mentioned. Then, these patients are at more high risk of other among AIDs related conditions, such as strokes and heart disease. What you now have in these poor resource countries or limited resource countries, where clinics and the logistical support is only set up to deliver cardiovascular risk prevention strategies and therapy. Which is not expensive in terms of antihypertensives, in terms of [inaudible 00:16:06] and in terms of lifestyle factors.

                                                So, I think there is [inaudible 00:16:10] here that the region has to further reduce the cardiovascular burden in this population.

Dr Carolyn Lam:                Bongani, you too recognize the very important clinical implications and in fact invited the editorial by Priscilla Sue and David Waters from San Francisco General Hospital. I love the title of it. Is it time to recognize HIV as a major cardiovascular risk factor? Bongani, what are your thoughts?

Dr Bongani Mayosi:         I think it is time we should be considering the HIV as a risk factor for cardiovascular disease. You know these data arriving from this [inaudible 00:16:48] are quite compelling and when you look, for example at that this is a hot study [inaudible 00:16:55] in the editorial and conferred by HIV, it is almost the same as the other [inaudible 00:17:02]. I mean if you go into it now that in fact the European Society of Cardiology it is already [inaudible 00:17:12] in HIV infected individuals with [inaudible 00:17:19]. So, if now may be entering their [inaudible 00:17:27] of practice, they consider HIV as a significant risk factor for cardiovascular disease and maybe contribute to bring a drug that will modify outcome. I do think though that because of the mechanism of cardiovascular disease it [inaudible 00:17:45] HIV it is not common on the basis of atherosclerotic disease. In Africa as an example, we know very well that the patient tend to [inaudible 00:17:55] with not a lot of traditional risk factors of cardiovascular disease, in fact, atherosclerotic diseases such as [inaudible 00:18:07] still have a relatively low level of [inaudible 00:18:10].

                                                So, we still, I think need to discover what are the other [inaudible 00:18:14] mechanisms that are involved, I mean they do that very much more targeted drug [inaudible 00:18:21] where it needs to be tested, that don't know our traditional interventions for reducing risk and preventing cardiovascular disease. So, there is need for further research here and the mechanisms and specific intervention. That is the important in this large HIV infected populations because at the moment there at least 27 million people in the world, living with HIV who already facing a major public health issue on a global scale.

Dr Carolyn Lam:                Exactly and all these new research efforts, paying attention to this, making sure that we don't underestimate cardiovascular risk and HIV based on traditional risk calculators. All of this starts with awareness and with important papers such as yours, Anub. Thank you so much for publishing that with us at Circulation.

                                                Well, listeners you know how important this is globally, so please share this podcast with your colleagues and don't forget to tune in next week.


Sep 4, 2018

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

                                                Current guidelines recommend measurement of one of the cardiac specific isoforms of cardiac troponin complex. However, what's the utility of combining measurements of troponins I and T in the early diagnosis of acute myocardial infarction? Well, you have to wait for our upcoming feature discussion, but it's coming right up after these summaries.

                                                The first original paper this week sheds light on the genetic basis and mechanisms of bicuspid aortic valve, the most common congenital heart defect in the population. We know that bicuspid aortic valve is an autosomal dominant trait with variable expression and incomplete penetrants suggestive of genetic and environmental modifiers. In the current study, first author Dr Gharibeh, corresponding author Dr Nemer from University of Ottawa, and authors of the Bicuspid Aortic Valve Consortium assessed cardiac structure and function in mice, lacking a GATA6 allele. They found that GATA6 heterozygous mice had a highly penetrant type of bicuspid aortic valve with right and left leaflet fusion, which is the most frequent type found in humans. GATA6 transcript levels were lower in human bicuspid aortic valve as compared to normal tricuspid valves. Mechanistically, GATA6 haploinsufficiency disrupted valve remodeling and extracellular matrix composition through dysregulation of the importance in the molecules including matrix metalloproteinase nine. Cell-specific inactivation of GATA6 reveal that an essential rule for GATA6 in secondary heart field myocytes. Thus, the study identifies a new cellular and molecular mechanism underlying bicuspid aortic valve.

                                                In the field of cardiac regeneration, c-Kit positive adult progenitor cells were initially reported to produce new cardiomyocytes in the heart. However, more recent genetic evidence suggests that such events are exceedingly rare. Today's paper provides insights into this discrepancy and it is from first author Dr Maliken, corresponding author, Dr Molkentin from Howard Hughes Medical Institute Cincinnati Children's Hospital Medical Center. The authors took a novel approach of deleting the necessary cardiogenic transcription factors, GATA4 and GATA6, from c-Kit expressing cardiac progenitor cells to determine whether true de novo cardiomyocyte formation would occur. They found that deletion of the necessary cardiogenic transcription factors, GATA4 and GATA6, from these c-Kit+ cardiac progenitor cells remarkably resulted in greater apparent cardiomyocyte derivation from the c-Kit+ cells. Deletion of GATA4 from c-Kit–derived endothelial progenitors altered the integrity of the endothelial cell network in the heart, resulting in greater c-Kit+–derived leukocytes entering the heart and fusing with cardiomyocytes.

                                                Thus, they demonstrated a new role for GATA4 in endothelial differentiation, specifically showing for the first time that GATA4 is essential for vascular development by the c-Kit lineage. The study shows that leukocyte to cardiomyocyte fusion is the primary basis for path lineage tracing results, incorrectly suggesting that c-Kit+ cardiac progenitor cells generated de novo cardiomyocytes in the heart.

                                                Lecithin–cholesterol acyltransferase, or LCAT, is the sole enzyme that esterifies cholesterol in the plasma. Its role in the supposed protection from atherogenesis remains unclear, because mutations in LCAT can cause more or less carotid atherosclerosis. Addressing this conundrum, co-first authors Drs. Oldoni and Baldassarre, co-corresponding authors Dr Kuivenhoven from University Medical Center Groningen, Dr Holleboom from Academic Medical Center Amsterdam, and Dr Calabresi from University of Milano in Italy hypothesized that genetic mutations causing complete LCAT deficiency versus partial LCAT deficiency would be differentially associated with carotid atherosclerosis in carriers of LCAT mutations. To study this, they looked at 74 heterozygotes for LCAT mutations who are recruited from Italy and the Netherlands and who were assigned to complete versus partial LCAT deficiency. These were also compared to 280 controls. Using carotid intima-media thickness as a measure of atherosclerosis, the authors demonstrated that carriers of LCAT mutations leading to complete LCAT deficiency exhibited less carotid atherosclerosis, indicating a reduced risk of cardiovascular disease.

                                                By contrast, however, carriers of LCAT mutations leading to partial LCAT deficiency showed marginally more atherosclerosis. The association of mutations in LCAT with subclinical atherosclerosis appeared to be related to the capacity of LCAT to esterify cholesterol on apoB-containing lipoproteins since the abnormal LCAT present in the partial deficiency was only active on this class of lipoproteins. These important findings bear relevance for pharmaceutical strategists that target LCAT.

                                                After a bioprosthesis aortic valve replacement, what is the incidence, correlates, and outcomes of hemodynamic valve deterioration? First author Dr Salaun, corresponding author Dr Pibarot from Quebec Heart and Lung Institute and their colleagues studied 1,387 patients who underwent bioprosthetic aortic valve replacement and found that hemodynamic valve deterioration identified by Doppler echocardiography occurred in one-third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes and renal insufficiency were associated with early hemodynamic valve deterioration whereas female sex warfarin use and stented bioprosthetic valve versus the stentless ones were associated with late hemodynamic valve deterioration. These findings suggest that following bioprosthetic valve replacement, a systematic echocardiographic follow-up may be considered to ensure adequate detection and quantitation of hemodynamic valve deterioration.

                                                That wraps up on the summaries this week. Now for our feature discussion.

                                                We are recognizing the critical role that cardiac troponins play for the early diagnosis of acute myocardial infarction. We also know that there are different isoforms of cardiac troponins, the cardiac troponins T and I. Now, have you ever considered combining the two? How does that help the early diagnosis of acute myocardial infarction? Well, I am delighted to have with us the corresponding author of our feature paper today, Dr Christian Mueller from University Hospital Basel in Switzerland, a very familiar voice on this podcast. Welcome, Christian, and thank you so much for publishing yet another wonderful paper with us.

Dr Christian Mueller:      Thank you very much for highlighting this important work and allowing me to comment on it in the podcast.

Dr Carolyn Lam:                Christian, first of all, could you paint the background to help us understand what's the difference between the two isoforms, I mean, in terms of diurnal variation, the way that they may be released earlier or later, the way they may or may not be impacted by comorbidities like renal dysfunction or hemolysis? Could you help us understand why there may be rational to combine the two in looking at their impact on the diagnosis of acute myocardial infarction?

Dr Christian Mueller:      The measurement of cardiac troponin as a structural protein unique to the heart clear is a central piece in our early diagnosis of acute myocardial infarction, so both for the early rule out in patients who present with chest pain and are finally found to have more benign disease as well as the early ruling. In general, I think it's important to highlight that there are two isoforms exactly as you have mentioned, so there is cardiac troponin T and cardiac troponin I. So these two proteins are cardiac specific and are used in the diagnosis of acute myocardial infarction. Now with the development of high-sensitivity methods or measurements of both cardiac troponin T and cardiac troponin I concentrations, we have been able to get a little bit of a better understanding of in fact differences in the pathophysiology as well as analytical details between cardiac troponin T and I.

                                                Before I start highlighting the differences, I think it's important, I mean, both signals show a very strong correlation, so still very, very similar to each other. However, the small differences that have begun to emerge kind of allow to suggest that possible we could use them together as two pieces of information in the diagnosis.

                                                So, what are the differences? First, exactly as you have highlighted, that if in fact that diurnal rhythm with cardiac troponin T, which means that cardiac troponin T concentrations are higher in the morning hours as compared to the evening, we still have no clue why that's the case, but it's a relevant difference about 25% and it has been shown in two cohorts and a group from Maastricht who was the first one highlighting this. This rhythm has not been found for cardiac troponin I. The second difference is that, again, probably understood in many, many population studies cardiac troponin T concentrations are even stronger predictors of death as compared to cardiac troponin I concentration. Then the third difference it seems that if we measure it with high-sensitivity assays, for example high sensitivity, it seems to rise or if you released from injured cardiomyocytes even slightly earlier as compared to T and possibly even less injuries necessary to release I as compared to T.

                                                Then you mentioned renal function. Cardiac troponin T concentration shows slightly higher correlation with renal function as compared to I. Also, other pre-analytical issues, hemolysis seems to affect T and I concentration in a different way. So a lot of small tiny differences that have emerged and that underlie the hypothesis that possibly by combining the two signals we could be even more accurate in the diagnosis rather than relying on one on its own.

Dr Carolyn Lam:                That's good. That really sets up the rational very well. I think in and of itself is a learning lesson, because I think most clinicians sort of take the two equivalently. So could you tell us what you found?

Dr Christian Mueller:      I would like to of course thank the fantastic team that has allowed us to generate this data. It's a collaboration between the APACE investigators, the ADAPT investigators and experts in clinical chemistry from Maastricht University and Noreen Fandalin and Karen Villa of the first office. So we used two large diagnostic studies, APACE and ADAPT. We measured high-sensitivity cardiac troponin T and I and both of them and compared the diagnostic performance as compared to the final adjudicated diagnosis by two independent cardiologists who, of course, had all information, cardiac imaging and whatever you need to adjudicate.

                                                So, what we found is that in general if you look at diagnostic accuracy, overall is quantified by the area under the curve. Combining the two signals did not consistently increase overall diagnostic accuracy as compared to the individual isoforms. However, we were able to document some improvement for the rule out for the very early rule out of acute myocardial infarction. So the concept that is extremely attractive of course from a medical as well as from an economic perspective is to rule out the presence of acute myocardial infarction with a single blood draw. So, we can do this if we assess the ECG. The ECG doesn't show relevant changes. Then if the troponin concentration measured with a high-sensitivity assay is very low, then the likelihood that the patient would have an acute myocardial infarction again is extremely low or in scientific term sort of a negative predictive value approach is 99 to 100%. By combining very low concentration for high-sensitivity T and very low concentration for I, we were able to increase the efficacy of the early rule out and that seemed to be the most likely possible clinical utility of combining the two signals.

Dr Carolyn Lam:                Even that so-called neutral findings are very important. It's an important question to ask and important answer to get. Could you give us an idea for the rule-out part? How much do we gain? How much exactly do we gain by using both assays instead of just one?

Dr Christian Mueller:      So, the efficacy of the early rule-out depends to some extent on the assay used and the cut off applied. So the current you see algorithm uses cut-off that has been shown to be very safe. However, they are regarding their efficacy not very high. So the current you see recommended cut-offs and approach, allows the rule-out only in about perhaps 10 or 15% of patients. That number can be significantly increased, likely doubled or perhaps even increased threefold by using the combination approach. So this has been consistently showed both in the derivation and the validation cohort.

Dr Carolyn Lam:                Yeah. Do you think this is ready for prime time? I noticed a very balanced discussion actually calling for future studies, but perhaps you could state it better now.

Dr Christian Mueller:      The main limitation regarding prime time is the fact that currently manufacturers either of a high-sensitivity TSA or of a high-sensitivity high method, which means that the vast majority of hospitals at this point in time do only have one method available. It would require quite substantial investment in both hardware as well as changing of the logistics in the lab to implement measurement of both assays. So I think it's likely feasible, but it would be associated with relevant investment from a hospital perspective. In addition, I mean, also the rule-out approaches that use of only one assay also there are studies ongoing in trying to further increase the efficacy of the single marker approach. So I think it's the best tool marker strategy that we were able to come up with recently, because many of the other biomarkers that we had tested really didn't work out. Still, as you mentioned, I think it's also important to be very, very honest that it will be difficult to implement tomorrow in most institutions.

Dr Carolyn Lam:                Yeah, and perhaps a little bit more work needs to be done to sort first identify perhaps special situations where these may be particularly helpful. I supposed like you just said when we're thinking of the ESCs to review one-hour type algorithm, who knows maybe we should be having that extra insurance of the second test in those that test it negative in the first or something like that. Do you plan further work? I always ask you because you're always in the forefront of these things and we just love touching your work.

Dr Christian Mueller:      We have several additional analyses ongoing. Again, I think the main part is for just to go ... I go back from a clinical perspective. So I think for many hospitals that are using T at the moment, it's important to have I available for certain situations. So for example if you have a patient in whom you have evidence of chronic skeletal muscle disease, most of these disorders are rare but some of them have been shown to be associated with increasingly highly troponin T that do not seemed to be related for cardiac diseases but from skeletal muscle. This is rare but if you have a patient with that kind of history, then the dual mark measurement is I think mandatory.

                                                The same applies to iso that the other reasons to have false positive results for iso whenever you are ... If your hospital is using I, you should have the T method also available because once in a while you will identify patients in whom you have an I result that doesn't really match the clinical setting, then it's so easy and often so helpful to get the T result to decide on the most appropriate measurement of patient.

                                                For which patients are kind of a standard that measures T and I would be justified, I think that's something to tease out in future study. I think that the rational is there and likely it will depend also on kind of which T or which I method we might use in the future. So at the moment, we have one method for high-sensitivity T, but there are several other methods in development and kind of applying for FDA approval for high-sensitivity I and possibly combination of these might be even more beneficial regarding the single measurements and I think that has to be teased out in future studies.

Dr Carolyn Lam:                Exactly, but what great insights for us to consider as clinicians now for specific cases where we may consider find those if we have those in our institutions. At the end of the day, I supposed cost-effectiveness analysis will need to be done. Agree?

Dr Christian Mueller:      Absolutely, absolutely. The good thing about troponin, it's extremely inexpensive. So as compared to most of the new fancy biomarkers that are usually, rather prices of troponin is a routine marker. It's inexpensive. It's there for very likely that if we are able to document some clinical value that also the cost-effectiveness study that's definitely unnecessary will show also some economic benefit.

Dr Carolyn Lam:                Oh, Christian, thank you for publishing yet another impactful and clinically relevant paper with us here in Circulation. I mean, it's exactly the kinds of papers that we really treasure here, because they directly inform clinicians and open our eyes to actually things that we should be considering in our everyday practice. Clod I ask you maybe cheekily to share about your experience with publishing at Circulation? Someone like you will be the best person to tell the world what it's like.

Dr Christian Mueller:      Oh, of course. I mean, for us as a research group and for me as a researcher, it's fantastic. It's perfect to have some of our work published in Circulation that has fantastic impact factor, fantastic readership and ensures that the research catch the attention that's fantastic. Also, I think for us as a research group, the recognition of being able to publish in Circulation is outstanding and it helps us continue in the research group that we do. The comments made to large extent also by the editors. Also, on this manuscript, I think we're incredibly insightful and definitely had a major contribution to the final product to make it as attractive and also as balanced and insightful I think as it is at this point in time.

Dr Carolyn Lam:                Thank you so much for providing that feedback, because it is our aim, explicit aim to put a partner authors in getting the best of the manuscript and working really closely with you. So thank you once again, Christian, for your time today. Audience, I know you've heard many times from this favorite person that we have on our podcast.

                                                Do share this podcast with all your colleagues and don't forget to tune in again next week.


Aug 27, 2018

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

                                                Do we finally now have a simple, evidence-based way to make a diagnosis of heart failure with preserved ejection fraction? Well, today's feature paper certainly brings us closer to that goal and you must listen to the discussion coming right up after these summaries.

                                                Bleeding is commonly cited as a reason for stopping oral anti-coagulants. However, what is the prognostic significance of minor bleeding events, or so called nuisance bleeding, in patients with atrial fibrillation on oral anti-coagulants?

                                                First and corresponding author, Dr O'Brien from Duke Clinical Research Institute and her colleagues, identified 6771 patients with atrial fibrillation in the Orbit AF Prospective Outpatient Registry. They ascertained nuisance bleeding from medical records defined as minor bleeding that did not require medical attention. Overall, 20% had documented nuisance bleeding giving an incidence rate of 14.8 events per hundred person years. Nuisance bleeding was not associated with a higher risk of major bleeding, or a stroke and systemic embolism over the next six months.

                                                These findings therefore suggest that the occurrence of nuisance bleeding or minor bleeding should not lead to changes in anti-coagulant treatment strategies in patients treated with anti-coagulants.

                                                The next study sheds new light on mechanisms linking NLRP3 inflammasome activation to atherogenesis. Dr Westerterp from Columbia University, New York and colleagues studied mice with myeloid deficiency of ATP binding cassette transporters A1 and G1 and concomitant deficiency of the inflammasome components NLRP3 or caspase-111.

                                                They showed that cholesterol accumulation in myeloid cells activated the NLRP3 inflammasome. NLRP3 inflammasome activation enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques thus accelerating atherogenesis.

                                                Patients with Tangier's disease, who had ATP binding at transporter A1 loss of function, had increased myeloid cholesterol content and showed markers of inflammasome activation. Thus, inflammasome activation may underline cardiovascular disease in these patients.

                                                The next study identifies TPX20 as a novel transcription factor regulating angiogenesis. TPX20 is a crucial transcription factor for embryonic development and its deficiency is associated with congenital heart disease. However, its role in angiogenesis has been not been previously described. At least until today's paper from co-first authors Dr Meng and Dr Gu and co-corresponding authors Dr Cooke and Dr Fang from Houston Methodist Research Institute.

                                                These authors use loss and gain function approaches to explore the role of TPX20 in angiogenesis both in vitro and in vivo. They showed that with VEGF stimulation, the transcription factor TPX20 upregulated PROK2 with is secreted from endothelial cells and gauges its receptor PROKR1 and thereby promotes angiogenesis in autocrine manner.

                                                This novel signaling pathway appeared to be highly conserved as it functioned in zebra fish vascular development and the angiogenic response to ischemia in a mouse model of peripheral disease. The authors furthered showed the selective role of TPX20 in endothelial migration but not proliferation. Furthermore, treatment with recombinant PROK2 the critical effector of TPX20, improved blood profusion and functional recovery in the mouse peripheral artery disease model. Thus, these data highlight the therapeutic potential of PROK2 in augmenting functional angiogenesis for diseases associated with this regulated angiogenesis.

                                                In patients with atrial fibrillation, left atrial appendage closure with the Watchman device, is known to prevent thromboembolism from the left atrial appendage. However, thrombus may still form on the left atrial face of the device, which then may potentially embolize. This next paper provides important data on the incidents, predictors, and clinical outcomes of device-related thrombus after left atrial appendage closure.

                                                First author, Dr Dukkipati and corresponding author Dr Reddy from Icahn School of Medicine at Mount Sinai, New York and their colleagues studied the device arms of 4 prospective FDA trials of patients undergoing the Watchman implantation. These were the PROTECT AF, PREVAIL, CAP, and CAP2 trials.

                                                They found that following percutaneous left atrial appendage closure with the watchman device, the incidence of device-related thrombus was 3.7% and this was associated with a more threefold higher risk of stroke and systemic embolism. Predictors of device-related thrombus were a history of trans- ischemic attack or stroke, permanent atrial fibrillation, vascular disease, a larger left atrial appendage diameter, and a lower left ventricular ejection fraction.

                                                Device-related thrombus was not associated with an increased risk of cardiovascular or all-cause mortality. Nearly 75% of patients that developed device-related thrombus did not experience a stroke. And ischemic strokes occurring in patients with device-related thrombus accounted for approximately 10% of all ischemic strokes, following left atrial appendage closure. Thus, given the ramifications of device-related thrombus, a judicious surveillance strategy using periodic transesophageal echo cardiography may be considered particularly when risk factors for device-related thrombus are present.

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

                                                Heart failure with preserved ejection fraction or HFpEF, notoriously difficult diagnosis to make, but do we finally have a validated diagnostic algorithm for HFpEF? Oh, you have to listen to our conversation today. I am so proud and pleased and thrilled frankly to have with me today the corresponding author of the feature paper, and that's Dr Barry Borlaugug from Mayo Clinic in Rochester, Minnesota as well as editorialist Dr Walter Paulusus from VU University Medical Center in Amsterdam.

                                                Thank you so much both of you for making it here. I want to dive straight into it. So, Walter, maybe could you please paint the background to this because you wrote I think the most highly cited diagnostic guidelines of HFpEF, but that was in 2007. Tell us how does today's paper take us forward?

Dr Walter Paulus:             Thank you very much, Carolyn. It's quite an honor for me to give you comments about this paper, which I think is going to be a landmark event. Over the years we have seen multiple algorithms being proposed usually by professional societies like V and C or the American Society of Echocardiography for the diagnosis of HFpEF. The major drawback of all these algorithms is that they have never been validated in clinical practice. And the reason they have never been validated was that it was extremely difficult to establish a gold standard for HFpEF.

                                                And Barry was so clever to already invest in an establishing a gold standard for HFpEF ten years ago, and he very vigorously subjected all his patients in whom he suspected HFpEF to an invasive stress test and could establish the diagonals of HFpEF using this as a gold standard. And then he used all these consecutive patients with subsequently used to devise some form of an algorithm that was immediately validated against a gold standard. I think this has been a giant leap forwards. And again, I want to congratulate him with this unique endeavor.

Dr Carolyn Lam:                Barry, I want to echo Walter's words and congratulate you. Now, has it really been ten years in the making? Tell us about this, Barry.

Dr Barry Borlaug:              It has. In fact, it was 12 years ago when we started doing this, in 2006. But, yeah, these patients were examined in our laboratory between 2006 when I joined the staff at the Mayo Clinic to 2016. And really just doing this work up, we kind of started out doing it on a few patients and then we realized how powerful the methodology was. We did the invasive exercise testing with hemodynamics and a larger number of patients and just through accumulating a large number, as Walter points out, with a gold standard assessment this allowed us to then determine which less invasive attributes could be used to identify the likelihood that heart failure was the diagnosis.

Dr Carolyn Lam:                That's so great. But you know beyond just that it is such a precious data set and so on, your paper is just so beautifully written and so clinically applicable. You've got this HFpEF score now for diagnosis. Everybody's going to be talking about it. So tell us about it. What does HFpEF score? What makes you think it'll work? How do you apply it clinically?

Dr Barry Borlaug:              Thinking about diagnosis a lot, you really have to go back to [00:19:19] thinking, estimating the probability of disease, and when you're able to do that then you can find people where you need to perform really more invasive testing like the exercise testing. So really, we started like we need to have a better way to define who needs that more expensive and invasive evaluation. So we have this large cohort of patients, over 500 patients, 414 in the initial cohort, and then another 100 in the validation cohort. And they had all undergone this work up, they'd all undergone very detailed clinical evaluation and pheno typing. And we hypothesized which characteristics we thought would be most relevant. And then we did logistic regression to identify all the predictors.

                                                There were many things that are associated that you would expect with HFpEF, but there were only 6 factors in the end in a multi-variable model that were all independently associated. That provided the most parsimonious sort of model or score that we could develop. We included these six different variables. So there's two for letter H- heavy and hypertensive, and by heavy we define that as a body mass index above 30. Hypertensive is defined as two or more antihypertensive medicines. The F in the H2 HFpEF score is atrial fibrillation, either paroxysmal or persistence a. Fib. The P is for pulmonary hypertension as estimated by echo with an estimated PA systolic pressure on echocardiography of 35. We wanted all of these to be noninvasive criteria for this score. E is for elder. I specifically didn't call it elderly because that can be a pejorative term and its only 60 years which is not that old. So E is elder. And F is for filling pressures, again estimated by echo doppler cardiography as an EE prime ratio greater than 9.

                                                All of the scores are not one point each. They were arranged based on the strength of correlation in the logistic model. So being obese, having a BMI above 30 was awarded two points because it has a strong correlation. Being in atrial fibrillation or having a history of atrial fibrillation was even stronger at three points. If you tally these up, the score can range from 0-9, and based on that score you can then estimate a probability that HFpEF is present, if you're evaluating a patient that meets the entry criteria of the study, which is basically normal ejection fraction, and exertional breathlessness.

Dr Carolyn Lam:                Nice. Okay, Walter, I think I can safely say that you have been thinking about this syndrome longer than either Barry or I. So I'd love your perspectives on how do you think this will be put into practice clinically perhaps, and where is the key area that it will change practice compared to perhaps the old diagnostic algorithms were like?

Dr Walter Paulus:             I think this is a very important point, Carolyn. I think this score is so easy to handle and it is so well validated that we can now go to general practitioners and cause a general awareness for the disease. What vies me is that many patients are still unreported. The reason is that general practitioners and even general internal medicine people do not realize the [00:19:19] heart failure with preserved ejection fraction. Now with this score at hand, we can convince them that there needs to be an awareness when they see people that have value higher than six on the score, that they should be suspicious of heart failure being part of the symptomatology. I think this score mainly has its usefulness for general practitioners and general internal medicine.

                                                Apart from the score, and it's more up to Barry to comment on this, but I want to highlight also, that he did not only develop the score, but he also had these very beautiful nomograms which is more of a find than a score, where he treated the variables in a continuous way. I think this is fairly useful for cardiologists and especially for people who want to have acute patients into trials because here we now have a very refined scale that goes from 0-160 and that allows you again to see what type of population you are addressing, what type of patients you are seeing that eventually what type of patients you are recruiting. I think for me the HFpEF score is of importance for general practitioners, general internal medicine, and especially I think we should also promote the nomogram. The nomogram, I think, are so refined that it would be useful tool, I think an excellent tool, for includement into trials.

Dr Carolyn Lam:                Oh wonderful. Both of the simplicity and the cleverness, if I may, of this paper are precious to generalists and cardiologists. But Barry, I do have a couple of questions for you. Both you derivation and validation were in Olmsted if I'm not wrong. Now how am I supposed to apply it to my skinny HFpEF patients in Asia or elsewhere?

Dr Barry Borlaug:              That's an important point, Carolyn. And it's a limitation of the paper. The people in Olmsted County, MN are not the same as they are in other parts of the United States or other parts of the world. I think that additional evaluation and other cohorts are important. We did the best we could with what we had. We did look at the patients carefully at Mayo Clinic. People think of it as quaternary referral center, but a pretty substantial number of the patients are from the local area, I think about 2/3 of them were. And when we looked in a subset in a sensitivity analysis of the people that were more local practice rather than coming from large academic medical centers, the HFpEF score, or as Walter pointed out, the continuous HFpEF model performed equally well. When we looked at people with so-called advanced HFpEF so high hemopressures at rest versus people at so called early stage HFpEF the people that have normal hemodynamics at rest but elevation during exercise. The model also worked well in that cohort.

                                                But, like most studies that come out of where I work in southeastern Minnesota, it is mostly Caucasian people, the mean BMI was in the low 30s. So we need to look at other populations to make sure this works elsewhere as well.

Dr Carolyn Lam:                Barry, let it go on record that I am your biggest fan. So thank you so much for this. I was just thinking even in other populations where the mean BMI may be lower for example here in Asia, we still definitely see an association with a higher BMI albeit at a lower cutoff with the presence of HFpEF. So it does raise this issue of do we need to maybe calibrate the score differently in different geographies or ethnicities. But that's not by any way take away from the tremendous input that you've made.

                                                One other question is also the strength of atrial fibrillation in impacting the score. What are your thoughts on the possibility of misdiagnosis for example atrial fibrillation as HFpEF or the similar situation since they share symptomatology?

Dr Barry Borlaug:              This is a great point, Carolyn. People still sort of argue about this. Somebody has breathlessness and effort intolerance and atrial fibrillation. Some doctors say they have symptomatic atrial fibrillation, but when we put catheters when we take these patients to the so-called table of truth and put catheters in and exercise them, we see hemodynamic arrangements that are diagnostic of heart failure. This led us to believe that this isn't just symptomatic a fib. It's really HFpEF. And that's why they have a fib. We published a paper earlier this year in circulation, more of a brief report, on the association between atrial fibrillation and HFpEF where we first reported this. That if you have normal EF, and especially permanent atrial fibrillation, you can pretty much take it to the bank that the patient probably does have heart failure with preserved ejection fraction, at least in the way that we have sort of defined it and the way that [00:19:19] initially defined it as an inability of the heart to pump blood adequately at normal filling pressures.

                                                These patients almost all have that criteria for cardiac failure. I think that it is a really strong indicator and we probably are really just like in the general clinics, under recognizing HFpEF. I think probably in other clinics where people have atrial fibrillation and effort intolerance, we're again really under recognizing HFpEF in these people.

Dr Carolyn Lam:                Indeed, and it's actually very consistent with Walter, your recommendations where atrial fibrillation played a big part too. Do you have any thoughts or advice?

Dr Walter Paulus:             My idea is that atrial fibrillation and HFpEF are both manifestations of the same underlying process, which is systemic inflammation because of a metabolic disturbance. We used to think of atrial fibrillation as a consequence of left atrial dilatation, which itself was caused by the high filling pressures. I think that this does not hold, there is more to it. I think the atrium is as sick as the left ventricle and it undergoes similar pathological changes. That's why the presence of a fib becomes such a strong determinant of the presence of HFpEF in Barry's H of HFpEF score. All of this makes a lot of sense to me.

                                                I just want to add something else. You spoke about the Asian population having less BMI and already having HFpEF. I think if you look at Barry's variables in uni-variant analysis, there's one which was presence of diabetes or prediabetes which did not make it in the multi-variant analysis on 0.06. It's my belief that if you got to the Asian population, that probably the BMI could be replaced with the presence of prediabetes and diabetes. Usually the insulin tolerance or insulin resistance is presence and the BMI is still low. I think there is need for some fine tuning, maybe in Asian populations, and I think this should be a challenge to go ahead with it. In fact, I'm leaving for Japan the day after tomorrow and I'm going to show the slides of Barry's paper. I'm going to try to set something up to also validate the score in Japanese populations.

Dr Carolyn Lam:                We've got our work cut out for us, Barry! Let's get on to this too in southeast Asia.

Dr Barry Borlaug:              I totally agree with Walter. I think that's great. And Carolyn, you, in a lot of papers, point this out, that the metabolic, cardio-metabolic associated with excess body mass, the way we define it with BMI, is shifted way down in southeast Asian population, and south Asian population, so I would agree with Walter's hypothesis that diabetes, prediabetes maybe that's the better way to go when we look at this in other patient populations.

Dr Carolyn Lam:                You both absolutely made my day with this discussion today. Thank you so much. What a thrill to be on the same podcast with the people I admire most.

                                                Listeners, I know you enjoyed this as much as I did. Don't forget to tune in again next week.


Aug 20, 2018

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

                                                Can we get better at predicting clinical benefit of PCSK9 inhibition based on the severity and extent of coronary artery disease? Well coming right up after these summaries we have an important discussion of an analysis from the FOURIER trial, so stay tuned.

                                                The first original paper this week suggests that targeting visceral adiposity may be the crucial step to limit age-related cardiac remodeling and to promote healthy cardiac aging. Co-first authors Drs Sawaki and Czibik, corresponding author Dr Derumeaux, from INSERM France, and their colleagues, hypothesize that since aging induces cardiac structural and functional changes, linked to increase deposition of extracellular matrix proteins including osteopontin, well osteopontin may play a role in myocardial aging.

                                                To test this hypothesis, they studied osteopontin-deficient mice and their wild-type litter mates at two and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. They found that during aging, visceral adipose tissue represented the main source of ostepontin and altered heart structure and function via its profibrotic secretome. Furthermore, interventions targeting osteopontin, such as visceral adipose tissue removal and osteopontin deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. This work uncovers ostepontin's role in the context of myocardial aging and suggests that osteopontin may be a potential new therapeutic target for a healthy cardiac aging.

                                                The next study shows that higher triglyceride rich lipoprotein cholesterol may be a risk factor for cardiovascular disease and potential therapeutic target. First author Dr Vallejo-Vaz, corresponding author Dr Ray from Imperial College London, and their colleagues assess the relationship between triglyceride-rich lipoprotein cholesterol and cardiovascular risk and whether this risk was modifiable among patients receiving statins in the TNT trial. They found that higher levels of triglyceride rich lipoprotein cholesterol were associated with a significantly higher rate of cardiovascular events among coronary patients treated with statins. Statin therapy reduced triglyceride-rich lipoprotein cholesterol and to a greater extent among those treated with a higher statin dose.

                                                Based on their post hoc analysis of the TNT trial, they found that more intensive statin therapy with atorvastatin 80 milligrams, compared to atorvastatin 10 milligrams, resulted in a significantly greater cardiovascular risk reduction among patients with higher triglyceride-rich lipoprotein cholesterol. These results were consistent for higher triglycerides and directionally concordant for non-HDL cholesterol. A higher percentage reduction in triglyceride-rich lipoprotein cholesterol was associated with lower cardiovascular risk independent of LDL cholesterol reduction. Thus, these findings suggest that triglyceride-rich lipoprotein cholesterol is not only a cardiovascular risk marker, but also potentially a therapeutic target.

                                                Late gadolinium enhancement on cardiac magnetic resonance imaging represents fibrosis and is seen in 60% of adult patients with hypertrophic cardiomyopathy. However, what about in children and adolescents with hypertrophic cardiomyopathy? First author Dr Raja from University of Copenhagen in Denmark, corresponding author Dr Ho from Brigham and Women's Hospital in Boston, and their colleagues looked at cardiac magnetic imaging data from 195 children and adolescents with hypertrophic cardiomyopathy. Late gadolinium enhancement was present in 46% of patients with overt hypertrophy as opposed to 60% typically represented in an adult population of hypertrophic cardiomyopathy. On the other hand, late gadolinium enhancement was not seen in mutation carriers without left ventricular hypertrophy.

                                                In patients who underwent serial imaging, increases in late gadolinium enhancement, left ventricular mass, and left atrial size were detected over two and a half years. Thus these findings in children provide additional insights into the biology and natural history of hypertrophic cardiomyopathy and confirmed that fibrosis is a significant part of the disease process in both children and adults.

                                                Whether the adult mammalian heart harbors cardiac stem cells for the regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. This week's paper adds to the growing knowledge in this area. First author Dr Li, corresponding author Dr Zhou from Chinese Academy of Sciences and their colleagues developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, they assessed if non-myocytes generated any new myocytes during embryonic development, adult homeostasis and after myocardial infarction. Skeletal muscles were also examined after injury and acted as internal controls.

                                                By using this stem cell marker free and dual recombinases mediated cell tracking approach, the author showed that new myocytes arose from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive controls, the same lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. Thus, this study provides in vivo genetic evidence for non-myocyte to myocyte conversion in the embryonic but not the adult heart. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.

                                                Well, that wraps it up for our summaries this week, now for our feature discussion.

                                                Are there subsets of patients that derive greater clinical risk reduction with the PCSK9 inhibitors? Well we're gonna find out about that right now with a discussion of our feature paper entitled the “Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease.” So pleased to have with us Dr Marc Sabatine from the TIMI Study Group, who is the first and corresponding author of today's feature paper, as well as our editorialist, Dr Roger Blumenthal from Johns Hopkins University. And of course, we have a familiar voice, a very important editor of our digital strategies and that's Dr Amit Khera from UT Southwestern.

                                                Welcome everyone, I think I'd really like to start with maybe asking Roger to paint the background of the importance of this paper. Simply because I just love the title of your editorial, which is “Realizing the Value of PCSK9 Inhibitors: Are We Closer to Finding the Sweet Spot?” I think that really encapsulates it. So Roger, your thoughts?

Dr Roger Blumenthal:     As Amit Khera knows, I'm a golfer, so when you think about the sweet spot on the club, and we know that PCSK9 inhibitors are a great story of translation from bench to bedside, and we also know that the high cost of the therapy presents a challenge. So what Dr Sabatine and colleagues did was to try to identify the sweet spot for its most effective use and that was a pleasure to comment on Dr Sabatine's excellent study.

Dr Marc Sabatine:            I think taking a step back I would say from pure biologic perspective, we know that lowering LDL cholesterol will reduce events and that's true and primary and secondary prevention and so if you have therapies that were safe and inexpensive, then I think you wouldn't need to really look for that sweet spot cause it would be all sweet if you will to extend the analogy. But Roger's absolutely right that when you have therapies that are then expensive, then you have to decide, okay in which patients will I get the biggest bang for my buck? And that's a very legitimate question to ask.

                                                And so in FOURIER, overall the trial was positive but as we look for subgroups we say, "Can we find individuals who enjoy a greater absolute risk reduction?" Because therefore the benefit cost ratio is gonna be particularly favorable. And so we approach that in a couple different ways. First you can look for just predictors of baseline risk, so if someone has twice the baseline risk and the same relative risk reduction, you should get about twice the absolute risk reduction and therefore the number needed to treat would be cut in half. And so based on our experience from other TIMI trials and other datasets, we looked at three features that have identified patients with higher baseline risks.

                                                Amongst those with a history of MI which is in and of itself a heterogeneous group. And so those features were patients with a more recent MI, those with multiple prior MIs and those with known residual multivessel coronary disease. And all three features in the FOURIER dataset, not surprisingly, were predictors of risk with patients having an average about a 50% higher baseline risk. But what was particularly nice was that the subgroups also identified patients who had greater relative risk reduction. And so when you couple the two, the higher baseline risk with the greater relative risk reduction, that translated into greater absolute risk reduction then in each of these high-risk groups, the absolute risk reductions over three years or for CV death, MI, and stroke was around 3% versus around 1% for the low-risk groups.

                                                And so that changes the number needed to treat by a factor of three.

Dr Carolyn Lam:                Wow, that's so cool. Amit, do you think you could just give us a sneak peek into the editors’ discussions when you saw this paper?

Dr Amit Khera:                  This was an easy one, it's clearly a very important paper and if you step back 10,000-foot view, these drugs were initially approved based on LDL lowering and people were using them without knowledge of whether or not they actually lowered events. Marc's group and others have now shown us that certainly they do lower events, but really the next most important thing is application. Who should we use them in and when should they be used and where might they be most effective and I think it was said out in the introduction of this paper, this idea of personalized medicine. And I think this really is an important step forward, not just for PCSK9 field but in general, how we should be thinking about drugs, about balancing cost and benefits and who would benefit most.

                                                So maybe one analogy, I think PCSK9 was not prescribed as much as they had been predicted given costs and other considerations and maybe with analysis like this they've hit it out of the rough back on the fairway, I threw that in for you, Roger. And I do have one question for Marc, which is this is clearly important to better define who would benefit the most and I guess in terms of action abilities, the goal here to provide guidance for clinicians where, you know, if I'm seeing a patient this morning I would take this into account or is this something larger where we recently saw with alirocumab, they changed pricing based on sub-group analysis of a higher risk group. How do you think we should move forward with this type of information?

Dr Marc Sabatine:            I’ll get back to the point I raised earlier, I do want to underscore that I think that the true biologic notion is that all these patients, sub-types of secondary prevention or primary prevention all benefit from LDL lowering. So I wouldn't want people to walk out with the notion that it's the only subset that would benefit and really from a population level, obviously Roger's in a better position to speak about this, but sort of shifting the population LDL lower in general would have a huge impact on the risk for cardiovascular disease. But to your question Amit, looking in for a patient in front of you, I think it's quite fair to say right now there's this kind of tug of war back and forth between payers and clinicians.

                                                Clinicians saying, "I have a patient in front of me, they have known atherosclerotic cardiovascular disease, I wanna lower their risk, I wanna manage their risk factors and I wanna get their LDL cholesterol lower and I have a bunch of great tools in front of me." Statin for sure is the foundation, maybe acetamide and PCSK9 inhibitors. And then payers saying, "Well wait a minute, these are expensive drugs and so we're gonna try to restrict that and create a lot of hoops for clinicians to jump through." And so I would rather than wasting all that time back and forth, I think it is logical to say, "What are the high-risk groups?" Where we can agree there's the large enough absolute risk reduction that for a given cost, that makes sense.

                                                Allow there to be alignment for that and have clinicians just be able to write a script and have it filled rather than wasting a lot of time with preauthorization and letters back and forth.

Dr Amit Khera:                  That's a great point, maybe I'll just take one follow-up, which is now trying to sift through all the high-risk groups and they end up maybe becoming a bit of a Venn diagram. I know in Roger's editorial he talked about the other FOURIER analysis with PAD and there's more groups to come or do we have enough of a starting place where we think we have enough for decision making?

Dr Marc Sabatine:            I would say there are a variety of groups, there is some overlapping even in the paper then we looked at the union of those three high-risk features, which identified about two thirds of the patients who were enrolled in the trial with a history of MI. But you're right, the other slices of the data that will also identify high risk groups, PAD is a particularly good one because most of the therapy for those patients has focused on antithrombotic therapy, which always will have some downside for increased bleeding, whereas risk factor modification in this case has no downside. So that's a very high-risk group, it certainly is important to focus on. But I think within the MI subset, this is a great place to start the other analyses we're doing.

                                                And probably after we've sort of finished the series of, if you will, these kind of univariant slices, then we'll try to put that together into a more comprehensive picture.

Dr Roger Blumenthal:     We tried to say that we still need the formal cost-effective analyses in these specific high-risk groups, but it seems most reasonable to focus on engaging in shared decision making now with our patients about PCSK9 inhibitor use and those with a recent ACS and the basis of Odyssey Outcomes and we're awaiting the final publication of that. Symptomatic peripheral arterial disease, which Marc previously published in Circulation, and then looking at these high-risk features that was the subject of this article, those with a more recent MI within the past two years, multiple prior MIs and residual multivessel coronary disease.

                                                And one of the things that we especially found interesting was among the more than 8,000 individuals without a high-risk feature, the event rates were nearly unchanged in the evolocumab versus placebo groups. So I think that's very important, but one other point that we have to keep in mind is that the focus of the last set of guidelines and probably the next cholesterol guidelines that likely will be out in November, will have a large component of the shared decision making and we need to see where the cost comes down, whether these companies that make these medications will be able to significantly lower the cost in a reproduceable manner and patients and clinicians will have to jointly decide what to do, do we add acetamide? Do we add a PCSK9 inhibitor?

                                                But we finished our editorial saying that all clinicians and patients should currently pursue a comprehensive lifestyle and medical regimen for secondary prevention. We all have to remember that and if a person's LDL, a high-risk individual is at least 70 with high-risk features and certainly above 100 on maximum tolerated statin therapy, it's important to strongly consider a PCSK9 inhibition and it'll be very interesting to see what the final wording is when the ACC/AHA cholesterol guidelines come out in November.

Dr Carolyn Lam:                Amit, would you like to add any further take-home for the clinicians listening in?

Dr Amit Khera:                  I just first want to congratulate both of these discussions today, I think the paper was so incredibly important and I think Roger's group really helped frame it well in the field. The one thing I'd say is this is a moving target, we have some early guidance now that I do think is actionable, so I actually have clinic in about an hour and I'm sure I'll be thinking about this as I think about how to apply PCSK9. Which groups might benefit most, so I do think this is actionable now, I think the points that were made about cost effective analysis, how do we bundle all these concepts or high risk patients into maybe an algorithm and how do the guidelines interpret this as a moving target. We'll wait to see, but I do think there's some important actionable information even now for our clinical patients.

Dr Carolyn Lam:                I just love that, and you know that is just so much in line with the ethos of what Circulation is about now. We really, really love the papers that you have to pick up because they're of immediate applicability to your clinical practice.

                                                Well audience, you heard it right here. Thank you so much for joining us this week and of course don't forget to tune in again next week.


Aug 13, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. I'm the one you usually hear chatting about all the papers in your weekly issue, however I am so delighted to be handing over the mic this week to two beloved colleagues, and they are Dr Greg Hundley and Dr Vlad Zaha, who will be taking us through this week's very special issue centered around cardio-oncology. Here they are.

Dr Greg Hundley:             My name is Greg Hundley. I'm a professor at VCU Health Sciences in Richmond, Virginia. We also have Vlad Zaha, who is an assistant professor at University of Texas Southwestern in Dallas.

Dr Vlad Zaha:                     Hello, everybody.

Dr Greg Hundley:             We're going to be talking about the field of cardio-oncology today. As we all know, there have been many advances in the treatment of cancer lately, such that cancer is now becoming in some regards almost a manageable disease or a chronic disease for many individuals. But unfortunately we're seeing the emergence of cardiovascular disease in many patients, so much so that for some cancers, for example breast cancer survivors, cardiovascular events have supplanted the occurrence of cancer-related morbidity and mortality overall.

                                                And so emerging today is this new field of cardio-oncology, which is really a bridging discipline between oncologists and cardiologists that have been focused almost on examining the relationship between chemotherapies, radiation therapies, newer targeted immunologic therapies on the development of cardiovascular events. We as cardiovascular medicine specialists often become involved and then we are consulted to see a patient that might be scheduled to receive a cardiotoxic therapy and what should we do. Maybe they've already received, they're in the middle of the therapy, and we're asked to provide guidance to help the patient move through that therapy successfully.

                                                We're examining survivors now, those that have gone on the therapy and are experiencing increased cardiovascular risk. And then finally, a new emerging field that examines the association of risk factors that seem to be common between cancer and cardiovascular disease.

                                                In this issue of Circulation there are theories, really a miniseries of manuscripts, that are at this interface between cardiovascular and oncologic science and medicine. Following a similar miniseries that we published in 2015, this new block of manuscripts looks on some of the risk factors and mechanisms that may be common between these disorders.

                                                We're going to start today and look at this particular issue and examine the original manuscripts, look at the letters, and then talk a little bit about the review articles. I will walk through some of the introduction and then Vlad Zaha, who is working in cardio-oncology at University of Texas Southwestern, will help interpret for us some of the results and the meaning.

                                                The first study, an original manuscript by Simes et. al that's a subanalysis of the lipid study, and that's the Long-Term Intervention with Pravastatin in Ischemic Disease. The study is going to examine the relationship between D-dimer and the future development of cardiovascular events, but also importantly, cancer-related events. Remember, D-dimer is the degradation product of cross-linked fibrin markers of hypercoagulation and thrombosis. We use this a lot in the emergency department as an identifier of those at risk when we're suspecting one of CVT, pulmonary emboli, etc.

                                                This particular study focused on individuals aged 31 to 75 years that had experienced previously a myocardial infarction. The patients were randomized to receive 40 mg of pravastatin versus a placebo and as part of the study they were followed for six years to identify cardiovascular events. But at the end of the study another examination, an extended review, was enabled so that the patients or participants could be followed for another ten more years and in addition to looking at cardiovascular events, they also looked at all-cause mortality and etiologies of that mortality and specifically cancer.

                                                Vlad, can you tell us a little bit about some of the results and what did D-dimer predict?

Dr Vlad Zaha:                     D-dimer has been considered a rather non-specific product that was first introduced in clinical practice in the 1970s for diagnosis of venous thromboembolisms. It is really interesting in this study that the others identified D-dimer that it is an independent predictor of not only long-term risk of arterial and venous events but all-cause mortality, cardiovascular disease mortality, cancer incidents and mortality and non-cardiovascular disease and non-cancer morality.

                                                It raises interesting questions that are further explored in an editorial in the same issue about what is a low and what is a high D-dimer and also what drives the D-dimer generation in these patients.

Dr Greg Hundley:             And so, it's interesting as well that one is identifying those at risk of cardiovascular disease but also cancer. Do the authors and the editorialists speculate on what that connection may be?

Dr Vlad Zaha:                     The question that is discussed is a common area of etiology that is being more and more discussed nowadays as bridging the domains of heart disease and cancer, and that is information. Information resulting then in alteration of the clotting cascade and hypercoagulability that may then influence downstream both atherosclerosis and cancer processes.

Dr Greg Hundley:             Very good. It's interesting that we're bringing up this whole area of thrombosis because that really follows in the next study, which is a large population cohort assessment that is collected from a Danish registry of 6600 subjects that had experienced a lower extremity arterial, not venous, but arterial thrombosis. In that study what did they uncover, Vlad, in terms of an association with cancer and previously experiencing a lower extremity arterial thrombosis?

Dr Vlad Zaha:                     Another interesting study where the patients uncovered an increased risk of cancer compared to the general population, especially during the first six months before, the investigators identified an association between lower limb arterial thrombosis and increased all-cause mortality in common especially for the smoking-related cancers. This is a very interesting study that brings up the possibility of opportunistic screening, again focused on cancer-related signs and symptoms during the diagnostic workup for lower limb arterial thrombosis.

Dr Greg Hundley:             And so, in these first two studies, both large in number, were identifying issues related to thromboembolic events and cardiovascular disease that also appear related or associated with the future development of cancer. The next couple of studies now switch and address issues related to mechanism. The first is a relatively large complex translational study by Meijers and associates that were examining the relationships between heart and vascular injury and the future development of colon cancer.

                                                In this particular study there were two separate experiments, one group performed in mice and the other performed in analyses of serum and plasma that were collected from human subjects that had experienced colon cancer. In the first series of experiments in mice, the mice were induced myocardial infarction and then they were a strain that were somewhat predisposed to development of colon cancer. What the investigators did is they examined in this strain predisposed to the development of colon cancer, the impact of inducing a myocardial infarction and promoting heart failure versus those that were not and they identified what looks to be some sort of association between an increased risk of development of colon cancer.

                                                Vlad, what were your observations and thoughts in terms of these particular findings and results?

Dr Vlad Zaha:                     This is an interesting paradigm of bringing basic science observations and testing them in a translational fashion. It is a combination of really elegant studies in a mouse model that identifies potential targets of clinical relevance in a model of myocardial infarction. The authors evaluate the fact that such molecules in human cell line models and test the proliferation in that environment. The question is then: How does this reflect in a cohort of patients? That, I think, is really the strength of the study to be able to show that some of the biomarkers identified which events can have an implication at the bedside.

Dr Greg Hundley:             It was really interesting in that in the animals, independent of the hemodynamic compromise, so the hypotension, the reductions in EF, these circulating biomarkers that you identified seemed more associated with the development of colon cancer and then in the human study, examining similar factors were observed in patients with colon cancer and heart failure from the circulating blood of those individuals. Very interesting relationship identified in a very elegant translational study that involved both animal models and human subjects.

                                                The second mechanistic paper is by Li and associates and it's really addressing the issue of anthracycline-related cardiovascular injury. Remember, we still utilize anthracycline chemotherapy today as a fundamental curative component of the therapeutic regimen for lymphoma, leukemia and sarcoma, also in those with triple-negative breast cancer as an important component of that regimen for adjuvant treatment. In this particular study, the investigators were examining the implication of phosphoinositide 3-kinase. That is an important enzymatic regulator of tumorigenesis, but it also when it's expressed is up-regulated during cardiac stress and really impacts adverse remodeling and promotion of heart failure.

                                                In this particular study, the investigators in a mouse model were looking at blocking this particular enzyme and they had some really interesting results pertaining to the development of heart failure and cancer. Vlad, what did you see in this study that looked unique in that perspective?

Dr Vlad Zaha:                     This is an especially interesting study for the perspective of the oncologists who still have to prescribe anthracycline, given the uncertainty of early toxicity that can manifest in some studies in five to ten percent of patients. Also, related to the late toxicity of anthracycline treatment in survivors of childhood cancer. What is particularly interesting about this isoform of phosphoinositide 3-kinase, the gamma isoforms, is that at the same time blocking this enzyme in macrophages increases the anti-tumor, I think it's the anthracycline therapy, and blocking it in the cardiomyocytes, suggests a potential cardioprotective mechanism.

                                                Having a target that can be used both to enhance the anti-cancer effect of anthracycline and to enhance the cardioprotective mechanism is really a potential ideal intervention that would help maximize the anti-cancer treatment and at the same time protect the heart.

Dr Greg Hundley:             Fantastic. Again, new research helping to come up with ways for those that continue to need anthracycline therapy that we may be able to attenuate some of the untoward cardiovascular effects, all the while preserving the antagonistic features associated with the treatment for cancer.

                                                Let's switch to the other sort of prospective original research format that we have in Circulation, and that's our letter format. Remember, our letters are addressing a specific point that can be readily appreciated in 800 words or less. The first is a letter by Anquetil et al that examines individuals recorded in the VigiBase World Health Organization database. This is basically a database organized around treatment of cancer and cancer therapeutics and it is examining those individuals that received sort of a newer class of agents called immune checkpoint inhibitors. Remember, that is modulation of our immune system to help attack cancer.

                                                In some rare circumstances, relatively infrequent, when these agents have been administered, the immune system has been unlocked and attacks the heart, promoting a myocarditis that if not recognized can be fulminant and lead to death. This particular group identified a new phenomenon that we need to be aware of and that's just frank myositis.

                                                Vlad, what are your thoughts on now perhaps these agents being associated with the development of myositis in the skeletal muscle?

Dr Vlad Zaha:                     Often when adverse events, as you mentioned Greg, are an important concern for these new powerful tools for the oncologists and it has been pretty early in the process where some of the cases have demonstrated severe cardiovascular events. Fortunately it is a very low percentage, less than 1% of cases that can manifest with fulminant myocarditis, but this raises again a question of expanding the view towards other systems when we are applying one of these early novel molecular interventions.

                                                In this context, the recognition of myositis in another small percentage of patients is an important observation and increasing awareness of both cardiologists and oncologists towards this side effect is important as not all fatigue is equal and sometimes that can be due to manifestations of cardiomyopathy and sometimes it can be a manifestation of oxygen extraction in the peripheral tissue than muscle contractility. It is an important hypothesis-generating piece that will allow people to appreciate more of the complexity of addressing the intrinsic molecular mechanisms in cancer and heart disease.

Dr Greg Hundley:             It sounds that we need to be aware of another potential etiology of fatigue to put in an armamentarium of differential diagnoses for those patients that are not getting quite back to where they were from an exercise and activity level after treatment. The second research letter focuses on individuals that are receiving a Fontan procedure. Remember, Fontan procedures are surgical corrections for those primarily with single ventricles where we're diverting caval blood to the pulmonary circulation, since in some situations there's really no functional right ventricle. These patients over time experience chronic venous hypertension and have associations with liver disease.

                                                In this particular research letter, the authors are examining the relationship between really for the first report in an aggregate form of the relationship between undergoing a Fontan procedure and the development of hepatocellular carcinoma. Vlad, any quick comments to highlight on this particular procedure? I thought something that was interesting is that these individuals experienced these hepatocellular carcinomas in their 20s and 30s.

Dr Vlad Zaha:                     That's right, Greg. This study confirms observations from previous case reports and the early occurrence of hepatocellular carcinoma is raising still important hypotheses for future clinical trials. On one hand, either there is an increased risk of hepatocellular carcinoma development in patients with non-cirrhotic livers after a Fontan operation, or the current screening modalities using imaging are insufficiently sensitive to identify early signs of cirrhosis in such patients and this stratifies them effectively at an early stage in their disease post-op Fontan procedure.

Dr Greg Hundley:             Lastly, let's just briefly discuss here, Vlad, some of the other editorials and review article formats that we have in Circulation. A particular one, a perspective that was written by Peter Libby and Ebert and associates that highlights this phenomenon potentially implicating inflammation and the link between cancer and atherosclerotic cardiovascular disease. The topic of this perspective is really on something called CHIP, which stands for clonal hematopoiesis of indeterminate potential.

                                                What is this CHIP? As we age, basically what happens is we accumulate mutations of hematopoiesis stem cells in our bone marrow. Over time these little clones, they actually have within our bone marrow some survival advantages and they can spill out into the blood and actually can be associated with future leukemias. Those that have a large population of this particular clonal progeny, these CHIP-type cells, they have an increased risk of developing cancer, but also the levels of these are associated with increased overall mortality and it appears some risk of cardiovascular disease. How could that be? One characteristic of this particular cell line is they are associated with dysregulation of inflammatory genes that go on to produce, are associated with other inflammatory mediators.

                                                Vlad, this is calling in question and helping us to examine the relationship between inflammation, cancer and cardiovascular disease. What are your thoughts here about these very important insights provided by Libby and Ebert?

Dr Vlad Zaha:                     This is a fascinating perspective, Greg. It really brings, again, in the offline novel molecular mechanisms that have been discovered recently and that are becoming a turning point into the molecular interventions, not only in cancer but potentially soon in cardiovascular disease prevention and treatment. Having a common root for a problem set involving such a prevalent cardiovascular problem as atherosclerosis and cancers reveals the connection between the different systems and the fact that integrating our understanding of the molecular regulation of cell proliferation results in an effective translation of leading to new targets and new approaches to treat disease.

                                                It is striking that there are multiple areas where cancer and inflammation are interacting, one of them being at the cellular level and other ones at humoral levels, in a way reproducing other complex mechanisms that we see in regulation of inter-system interactions within the body.

Dr Greg Hundley:             And so, summarizing this entire issue in Circulation, what a wonderful collection of a series of original manuscripts, both in the extended and the letter format as well as review articles, including a primer by Handy and associates that evaluates or draws attention to our screening tools that how we might examine the relationship between cardiology and the whole world or hematologic oncology related issues. And then this very unique perspective by Peter Libby and really is a continuation of the growth of this, as we called earlier, the bridging discipline of cardiovascular medicine and oncology as we work toward improving survivorship of all individuals with cardiovascular disease and cancer.

                                                I want to thank you for the opportunity to be with you today and encourage you to follow these issues further with the journal. I'll turn this over to Vlad for any closing remarks.

Dr Vlad Zaha:                     Thank you, Greg. This has been a really exciting overview of important points that are emerging now at this nexus between cardiology and oncology that give us a broader view of the complex interactions that the future will materialize for us, emerging from a molecular intervention on cancer, heart disease, immunologic disease and probably metabolic endocrinology disease.

                                                Thank you for listening.

Dr Carolyn Lam:                Thank you so much, Vlad and Greg. This is a tremendous issue and I'm sure, audience, you will be reaching for it right now, I would.

                                                Please let all your colleagues know about this podcast and tune in again next week.


Aug 7, 2018

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

                                                Can proteomic biomarkers distinguish between subtypes of aortic stenosis even years before surgery? Well, to find out more, stay tuned. That's coming right up after these summaries.

                                                The first original paper this week adds to the evidence that smoke-free policies are associated with a lower risk of cardiovascular disease. First and corresponding author, Dr Mayne from Northwestern University Feinberg School of Medicine, and her colleagues linked smoke-free policies to participants of the Coronary Artery Risk Development in Young Adults, or CARDIA study, which has a follow-up of up to 20 years. They found that smoke-free policies in workplaces were associated with significantly lower risk of incident cardiovascular disease after controlling for a wide range of covariants. Results were weaker for bar and restaurant bans, but in the same direction.

                                                Preventive fractions range from an impressive 24 to 46%. Thus, smoke-free policies may improve cardiovascular health through reducing population exposure to tobacco smoke. However, we should remember that much of the US population remains unprotected by smoke-free policies. Thus, taken together with prior ecological work, these results support the continued expansion of smoke-free policies in indoor public places.

                                                Most phase-3 randomized control trials feature time-to-first event end points for their primary analysis. In chronic diseases, however, a clinical event can occur more than once and recurrent event methods have been proposed to more fully capture the disease burden, as well as to improve statistical precision and power.

                                                However, is this really the case? This question was examined by first author, Dr Brian Claggett, corresponding author, Dr Scott Solomon, from Brigham Women's Hospital in Boston, Massachusetts, and their colleagues, who sought to better characterize factors that influence the statistical properties of recurrent events and time-to-first event methods in the evaluation of randomized therapy.

                                                They performed repeated simulated trials with 1:1 randomization of 4000 patients to active versus control therapy. Through simulation, they varied the degree of between-patient heterogeneity of risk as well as the extent of treatment discontinuation. They then compared their findings with those from the actual randomized control trials.

                                                The authors found that the statistical power of both recurrent events and time-t- first event methods were reduced by increasing heterogeneity of patient risk, a parameter that's not usually included in conventional power and sample size formulae. Furthermore, data from real clinical trials were consistent with the simulation studies, confirming that the greatest statistical gains from the use of recurrent events methods occurred in the presence of high patient heterogeneity and low rates of study drug discontinuation.

                                                The next paper uncovers a novel biomarker and therapeutic target of pulmonary arterial hypertension, and that is selenoprotein P. First author Dr Kikuchi, corresponding author, Dr Shimokawa, from Takaoka University Graduate School of Medicine in Japan and their colleagues performed micro-array analyses using pulmonary arterial hypertension, pulmonary artery smooth muscle cells, and found a 32-fold up regulation of selenoprotein P compared with controls.

                                                Selenoprotein P promotes cell proliferation and apoptosis through increased oxidative stress and mitochondrial dysfunction. Using five strains of genetically modified mice, the authors demonstrated a pathogenic role of selenoprotein P in the development of hypoxia-induced pulmonary hypertension.

                                                Furthermore, sanguinarine, which is an orally active small molecule identified by throughput screening reduced selenoprotein P expression and pulmonary arterial smooth muscle cell proliferation and ameliorated pulmonary hypertension.

                                                In summary, this study shows that selenoprotein P plays a crucial role in the pathogenesis of pulmonary arterial hypertension and may be a useful and novel biomarker and therapeutic target in this disorder.

                                                Familial hypercholesterolemia is known to be associated with a high risk of ischemic heart disease, including myocardial infraction, but what about the risk of ischemic stroke? Well, first author, Dr Beheshti, corresponding author, Dr Nordestgaard, from Copenhagen University Hospital and their colleagues examined the associations of familial hypercholesterolemia and high LDL cholesterol with ischemic stroke in both causal, genetic, and observational analyses using more than 106000 individuals from the Copenhagen General Population Study, and more than 10000 individuals from the Copenhagen City Heart Study.

                                                They used a Mendelian randomization design to test whether high LDL per se had a causal effect on ischemic stroke risk using a combination of the familial hypercholesterolemia causative mutations and common genetic variants associated with high LDL.

                                                The authors found that there was no association between familial hypercholesterolemia mutations and ischemic stroke risk. In the Mendelian randomization analysis, also including common genetic variants, there was also no causal effect of high LDL on the risk of ischemic stroke.

                                                These findings imply that the predominant goal of targeting LDL lowering in those with and without familiar hypercholesterolemia is likely to reduce myocardial infractions, rather than ischemic stroke. Well, that wraps it up for our summaries. Now for our feature discussion.

                                                Circulation publishes numerous papers regarding circulating biomarkers. We talk about biomarkers in the diagnostic, prognostic sense, but what about in a pathophysiologic sense, and especially in a disease as important as aortic stenosis? Well, that's what our featured paper this week is all about and I'm so excited to have with us corresponding author, Dr Stefan Söderberg, from Umeå University in Sweden, as well as our associate editor, Dr Peipei Ping from UCLA. We will be discussing the paper entitled “Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement.” Stefan, could you tell us a bit about what made you look at this very interesting question, and perhaps the unique resources you had in Sweden to look at this?

Dr Stefan Söderberg:      I'm a practicing cardiologist, and I have been working a lot with aortic stenosis over the years. It's frustrating that we can't do anything to stop the process. In many cases, the patients are old and frail, and if you could find the means to stop the process long before they need surgery, it will be of great benefit for the human and for the society.

                                                Also, knowing that the interventions on the statins, for example, have been unsuccessful, we thought that there must be better ways or other biomarkers. Furthermore, that many of these studies, the phenotype of aortic stenosis has been very poorly described and there is probably much more behind just aortic stenosis than just, for example, calcium deposits in an X-ray, et cetera, et cetera.

Dr Carolyn Lam:                You used some very unique resources in Sweden to therefore look at the proteomic signatures of aortic stenosis. Could you describe that and simplify perhaps the results so we can understand it?

Dr Stefan Söderberg:      First of all, I got this idea from other studies done up in northern Sweden. If you have an absolutely unique setting, the combination of huge population-based studies in 30 years back, we have a huge biobank with examples of extraordinary good quality from each of these participants. For example, for each participant, the blood has been spun and put into freezer, deep freezer, within one hour for 30 years, and they are now, as I said, about 100000.

                                                Furthermore, I'm working as a cardiologist at a university, and up here, you do all of the aortic surgery for the whole northern Sweden. That is, we can combine the names of the person undergoing surgery together with these population-based surveys and we can get details from all those who have participated in the surveys long before they did the surgery, and they can go and retrieve samples from cases and match controls from the freezers. It's a unique setup. Then, when we were designing the study, we got the chance to get these analyses done by our friends at the university to get the proteomic analysis via a unique data technique.

Dr Carolyn Lam:                Wow. Could you describe your results?

Dr Stefan Söderberg:      The results that we found in the first set of 334 patients who underwent surgery is 10 years after their first sampling, we found six proteins. Then, we got the question back from Circulation to establish a validation cohort, and we were able to do so to include all those new cases in the last 2 years, and there we could replicate five of these proteins.

                                                The interesting thing that the pattern is completely different between those having coronary artery disease from those without. That kind of phenotyping has not been done throughout other aortic stenosis studies. Therefore, this study is unique. We have had two papers in the last year in the Journal of American Heart Association from the cohort, as well, showing the thing that happened.

                                                For example, lipoprotein little A is only associated with future aortic stenosis valve replacement only in those with concomitant coronary artery disease. There are many unique things, the prospective design, and the phenotype differentiating those with and without coronary artery disease.

Dr Carolyn Lam:                Yeah, and if I may just reiterate that the population base that you work with is just enviable and just so that the audience realizes, these are biomarkers that were collected 11 years before the aortic stenosis surgery, isn't it? You really had a long follow-up.

                                                Also, just to let everyone know, it was a proximity extension assay that you used for the discovery, and the six proteins were growth differentiating factor 15, or GDF15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and PCSK9, so very interesting. Peipei, you have a way of putting things into context so beautifully. Could you tell us your thoughts when you saw this paper?

Dr Peipei Ping:                   I thought this is a very high-quality study that actually benefited from the long-term established, well-controlled cohort in northern Sweden, as Dr Söderberg just shared with us. On the other end, it married a technology platform that's very well-established and -validated, and this situation targeted proteomics platforms using multi-proximity extension assays with carefully controlled markers and screened 92 cardiovascular candidate markers.

                                                This is the kind of approach that provides semi-quantitative as well as quantitative outputs and is capable to offer validated screens on large population clinical subsets. A study of such with a high value cohort combined with a validated and well-controlled technology platform offered results that clearly have clinical significance, as well as setting up examples for other studies to follow. The enthusiasm from the editorial boards, as well as the reviewers, have been substantially high and supportive.

Dr Stefan Söderberg:      Fantastic. I'm very glad to hear this.

Dr Carolyn Lam:                Stefan, you also mentioned that a very unique element was the separation of aortic stenosis with and within coronary artery disease, or at least established or visible coronary artery disease. Could you explain how that provided pathophysiologic insights?

Dr Stefan Söderberg:      First, I should say we were very, very strict. Our routine is that everyone was 100% undergoing, aortic valve replacement, they undergo a coronary angiogram before. If we saw any sign of atheromatosis, it was not enough that they had the significant stenosis, but any signs, they were put into the group of coronary artery disease. Those without, we couldn't see anything there. Radiograph here reported absolutely clean coronary arteries. Of course, we cannot exclude if there were aortic changes within them all, of course.

                                                We believe that this is a very important message that in order to further study aortic stenosis, we should be very careful in phenotyping the disease. We hope the growing cohort will be able to do this further. For example, cuspid versus tricuspid valves, women versus men, et cetera.

                                                My answer in short is phenotype. Let me take one example which I found very, very exciting. That is the finding of PCSK9, which is closely related not only to cholesterol symptoms, but also to lipoprotein little A emphasis. As you know, the first strong finding in aortic stenosis was the LP little A. This is related to that genetic finding, and that was in the huge study from Canada. They did not have the same phenotyping, so we had information to his important findings. That's one example.

                                                Another example is the transferring receptor, where data has shown that bleeding acutely in the valvular tissue causes damage, and this relates iron metabolism to the formation of the aortic valve. Obviously, it seems that the process in the aortic valve is very much similar to the vessel arteriosclerosis. It seems to be different. This is the indication that when we formulate new studies or new drugs on aortic stenosis, we must be very careful to use the right drug for the right type of valvular disease.

Dr Carolyn Lam:                Those are great points. Peipei, do you think that's the main clinical take-home message, beyond that great comment you made earlier that this paper's just a great example of the use of tools, modern tools, that we have in proteomic characterization like the proximity extension assay to provide pathophysiologic insights when you have a really well-phenotyped cohort? What's the critical take-home message, though? Is there one now?

Dr Peipei Ping:                   The take-home message is marriage of amazing high value cohort's data sets with that of the well-controlled clinical study using target proteomics approaches. In this particular study, one main critical innovation is the study is capable of providing insights regarding molecular signatures that have predicted values. As stated in the manuscript, the circulating proteins that found critically important, their alterations took place years before the surgery were associated with aortic stenosis. That is of value, clinical value, to many other clinical studies to follow.

Dr Carolyn Lam:                Wow. That's wonderful. Thank you so much for putting these findings in context for us. Thank you, listeners, for joining us today. Don't forget to tune in again next week.


Jul 31, 2018

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

                                                Does measuring baseline BNP add prognostic information in patients undergoing revascularization for left main coronary artery disease? Well, to find out the answers, you have to stay tuned and listen up for our feature discussion coming right up, after these summaries.

                                                The first original paper this week reports a new role for bone morphogenetic protein 9, or BMP9, as an endogenous inhibitor of cardiac fibrosis. Now, we are familiar with transforming growth factor beta-one, or TGF-β1, as a promoter of cardiac fibrosis. TGF-β1 also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. BMP9 is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1.

                                                In the current paper from first author Dr Morine, corresponding author Dr Kapur, from Tufts Medical Center in Boston, and their colleagues. The authors examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. They utilized the thoracic aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. The authors’ results identified a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload. They further showed that treatment with either recombinant BMP9 or inhibiting a high affinity receptor for BMP9 known as endoglin promoted BMP9 activity and limited cardiac fibrosis in heart failure. Thus, this provides a potential novel therapeutic approach for patients with heart failure.

                                                The next paper shows that endothelial C-type natriuretic peptide, or CNP, regulates microcirculatory flow and blood pressure. First author, Dr Špiranec, corresponding author Dr Kuhn, and colleagues from University of Würzburg in Germany analyzed whether vasodilating response to CNP changed along the vascular tree. In other words, whether the guanylyl cyclase–B receptor was expressed in microvascular types of cells. The authors used novel gene-modified mouse models to show that guanylyl cyclase–B cyclic GNP signaling in parasites diminished microcirculatory resistance and arterial blood pressure. In contrast, endothelial, or macrovascular smooth muscle cell guanylyl cyclase–B signaling was not involved. This indicated that CNP participated in the local cross talk between endothelial cells and parasites, thus playing an important role in the maintenance of normal microvascular resistance and blood pressure. Thus, pharmacological augmentation of endogenous CNP signaling in parasites may provide a useful therapeutic tool to combat increased vascular resistance and hypertension.

                                                Has the rapid and exponential growth in transcatheter aortic valve replacement, or TAVR, demand overwhelmed capacity, thus translating to inadequate access and prolonged wait times? Well, the next paper provides some answers. First author, Dr Elbaz-Greener, corresponding author Dr Wijeysundera, from University of Toronto, evaluated temporal transient TAVR wait times and the associated clinical consequences in their population-based study of all TAVR referrals from April 2010 to March 2016 in Ontario, Canada. Their study cohort included 4,461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons, and 11% remained on the wait list at the conclusions of the study.

                                                For patients who underwent a TAVR, the estimated median wait time in the post reimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability at 80 days of wait-list mortality was 2% and of heart failure hospitalization, 12%, with an increase in events with increased wait times. Thus, post reimbursement wait time has remained unchanged for patients undergoing a TAVR procedure, suggesting that the increase in capacity has kept pace with the increase in demand. The current wait time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access.

                                                The final paper shows that patients with type 2 diabetes and a history of heart failure are particularly likely to benefit from treatment with the SGLT2 inhibitor canagliflozin. First author, Dr Rådholm, corresponding author Dr Figtree, from Royal North Shore Hospital in Australia, and colleagues, studied more than 10,000 participants with type 2 diabetes and high cardiovascular risk in the CANVAS Program who were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. Participants with a history of heart failure at baseline constituted 14.4% of the study population and were more frequently women, white, and hypertensive, with a history of prior cardiovascular disease. The benefit of canagliflozin on cardiovascular death and hospitalized heart failure was greater in patients with a prior history of heart failure compared to those without heart failure at baseline with a p for interaction of 0.02. The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in patients with and without heart failure at baseline. Effects were apparent across a broad range of participant subgroups, including those using established treatments for the prevention of heart failure, such as renin-angiotensin-aldosterone system inhibitors, diuretics, and beta-blockers. Thus, patients with type 2 diabetes and a history of heart failure may be particularly likely to benefit from treatment with canagliflozin. The beneficial effects of canagliflozin on heart failure outcomes unlikely to be accrued on top of other therapies for heart failure management.

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

                                                In patients with left main coronary artery disease who are undergoing revascularization, could BNP assessment be that precision medicine tool to aid us in our clinical decision making? Well, I am just so excited to discuss this very topic with the corresponding author for this feature paper, Dr Gregg Stone from Columbia University Medical Center, as well as our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo.

                                                Gregg, it was a super smart idea to look at circulating BNP and how this may associate with outcomes, as well as therapies in the EXCEL trial. Please tell us what inspired you to do this and please tell us what you found.

Dr Gregg Stone:                As everybody knows, BNP has been identified as an important prognostic factor in patients with heart failure and ischemic heart disease. It correlates with both cardiovascular and noncardiovascular mortality. Patients with left main disease are among the highest-risk patients that either interventional cardiologists or cardiac surgeons treat because of the amount of myocardium at risk, they often present in heart failure, and even if they're not in overt heart failure, they can be prone to large severe left ventricular dysfunction. So first we wanted to establish the prognostic utility of BNP in this patient population and then we were interested to see if it might have a role in helping differentiate which patients might have a better prognosis with either PCI or coronary artery bypass graft surgery.

                                                EXCEL is the largest trial to date of left main PCI versus CABG in a randomized format with 1905 enrolled patients. And overall, we found that PCI and CABG had similar rates of deaths, large myocardial infarction, or stroke in 3 years. But of course, there are high risk-patients and low-risk patients buried within those overall aggregate outcomes, and BNP was an important prognostic predictor of overall mortality in the trial. Both cardiovascular and noncardiovascular, but not of any other ischemic end points interestingly. Not myocardial infarction, stent thrombosis, graft occlusion, bleeding, revascularization. But definitely, mortality. Even independent of left ventricular ejection fraction and heart failure status.

                                                Now, when we looked at the outcomes of PCI versus bypass surgery, we actually found a very powerful interaction, such that at relatively lower BNP levels, patients who underwent PCI had a better prognosis and tended to have lower mortality. Where patients with high baseline BNP levels tended to have a better prognosis after surgery.

Dr Carolyn Lam:                You know, Torbjørn, I love your editorial where you contextualize these findings so nicely. Could you do that for us now?

Dr Torbjørn Omland:      First, I would like to congratulate Gregg and his team with this very interesting and very well-done study, and I think Circulation is very fortunate to be able to publish papers like this. We have known for quite a long time that BNP is a strong prognostic indicator across the spectrum of cardiovascular diseases and it seems to be particularly strongly associated with risk of heart failure events, cardiac arrhythmias, and risk of death. And, as shown in the EXCEL trial, the association with left ventricular ejection fraction is actually quite weak, and also the association with ischemic events. So, these findings fit very well with previous observations. The really novel and intriguing finding of this study is the very strong interaction between procedural BNP levels and the effect of the randomized therapies and, as you alluded to, all the investigators have tried to look at this in other more low-risk populations like in the LIPID trial but actually failed to find any significant interaction. It's really a novel and important finding.

Dr Carolyn Lam:                That's true. Does it bring up the question are the natriuretic peptides just a better EF measurement? You mentioned that there was a correlation, what do you think, Gregg?

Dr Torbjørn Stone:          Well, you know, there was a weak correlation between BNP and ejection fraction and history of heart failure but the prognostic utility of BNP in this study and its ability to differentiate between the outcomes of PCI versus CABG in patients with low versus high BNP was actually strongly independent of both congestive heart failure history and acute left ventricular ejection fraction. So, I think the BNP is giving a useful independent information. It's a strong reflector of both atrial and ventricular pressures and volume status, but it also reflects myocardial hypoxia, it may be involved in glycolysis and lipid peroxidation, and other mechanisms that we don't fully understand. There may be elements of diastolic dysfunction that we have not measured in this study and other mechanisms related to prognosis in these patients. So, while EXCEL was not set up to truly differentiate and delve deeply into the mechanisms of our observations, statistically these were strong associations that may prove clinically useful.

Dr Carolyn Lam:                Right, I thought that was so intriguing as well, just the points that you brought up. First, let's just clarify for the audience that when you say low and high you were using a cutoff of 100.

Dr Gregg Stone:                We did use a cutoff of 100 pg per mL as is common, but we also modeled BNP as a continuous measure. And actually the relationships were even stronger when modeled as a log hazard ratio continuous measure, both for mortality and for the primary end point.

Dr Carolyn Lam:                Yeah, that's so cool. And Torbjørn, you talked about this in your editorial as well and I thought your point about the distributions of the ejection fraction versus the distribution of natriuretic peptide, that was very revealing, too. Would you like to explain your thoughts there?

Dr Torbjørn Omland:      I found it very interesting that all of this is clearly a high-risk operation overall. More than 90% actually had what we regard a normal, or at least not a reduced ejection fraction. Whereas the distribution of BNP values were more widely distributed so that actually about 40% of participants had BNP levels above this ratio of 100 pg per mL. And that probably shows that in this population, BNP provides additional and independent information about the status of the myocardium that is not revealed by angiography or ejection fraction measurements.

Dr Carolyn Lam:                That's true, and that's an important point because it added above the SYNTAX score, too, right Gregg?

Dr Gregg Stone:                That's right, it was an independent predictor, and in fact the SYNTAX score and the severity of left main coronary disease did not vary, according to BNP levels, that is. High versus low BNP were equally distributed, not related to the anatomic extent and complexity of coronary artery disease. So, BNP is clearly reflecting a different state of the myocardium in a way that we can't measure with any other available test and that makes it quite a useful biomarker.

Dr Carolyn Lam:                Exactly, so I think I'd like to wrap up with asking you both, you can already see what the potential clinical implications are, right? Which means that perhaps in a similar type of patient where there's equipoise of the revascularization method and has left main disease, maybe we should be using natriuretic peptides to guide our clinical decision making. What do you think are next steps before this is prime time?

Dr Gregg Stone:                Well I can mention that when one makes a decision of the best revascularization modality for patients with extensive multi-vessel or left main coronary artery disease, there are many factors that go into that determination, both clinical, anatomic, is the patient a good candidate for one versus the other revascularization modality, what are the patient's preferences, what's the surgeon's or interventionalist's likelihood of being able to safely get the patient through the procedure and achieve complete revascularization.

                                                The SYNTAX score makes a difference, as does gender and age and kidney disease and COPD and ejection fraction and many other factors. So I think we can now add to that list BNP, although I will say this was a post-hoc study, we only had BNP available in approximately 60% of the patients, and while the outcomes were similar in the patients who we did not versus who we did have BNP, this has to be looked at as hypothesis-generating analysis, and we would love to also see this type of finding replicated in other large datasets. That being said, there are no other large left main or new multi-vessel disease trials that are planned right now to my knowledge, and I think given the breadth of this dataset and its size and scope, I do think that these findings are robust enough to use BNP as one of the clinical factors to consider in revascularization decisions.

Dr Torbjørn Omland:      I actually agree with that and I think ideally, we would, of course, like to see external validation in another dataset and even retrospective randomized study comparing conventional versus BNP-guided strategy but that may not be realistically undertaken. So, I think these are clearly the best data we have and as clinicians need to integrate this in our overall evaluation in making this important decision.

Dr Carolyn Lam:                Yeah, I mean Gregg, could I ask you, do you apply this clinically already?

Dr Gregg Stone:                We have not been before this, although I believe we will now. I believe BNP should be a biomarker that we more routinely measure in patients with ischemic heart disease as well as those with overt congestive heart failure. And again, use as one of the factors of many when making revascularization decisions. And I think it's important to note also that the PCI patients tended to preferentially benefit, in fact with even lower mortality when BNP was lower. Where the surgical patients tended to benefit when BNP was higher. So, it's one factor, not the only factor, but I think it's one additional piece of the puzzle.

Dr Carolyn Lam:                Yeah, I have to say too I mean, after reading this, after reading this awesome editorial, it's hard not to think I should be applying this clinically because it's going to be really hard and take a long time to prove this with more prospective data, for example. Although, external validation and other datasets may be better, this is the largest trial already to show this and show it so clearly with a significant interaction. I think that is striking to me.

                                                Torbjørn maybe I've put you on the spot with the last word, does this change your clinical practice?

Dr Torbjørn Omland:      I agree with Gregg. This will be one of maybe several other factors but I think it's ready for being taken into account when making this sometimes very difficult decision.

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


Jul 24, 2018

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Did you know that despite being one of the wealthiest nations in the world, the United States population has a shorter life expectancy compared to almost all other high-income countries in the world? Well, stay tuned to learn what Americans could do to narrow the life expectancy gap between the United States and other industrialized nations. Coming right up after these summaries.

                                Are microRNAs involved in nitrate tolerance? Well, the first original paper this week provides some answers. This is from co-corresponding authors Dr Bai and Zhang from Central South University in Changsha, China. Nitrate tolerance develops when there's dysfunction of the prostaglandin I2 synthase and prostaglandin I2 deficiency. These authors hypothesize that prostaglandin I2 synthase gene expression may be regulated by a microRNA-dependent mechanism in endothelial cells. They induce nitrovasodilator resistance by nitroglycerin infusion in Apoe deficient mice and studied endothelial function in both the mouse models as well as human umbilical vein endothelial cells. They found that nitric oxide donors induced atopic expression of microRNA 199a/b in endothelial cells, which was required for the nitrovasodilator resistance via repression of prostaglandin I2 synthase gene expression. Targeting this axis effectively improved nitrate tolerance. Thus, the atopic expression of microRNA 199 in endothelial cells induced by nitric oxide may explain prostaglandin I2 synthase deficiency in the progression of nitric tolerance. Thus, microRNA 199a/b may be a novel target for the treatment of nitric tolerance.

                                What are the long-term outcomes of childhood left ventricular noncompaction cardiomyopathy? Well, the next paper presents results from the National Population-Based Study in Australia. First author, Dr Shi, corresponding author, Dr Weintraub, from Royal Children's Hospital in Melbourne, looked at the National Australian Childhood Cardiomyopathy Study, which includes all children in Australia with primary cardiomyopathy diagnosed at less than 10 years of age between 1987 and 1996. Outcomes for left ventricular noncompaction patients with a dilated phenotype will compare to those with a dilated cardiomyopathy.

                                There were 29 patients with left ventricular noncompaction with a mean annual incidence of newly diagnosed cases of 0.11 per hundredth thousand at risks persons.

                                Congestive heart failure was initial symptom in 83%, and 93% had a dilated phenotype. The median age at diagnosis was 0.3 years of age. Freedom from death or transplantation was 48% at 10 years after diagnosis, and 45% at 15 years. Using propensity score inverse probability of treatment-weighted Cox regression, the authors found evidence that left ventricular noncompaction with a dilated phenotype was associated with a more than two-fold greater risk of death or transplantation.

                                The next paper reports the first application of multiomics and network medicine to calcific aortic valve disease. Co-first authors Dr Schlotter and Halu, corresponding author Dr Aikawa from Brigham and Woman's Hospital and Harvard Medical School in Boston, and their colleagues examined 25 human stenotic aortic valves obtained from valve replacement surgeries. They used multiple modalities, including transcriptomics and global unlabeled and label-based tandem-mass-tagged proteomics.

                                Segmentation of valves into disease stage–specific samples was guided by near-infrared molecular imaging. Anatomic-layer specificity was facilitated by laser capture microdissection. Side-specific cell cultures was subjected to multiple calcifying stimuli, and the calcification potential and basil or stimulated proteomics were evaluated. Furthermore, molecular interaction networks were built, and their central proteins and disease associations were identified.

                                The authors found that global transcriptional and protein expression signatures differed between the nondiseased, fibrotic, and calcific stages of calcific aortic valve disease. Anatomical aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression and identified glial fibrillary acidic protein as a specific marker of valvula interstitial cells from the spongiosa layer. In vitro, fibrosa-derived valvular interstitial cells demonstrated greater calcification potential than those from the ventricularis. Analysis of protein-protein interaction networks further found a significant closeness to multiple inflammatory and fibrotic diseases. This study is significant because it is the first application of spatially and temporarily resolved multiomics and network systems biology strategy to identify molecular regulatory networks in calcific aortic valve disease. It provides network medicine–based rational for putative utility of antifibrotic and anti-inflammatory therapies in the treatment of calcific aortic valve disease. It also sets a roadmap for the multiomic study of complex cardiovascular diseases.

                                The final paper tackles the controversy of antibiotic prophylaxis for the prevention of infective endocarditis during invasive dental procedures. This is from a population-based study in Taiwan. First author, Dr Chen, corresponding author, Dr Tu from Institute of Epidemiology and Preventive Medicine College of Public Health in National Taiwan University aimed to estimate the association between invasive dental treatments and infective endocarditis using the health insurance database in Taiwan.

                                They chose 2 case-only study designs. First a case-crossover, and second, self-controlled case series. Both designs used within-subject comparisons such that confounding factors were implicitly adjusted for. They found that invasive dental treatments did not appear to be associated with a larger risk of infective endocarditis in the short period following invasive dental treatment. Results were consistent from both study designs. The authors also did not find any association between invasive dental treatments and infective endocarditis even among the high-risk patients, such as those with a history of rheumatic disease or valve replacement.

                                In summary, these authors found no evidence to support antibiotic prophylaxis for the prevention of infective endocarditis before invasive dental treatments in the Taiwanese population. Whether antibiotic prophylaxis is necessary in other populations requires further study.

                                Alright, so that wraps it up for our summaries, now for our feature discussion.

                                The United States is one of the wealthiest nations worldwide, but Americans have a shorter life expectancy compared with almost all other high-income countries. In fact, the US ranks only 31st in the world for life expectancy at birth in 2015. What are the factors that contribute to premature mortality and life expectancy in the US? Well, today's feature paper gives us some answers. And I'm just delighted to have with us the corresponding author, Dr Frank Hu from Harvard T.H. Chan School of Public Health, as well as our dear associate editor, Dr Jarett Berry, from UT Southwestern.

                                Frank, could you begin by telling us a bit more about the inspiration for looking at this, what you did, and what you found?

Dr Frank Hu:       So, we look at the impact of healthy lifestyle habits, life expectancy in the US as a nation. As you just mentioned, Americans have a shorter life expectancy compared with almost all other high-income countries, so in this study we wanted to estimate what kind of impact of lifestyle factors have, premeasured that and life expectancy in the US population.

                                What we did is to combine three datasets. One is our large cohort, Nurses’ Health Study, and Health Professionals Follow-Up Study. We use this large cohort to estimate the relationships between lifestyle habits and mortality. And the second data set we use is to get age and sex to specific mortality rates in the US as a nation. This is the CDC WONDER dataset. And the third dataset we used is the NHANES dataset, this is the National Health and Nutrition Examination Survey. We used this dataset to get the prevalence of healthy lifestyle factors in the general US as a nation. So, we used the three datasets to create age-specific, sex-specific life tables and estimated life expectancies.

                                At age 50, according to the number of healthy lifestyle habits that people would follow, what we found is that following several lifestyle factors can make a huge difference in life expectancies.

                                Here we talk about five basic lifestyle factors: not smoking, maintaining a healthy weight, exercise regularly—at least a half hour per day—and eating a healthy diet, and not drinking too much alcohol. No more than one drink per day for a woman, no more than two drinks per day for men. What we found is that, compared with people who did not adapt any of those low-risk habits, we estimated that the life expectancy at age 50 was 29 years for woman and about 26 years for men. But for people who adapted all five healthy lifestyle habits, life expectancy at age 50 was 43 years for women and 38 years for men. So, in other words, a woman who maintains all 5 healthy habits gained, on average, 14 years of life, and the men who did so gained 12 years life compared with those who didn't maintain healthy lifestyle habits. So I think this is a very important public health message. It means that following several bases of healthy factors can add substantial amount of life expectancy to the US population, and this could help to reduce the gap in life expectancy between the US population and other developed countries.

Dr Carolyn Lam: Thank you, Frank. You know that is such an important public health message that I am going to repeat it. Adhering to five lifestyle risk factors mainly, don't smoke, maintain a healthy weight, have regular physical activity, maintain a healthy diet, and have moderate alcohol consumption, AND a woman could increase her life expectancy at age 50 by 14 years and a man could do that by 12 years more. That is absolutely amazing.

                                Okay so Frank, actually, I do have a question though. These are remarkable datasets obviously, but they also go back to the 1980s. So did you see any chief risk factor that may have played more predominant apart with time?

Dr Frank Hu:       We didn't specifically look at the changes in risk factors life expectancy, but among the five risk factors, not smoking is certainly the most important factor in terms of improving life expectancy. The good news is that prevalent smoking in the US has decreased substantially in the past several decades. However, the prevalence of other risk factors has actually increased. For example, the prevalence of obesity has increased two- or three-fold and the prevalence of regular exercise remained at a very low level, and also the diet quality in the US population is relatively poor. So, the combination of those risk factors have contributed to relatively low life expectancies in the US population.

Dr Carolyn Lam: Right. Obesity, not smoking, I hear you. I just wanted to point out to all the listeners too, you have to take a look at Figure 1 of this beautiful paper, it’s just so beautifully illustrated in it.

                                Jarett, you helped to manage and bring this paper through. What are your thoughts?

Dr Jarett Berry: Yeah, I just want to echo your comments, Carolyn, and Dr Hu. This is a fabulous paper, and a very important contribution characterizing these important associations in the US population. And I think, and the discussion thus far has been really helpful in putting all of this into context.

                                I do want to ask you, just a couple of, I guess more, philosophical questions about some of the observations in the paper. And one of them is the prevalence of the low-risk factor, those with a large number of low-risk factors, for example, in both the Nurses Health and in the Health Professional Follow-Up Study, you observed that the presence of five lifestyle factors was less than 2%. And it's interesting you see this in a large number of datasets and I think important, maybe for our readers to realize that there's two sides to the coin here.

                                One, the benefit of these low risk factors, but also, unfortunately, the low prevalence of these collections of healthy lifestyle factors that you've outlined.

                                Could you comment a little bit on that, and what that means, both maybe from a scientific point of view of perhaps, more importantly, from a public health stand point?

Dr Frank Hu:       Yeah and this is very important observation and the number of people or the percentage of people who maintained all the five low-risk lifestyle habits is quite low in our cohort, even the nurses and health professionals, they are more health conscience in the general population. They have much better access to health care and also better access to healthy foods and have physical activity facilities. Despite all this potential advantages, and these more percentage of people who are able to maintain all five lifestyle risk factors.

                                On the other hand, about 10 to 15% of our participants did not adopt any of the five low-risk lifestyle habits. So it means that we still have a lot of work to do in terms of improving the lifestyle habits that we discussed earlier. The five risk lifestyle factors and in the general population, I think the percentage of people who adapt all the five lifestyle factors, probably even lower than 2%. And so that means that we have a huge public health challenge in front of us and have to improving the five lifestyle risk factors. One of the most important public health challenges as mentioned earlier is obesity because currently we have two-third of the US population is overweight or obese. So that's something I think is major public health challenges for us.

Dr Jarett Berry: Right, and it’s interesting looking at your Table 1, and those individuals who have all five low risk factors. It's interesting that the prevalence of physical activity was incredibly high. I have a great interest of impact of exercise on these types of outcomes and it's interesting that in both cohorts, six or seven hours a week of exercise was the mean physical activity level in those with five risk factors. So, it's interesting and in some ways, these lifestyle factors, they do tend to congregate or covary with one another such that those individuals who do spend that kind of time, albeit unfortunately more rare than we would like to see it, the increase in physical activity does tend to have a positive impact, not only on the weight, but also on healthy lifestyle or healthy diet choices.

Dr Frank Hu:       Right, yeah this is a very good observation that what I do want to point out that our definition of regular exercise is pretty cerebral to put it in terms of the definition. So we define moderate to vigorous physical activity in our cohorts. We included not just running, playing sports, but it was also walking in a moderate intensity. So it means that people can incorporate physical activity into their daily life. For example, by walking from a train station and with climbing stairs in their workplace and so on and so forth. So here physical activity means both recreational activity and also moderate intensity activities such as graceful walking.

Dr Carolyn Lam: Frank, I think both of us listening are breathing a sigh of relief there and just for the listeners to understand too. These factors were dichotomized, right, and so you were describing the type of exercise and actually you used a three and a half hour per week limit to define healthy or not.

                                Similarly, just for reference the alcohol intake was 5 to 15g a day for women, or 5 to 30g a day for men. And normal weight was defined as a BMI of 18.5 to 24.9. I'm just thinking that if I were listening I'd want to know those cutoffs.

                                Now, can I ask a follow-up question, therefore to this dichotomy. As far as I understand you counted each of these risk factors equally, but did you try to do a weighted analysis by any chance? Did any one of them play a bigger role than others?

Dr Frank Hu:       That's an interesting mathematical question because it’s very difficult to assign different weights to different risk factors because we look at, not just total mortality but also cardiovascular mortality and cancer mortality. So, you would have to use different weights for different causes of mortality. That would make the analysis much more complicated. But we did calculate a different type of score using five categories of each risk factor and then using that score, we were able to rank people in more categories so for that score the range is from five to 25, and we categorized people into quintiles or even more categories and the contrast in life expectancy between the lowest and the highest group is even greater. So, it means that, the higher number of healthy lifestyle factors, the greater life expectancy. Also, with each category, each lifestyle factors a high degree of adherence to that factor, the greater health benefit people will get. So, I think it's really accumulative fact of multiple risk factors and also the degree of adherence to each of the factors.

Dr Carolyn Lam: Again, such an important public health message.

                                Jarett, how do you think this is going to be received by the public at large?

Dr Jarett Berry: Very well received. I mean this is a very important observation demonstrating some of these disconcerting observations about life expectancy in the United States and as we think about strategies for improving the public health, I think Dr Hu's group has really helped us outline, very clearly, what other bodies such as the American Heart Association have been saying for years now, that lifestyle factors are so important in influencing cardiovascular risk, and in this case, life expectancy. It really does put, once again, the right amount of emphasis on the role these lifestyle factors of improving the public health. I think it’s going to be very well received and really helpful and important observation that all of us need to hear.

Dr Carolyn Lam: Listeners, don't forget this important message and tell your friends about it, please.

                                Thanks for joining us today, don't forget to join us again next week.


Jul 17, 2018

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

                                                In this day and age of endovascular treatment for acute ischemic stroke, does time to treatment really matter? Well, we will be discussing results of the MR CLEAN Registry from real-world clinical practice, coming right up after these summaries.

                                                The first original paper this week describes the first mouse model of progerin-induced atherosclerosis acceleration. Progerin is an aberrant protein that accumulates with age, causes a rare genetic disease known as Hutchinson-Gilford Progeria Syndrome. Patients with Progeria Syndrome have ubiquitous progerin expression and exhibit accelerated aging and atherosclerosis, dying in their early teens mainly from myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part due to the lack of appropriate animal models. First author Dr Hamczyk, corresponding author Dr Andrews, and colleagues from CNIC in Madrid performed an elegant series of experiments and generated not only the first mouse model of progerin-induced acceleration of atherosclerosis, but also provided the first direct evidence that progerin expression restricted to vascular smooth muscle cells but not to macrophages was sufficient to induce premature atherosclerosis and death. Progerin-induced loss of vascular smooth muscle cells caused atherosclerotic plaque destabilization that led to myocardial infarction. Ubiquitous and vascular smooth muscle cell specific progerin expression increased LDL retention in aortic media, likely accelerating atherosclerosis.

                                                The next original paper implicates dysregulation of mitochondrial dynamics as a therapeutic target in human and experimental pulmonary arterial hypertension. Now, mitotic fission is increased in pulmonary arterial hypertension. The fission mediator, dynamin-related protein 1, or Drp1, must complex with adaptor proteins to cause fission. In the current paper from co-first authors Dr Chen and Dasgupta, corresponding author Dr Archer from Queens University in Ontario Canada, and colleagues, the authors examined the role of two recently discovered but poorly understood Drp1 adaptor proteins known as mitochondrial dynamics protein of 49 and 51 kilodalton. They found pathological elevation of these mitochondrial dynamic proteins in pulmonary artery smooth muscle cells and endothelial cells in both human and experimental pulmonary arterial hypertension that accelerated mitotic fission and supported rapid cell proliferation. Mitochondrial dynamics protein's expression was epigenetically upregulated by a decreased expression of microRNA-34a-3p. Circulatory microRNA-34a-3p expression was decreased in both patients with pulmonary arterial hypertension and preclinical models, silencing the mitochondrial dynamics proteins or augmenting microRNA-34a-3p regressed experimental pulmonary arterial hypertension, thus, proving to be potential new therapeutic targets for pulmonary arterial hypertension.

                                                Dyslipidemia guidelines currently recommend that non-HDL cholesterol and apolipoprotein B, or apoB, are secondary targets to the primary target of LDL cholesterol. However, how frequently does non-HDL cholesterol guideline targets change management, and what is the utility of apoB targets after meeting LDL and non-HDL targets?

                                                Well, answers are provided in the next paper from first author Dr Sathiyakumar, corresponding author Dr Martin, and colleagues from Johns Hopkins University School of Medicine. These authors analyzed more than 2,500 adults in the US National Health and Nutrition Examination Survey, as well as more than 126,000 patients from the Very Large Database of Lipids Study with apoB. They identified all individuals as well as those with high-risk clinical features, including coronary disease, diabetes, and metabolic syndrome who met the very high and high-risk guidelines targets of LDL cholesterol of less than 70 and less than 100 mg/dL, respectively, and this was measured using either the Friedewald estimation or a novel, more accurate method. They found that after using the more accurate method of estimating LDL cholesterol, guidelines suggested non-HDL targets could alter management in only 1 to 2% of individuals, including those with coronary disease and other high risk clinical features.

                                                However, using the Friedewald estimated LDL cholesterol gave a much higher percentage. Among all individuals with both LDL cholesterol less than 100 and non-HDL cholesterol less than 130 mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus, the utility of current non-HDL targets appears to be contingent on the accuracy of LDL cholesterol estimation. When using a novel, more accurate estimation method to assess LDL cholesterol, the non-HDL cholesterol is infrequently above current guidelines' suggested targets after the LDL target is met. Current guidelines suggest that apoB targets also provide only modest utility after cholesterol targets are met. These findings were robust to high-risk clinical features, sex, fasting status, and presence of lipid-lowering therapies.

                                                The final paper tells us that HIV infection increases the risk of developing peripheral artery disease. Dr Beckman from Vanderbilt University Medical Center and colleagues studied almost 92,000 participants in the Veterans Aging Cohort Study from 2003-2014 over a median follow-up of nine years. They excluded participants with known prior peripheral artery disease or prevalent cardiovascular disease. They found that infection with HIV was associated with a 19% increased risk of incident peripheral artery disease beyond that explained by traditional atherosclerotic risk factors. Once peripheral artery disease had developed, HIV infection increased the risk of mortality compared to uninfected patients. Whereas for those with sustained CD4 cell counts above 500, there was no excess risk of incident peripheral artery disease events compared to uninfected people. Furthermore, worsening HIV infection as measured by CD4 cell count and HIV viral load was associated with increased incident peripheral artery disease and mortality. In summary, HIV infection increased the risk of developing peripheral artery disease and mortality. The findings also suggest that aggressive antiretroviral therapy to reduce viral load and increase CD4 cell counts may reduce the risk of developing peripheral artery disease. Furthermore, clinicians should solicit clinical complaints and physical signs consistent with peripheral artery disease to facilitate the diagnosis of peripheral artery disease in patients with HIV and ensure the addition of guideline-based anti-atherosclerotic therapies in these patients.

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

                                                When it comes to acute ischemic stroke treatment, we've learned from trials of intravenous thrombolytics that time is brain. But what about the situation with endovascular treatment of strokes? Also, what's the situation like in the real world? Well, today's featured paper really provides precious data telling us about time-to-endovascular treatment and outcomes in acute ischemic stroke. I am so delighted to have with us the first and corresponding author of the MR CLEAN Registry, Dr Maxim Mulder from Erasmus University Medical Center, as well as our editorialist, Dr Micheal Hill, from University of Calgary, and our associate editor, Dr Graeme Hankey, from University of Western Australia, all here to discuss this hugely important topic.

                                                Maxim, could we start with you? So, MR CLEAN Registry means there was a MR CLEAN trial. Could you tell us a little bit more about your paper?

Dr Maxim Mulder:           Sure, well to start with, I think it's important to make sure all the people know the difference between the MR CLEAN trial and the registry since of course the trial was to show whether the intra-arterial treatment is effective when it comes to acute ischemic stroke treatments and then, of course, for people treated within six hours. When the MR CLEAN trial finished we continued in the Netherlands with all the participating centers from the trial to gather all the data from everybody who is treating in the whole country with the intra-arterial treatment, but they're not anymore in the light of the trial but in the clinical practice. We've had a lot of trials, but we don't have a lot of clinical practice date yet of the intra-arterial treatment, so that's where it all started.

                                                So, what we found is we consider our data, so with the least possible selections or the only selection was basically to treat within six and a half hours and have patients that had a proven large vessel occlusion that were treated in the Netherlands and of course as we also know from when intravenous therapy was introduced that what happens in clinical trials doesn't necessarily happen when a new treatment is introduced into clinical practice. There are less strict criteria for patients to get treated, and you know everybody, of course, there is a lot of debate about which patients should be treated. In clinical trials it is very strictly coordinated, but in clinical practice there's a lot more room to have an interpretation and also treat a different population. So, we also see that our population is somewhat older and has more comorbidities than in all the trials. Also what we found, of course, our most important finding was that when compared to all the trials or the large trials combined together in the Emberson analysis about time that when we look at the influence or the association of time with functional outcome of intra-arterial treatment that this association is clearly stronger than we found in the previous, the trial data.

                                                So, I think that's a very important finding. Also, for everybody who's now treating this patient in clinical practice.

Dr Carolyn Lam:                Exactly. I mean this is really stunning results. If I could paraphrase from your paper, every hour delay in time from stroke onset to the start of endovascular treatment resulted in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality. This is stunning. Thank you, thank you for publishing these results with us in Circulation. I would like to ask Michael, I love the point you made in the editorial that time of stroke onset is really quite a difficult thing to determine. Could you tell us your thoughts about that, Michael?

Dr Micheal Hill:                  I mean, it's something like 15-20% of the time stroke is unwitnessed, either because stroke occurs in sleep and the patient is discovered with their stroke symptoms on awakening. Or the patient is simply alone and has their stroke unwitnessed by any bystander. Even in so-called witness stroke, there are probably significant errors in determining the exact time of stroke onset because it's an emergency, and everybody's flustered and time anchors are not necessarily well known. And, so, I think it's an important point that the actual measurement of time is challenging, yet it's still an easier clinical tool for us to use in gauging the extent or evolution of stroke. That's the most important thing to point out here is that this population effect that Max has observed in the MR CLEAN registry is certainly concordant with clinical trial data.

                                                I certainly think it's correct, and, as you pointed out in your comments, dramatic, but a really important issue is that for the individual patient, there's quite a lot of variance in the evolution of stroke. So, whereas, on a population basis, it's absolutely true that the average time from estimated time of stroke onset to treatment initiation is absolutely critical; in some patients, the individual might be still a good candidate for treatment even in late time windows, and some patients, even after a couple hours, the damage is already extensive, and they may not be good candidates for treatment. It still requires individual decision making, and it still leaves a lot of room for clinical judgment largely based on imaging.

Dr Carolyn Lam:                True, and I think you've really succinctly put that solid take-home message in the title really, which is acute ischemic stroke biology really demands fast treatment. I think that's the one thing that we'd really like clinicians to come away with. You agree?

Dr Micheal Hill:                  Absolutely. Especially, I think, the advantage of looking at whole populations and large, I mean this is a large registry, the MR CLEAN registry, and the group should be congratulated because it's clearly the biggest registry in the world right now of available data, and it's only getting larger week by week as they carry on with their work. You know the whole Netherlands group, the MR CLEAN group, are a fantastic group, but absolutely right, on a population basis, we absolutely have to get our systems in place so that on average we're treating patients incredibly fast. On an individual basis, the clinicians and the teams treating an individual patient still need to make judgments about that patient's eligibility for treatment. It's easy when the times are fast, so if you're an hour and a half from onset, nearly everybody's gonna be a good candidate for treatment, but as time elapses you need to make judgements on the basis of imaging.

Dr Carolyn Lam:                Well put. You know, Graeme, you're over there in Australia. What are your take-home messages about how generalizable these findings are to places outside perhaps of the Netherlands?

Dr Graeme Hankey:        I think you're asking about the external validity. I think the internal validity is certainly there. As Michael said, this is the largest registry that we have that's been published data on this before. It's certainly novel, and we're very confident that the results are valid, although this is an observational study and not a randomized trial. The association between time and outcome seems to be independent of the major patient factors that may influence time to endovascular therapy. For example, younger people who are less frail and they're alert and they're mobile can get to treatment earlier. So, you might say, well of course they're gonna have a better outcome. But these factors were adjusted for. And, of course, there are procedural factors that could influence the association between time and outcome, but we're very confident in the results and the novelty of them in supporting and building on the randomized trial data.

                                                We're also very confident in the registry and the nature of the population. The results are likely to be generalizable beyond the Netherlands population where this was conducted in routine clinical practice, certainly across Caucasian populations that are similar and with similar stroke interventional and assessment protocols, and I would hope to see this sort of study validated externally in other populations. But, also, as Michael said, I think this study not just highlights the importance of time as a factor and its implications for systems of care and recognizing people with disabling stroke and ensuring they’re assisted urgently to the appropriate imaging but also to acknowledge that time isn't the only factor. And as Michael has alluded to, our brain tissue has different collateral circulations and different probable genetic factors and metabolic factors. So, someone with a stroke at one hour, it might be all over for them. Whereas, another person with a stroke at 24 hours ago, they might have salvageable tissue.

                                                So, although, generally time is an important prognosticator as we've learned here, there are probably other factors that need to be considered and accounted for. But this certainly takes us a step forward, and, in answer to your question, I think we have confidence in its generalizability.

Dr Carolyn Lam:                Thank you Graeme. Maxim, in line with that, are there any next steps you plan?

Dr Maxim Mulder:           In light of the most recent trials, the DAWN and DEFUSE 3 trial about 6 to 25-hour, 24-hour window, I think that both of the trials are very exciting, and they shine a new light into a new set of patients that are still able to offer a great benefit intra-arterial treatment. In my opinion, the most important thing, especially in those two trials, those are highly selective patients, especially selected on all the extra imaging parameters, and I guess that there's a whole larger population that could still benefit in this time window and that's also one of the things we're currently studying in one of our new trials in the Netherlands in the MR CLEAN-LATE trial, and that is randomizing patients who are having a large vascular occlusion 6 to 24 hours, and the only extra criteria they should meet is they should have at least a little bit of collateral circulation on the ischemic brain side.

Dr Carolyn Lam:                Michael and Graeme, what do you think are the priorities for next steps in research.

Dr Micheal Hill:                  I guess overall in the field, I don't think there's any doubt that faster treatment is better. What we need to do across the world is make sure that everybody's receiving it on a system-wide basis. Right? I think there needs to be a lot of more careful work done on getting systems of care in place to make sure that patients are getting the treatment they can get. We have very many weaknesses. Some are related to lack of accreditation. Some are related to the resources required to get people treated quickly. Some are related to continuing resistance in some specialties to even giving intravenous thrombolytic drugs. So, I think faster treatment in general for acute stroke is a theme; it's not just limited to endovascular treatment. It's treatment for patients for intravenous thrombolysis. It's also actually true for TIA and minor stroke. We've had recent data on fast antiplatelet therapy, so, it's not an emergency in the same way in terms of minutes, but it's still a general theme of acute stroke care.

                                                We need to be like the Ferraris and the Formula One, right? And get ourselves moving. That's a big challenge for people. Right? It's a big stress on systems. But, I think there are other examples in medicine. We've seen this evolution in acute coronary care, and we've seen the evolution in acute trauma care. In many ways, the next things that need to really continue to happen are publications like this and getting the message out that people need to start changing their mind. The biggest thing that I find when I talk to people or talk at meetings or talk to administrators is that they say, "Well, we can't do this many CTs that fast. We can't respond that fast." And the answer is actually that you can't change the biology of the disease, so if you decide you wanna treat stroke patients, you better figure out how to change your systems. It's a question of will here rather than trying to bend the disease to the system.

Dr Carolyn Lam:                Wonderfully put. Can't change the biology so we better change the systems. How about you, Graeme? Any last words?

Dr Graeme Hankey:        Just to concur with Michael’s comments there and Max's underlying theme that time is very important. And as Michael alludes to, it's not just acute ischemic stroke due to large vascular disease, it's also acute intracerebral hemorrhage. We're learning now really if we're gonna have an effect in the bleeding brain probably we have to do that within the first three hours and maybe not be waiting so late. And as Michael alludes to, someone with a minor ischemic stroke who's had a hot volcano gone off in their neck, as you know, ruptured atherosclerotic plaque, it's like those volcanoes in Hawaii, they're gonna keep going off again. And the risk is 5% in the next two days and 10% in the next week. So, a TIA and a mild ischemic stroke, it is a medical emergency to find the cause and to get it treated, and that's why the synopsis of this message from Max's study is that people, if they do avail themselves of acute assessment early, even if they don't have a large vessel occlusion causing an ischemic stroke, they may actually have their intracerebral hemorrhage treated quickly or, more evidence based at the moment, their TIA or mild ischemic stroke have the cause ascertained and treated emergently and reduce that early risk of recurrence should they survive.

Dr Carolyn Lam:                Excellent points. Thank you so much, gentlemen. This has been an amazing podcast.

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


Jul 10, 2018

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

                                                How do resuscitation teams at top-performing hospitals for in-hospital cardiac arrest actually succeed? Well, to learn how, you have to keep listening to the podcast, because we will be discussing this right after these summaries.

                                                The first original paper this week tells us that recent developments in RNA amplification strategies may provide a unique opportunity to use small amounts of input RNA for genome wide-sequencing of single cells. Co-first authors, Dr Gladka and Molenaar, corresponding author, Dr van Rooij, and colleagues from Hubrecht Institute in Utrecht, the Netherlands, present a method to obtain high-quality RNA from digested cardiac tissue, from adult mice, for automated single-cell sequencing of both healthy and diseased hearts.

                                                Based on differential gene expression, the authors were also able to identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cells subpopulations.

                                                For example, they identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlated with known myofibroblast markers, in both mouse and human cardiac tissue. This paper raises the exciting possibility for new biology discovery using single-cell sequencing that can ultimately lead to the development of novel therapeutic strategies.

                                                Myeloid-derived suppressor cells are a heterogeneous population of cells that expand in cancer, inflammation, and infection, and negatively regulate inflammation. However, their role in heart failure was unclear, at least until today's paper in this week's journal. Co-first authors Dr Zhou, Miao, and Yin, and co-corresponding authors, Dr Wang and Li, from Huazhong University of Science and Technology, measured the myeloid-derived suppressor cells by flow cytometry in heart failure patients and in mice with pressure overload–induced heart failure, using isoproterenol infusion or transverse aortic constriction.

                                                They found that the proportion of myeloid-derived suppressor cells was linked to heart failure severity. Cardiac hypertrophy, dysfunction, and inflammation were exacerbated by depletion of myeloid-derived suppressor cells but alleviated by cell transfer. Monocytic myeloid-derived suppressor cells exerted an antihypertrophic effect on cardiomyocyte nitric oxide, but monocytic and granulocytic myeloid-derived suppressor cells displayed antihypertrophic and anti-inflammatory properties through interleukin 10.

                                                Rapamycin increased accumulation of myeloid-derived suppressor cells by suppressing their differentiation, which in part mediated its cardioprotective mechanisms. Thus, these findings revealed a cardioprotective role from myeloid-derived suppressor cells in heart failure by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin 10 and nitric oxide. Pharmacological targeting of myeloid-derived suppressor cells by rapamycin constitutes a promising therapeutic strategy for heart failure.

                                                In the FOURIER trial, the PCSK9 inhibitor evolocumab reduced LDL cholesterol and cardiovascular risk in patients with stable atherosclerotic disease. However, was the efficacy of evolocumab modified by baseline inflammatory risk?

                                                While Dr Bohula from the TIMI Study Group and colleagues explored this question by examining the efficacy of evolocumab stratified by baseline high sensitivity CRP. They also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL concentrations. They found that the relative benefit of evolocumab for the prevention of adverse cardiovascular events was consistent, irrespective of baseline high sensitivity CRP. However, because patients with higher high sensitivity CRP levels had higher rates of adverse cardiovascular events, they also tended to experience greater absolute benefit with evolocumab.

                                                In an analysis of baseline high sensitivity CRP in achieved LDL cholesterol, the authors found that at first cardiovascular event rates were independently associated with both LDL cholesterol and high sensitive CRP. Event rates were lowest in patients with the lowest hsCRP and LDL cholesterol, supporting the relevance of both inflammatory and residual cholesterol risk.

                                                The next paper provides further evidence that residual inflammatory risk, as measured by on-treatment high sensitivity CRP, remains an important clinical issue in patients on combination statin and PCSK9 inhibitor therapy. Dr Pradhan, from Brigham and Women's Hospital and colleagues, evaluated the residual inflammatory risk among patients participating in the SPIRE-1 and -2 cardiovascular outcome trials, who are receiving both statin therapy and the PCSK9 inhibitor bococizumab, according to on-treatment levels of high sensitivity CRP and LDL cholesterol measured 14 weeks after drug initiation.

                                                They found that among high-risk stable outpatients treated with moderate or high-intensity statins and PCSK9 inhibition, roughly one in two had residual inflammatory risk defined by an on-treatment high sensitivity CRP level of 2 or more mg per liters, and roughly one in three had values above 3 mg per liter.

                                                PCSK9 inhibition was associated with a 60% mean reduction in LDL cholesterol but little change in high sensitivity CRP. Levels of high sensitivity CRP above 3 mg per liter were associated with a 60% greater risk of future cardiovascular events, corresponding to a 3.6% annual event rate, even after accounting for on-treatment LDL cholesterol.

                                                Thus, PCSK9 inhibition, added to statin therapy in stable outpatients, does not lower high sensitivity CRP. Persistent elevations of CRP is associated with future cardiovascular risk in these patients, even after low levels of LDL cholesterol are achieved. If corroborated, these data suggests that inflammation modulation may yet have a role in the primary and secondary prevention of cardiovascular disease when LDL cholesterol is already controlled. Well, that wraps it up for our summaries. Now, for our future discussion.

                                                In-hospital cardiac arrests are common worldwide and they're so important because they represent opportunities for us to improve survival. Now, yet, overall rates of hospital survival after in-hospital cardiac arrests remain poor and there is substantial variation across facilities. This may be surprising because we all seem to follow or should follow the same ACLS algorithms across the world and yet, there are different outcomes.

                                                How do resuscitation teams, at top performing hospitals, for in-hospital cardiac arrest, how do they succeed? Pleased to be discussing this with a real star team in today's podcast. We have first and corresponding author of our feature paper, Dr Brahmajee Nallamothu. We also have Dr Steven Kronick, who is the chair of the CPR committee and both are from University of Michigan Medical School. We also have Dr Sana Al-Khatib, who is a senior associate editor of Circ, from Duke University. So, welcome everyone! Let’s go straight into it. Maybe starting with you Brahmajee, could you tell us what inspired you to perform this study?

Dr Brahmajee Nallamothu            Thank you, Carolyn, for giving us the opportunity to talk about this study. I'm an interventional cardiologist here at the University of Michigan and typically, this isn't an area that interventional cardiologists are really greatly involved with. I became interested because I also, at times, I round in the cardiac intensive care unit, and that's a place where a lot of patients often times end up after they've had an in-hospital cardiac arrest at our institution and what I've noticed over the years, is the variability in care that would be occurring out there, and then also lots of gaps in the literature.

                                                Over a decade or so ago, I started partnering with a close friend and colleague, Paul Chan, from the Mid America Heart Institute and we started to do a series of studies on how in-hospital cardiac arrest care varies across institutions in the United States and we published a number of articles that have been in really high-profile journals over the last 10 years, but the problem has always been that even though we could describe really well what was happening, we had very little understanding of why it was happening or how certain hospitals were seeming to outperform others in this really challenging situation.

                                                We wanted to dive a bit deeper into the questions and reasons behind top performers doing so well and that's what brought us on to doing this study.

Dr Carolyn Lam:                Great. You want to tell us a little bit about it? It's really very different from the other CPR studies I've seen. Could you tell us about it and what you've found?

Dr Brahmajee Nallamothu:          Sure, so in the broader framework, it's a qualitative study and what I mean by qualitative is, we didn't really collect data either through surveys or through outcome assessments. What we did was, we actually went out and talked to people.

                                                The study though was really focused on what people call a mixed methods approach. We didn't just randomly talk to different hospitals, we actually focused on hospitals that were at the top-performing levels. We also focused on some hospitals that were non-top-performing as well, to get some contrast between the two and when I said we talked, we did this in a very systematic and pretty rigid way.

                                                We always had four interviewers go out to nine hospitals. We split them up, so we had two content experts and then two methodologic experts in qualitive studies, and we started to interview a bunch of people. In fact, we interviewed almost 160 people across these nine hospitals.

                                                We interviewed everyone from CEOs and hospital leadership, down to boots on the ground, including both clinical providers and even non-clinical providers, such as spiritual care, security. We tried to get this comprehensive view of what was actually happening during an in-hospital cardiac arrest across these nine hospitals, and really the results were quite fascinating to us.

                                                For someone, like myself, that's been in this space for ten years, I tell people I learn more talking to these nine hospitals than I have in the last ten years of looking at numbers on a spreadsheet. I really started to understand, for the first time, what was really going on, how these hospitals were dealing with these challenging situations because there's no bigger emergency in a hospital, and Steve, who we're going to hear from, we talk about this, but Steve has a great line about how when an in-hospital cardiac arrest occurs, that patient automatically becomes the sickest person in an institution and yet, we haven't set up systems that really build on how to handle that in the most consistent and positive way.

Dr Carolyn Lam:                Oh, my goodness, I just love that line! Now, you have to tell us, so what's the secret? What's the secret of the succeeding hospitals?

Dr Brahmajee Nallamothu:          What we found in general was, that resuscitation teams at top-performing hospitals really demonstrated the following features. They had dedicated or designated resuscitation teams. They really included the participation of diverse disciplines as team members during the in-hospital cardiac arrest. There were really clear roles and responsibilities of the team members that were set up right from the front.

                                                There was better communication and leadership, actually, during these events and finally, in the training aspect, one of the unique things we found was, the top-performing hospitals seem to have a high rate of in-depth mock codes, that they used as strategies for getting their clinicians ready for these events.

Dr Carolyn Lam:                As you were speaking I was just thinking through the experiences of in-hospital cardiac arrests that I've encountered, and you're right. These elements, though we don't talk about them much, make a huge difference. Steve, I am so curious about your outlook. I mean you must have attended a kajillion CPRs as chair of the CPR committee. Tell us, what do you think is the take home message for clinicians and hospitals?

Dr Steven Kronick:           My field is in emergency medicine and as chair of the CPR committee, I have responsibility of overseeing how we respond to cardiac arrests in our hospitals. I think that many institutions spend a lot of time and effort looking at in-hospital cardiac arrests are managed, and how to improve on it. We're able to use data to help compare ourselves to similar institutions, but beyond the bottom line of either ROSC or survival to discharge, we've most relied on process measures to figure out what we're doing.

                                                We're essentially flying blind, or at least not flying in any sort of formation when we do that. I think that this study validates some of the operational aspects of the arrest response, for those centers who use those and can help other decide where they want to direct their efforts. I think a good example that Brahmajee brought up, is this distinction we found between the use of dedicated teams, designated teams, or not having any organized team, and the impact that has on survival.

                                                The use of these teams can mean significant use of resources but showing that it's associated with better outcomes help provide support for that concept and for those centers who might already use one of those models, it helps them to steer their efforts to improving the delivery or the efficiency of that model.

Dr Carolyn Lam:                Yeah, and indeed. Congratulations to both of you, Steve and Brahmajee. I do think that these are novel contemporary data, at least the first that I know of. Sana, you handle the paper and recognize this. Could you tell us a little about what you think are the novel and important aspects?

Dr Sana Al-Khatib:            I really have been a fan of this paper from the get go and yes, it doesn't have the quantitative analysis that the statistical modeling, most of us are used to. It is a qualitative study, but I think that gives it strength. It makes it unique. This type of research, it can really only be effectively done through a qualitative study that really has all the important aspects of a good qualitative study, so I do want to congratulate them. Clearly, a lot of work went into this, and I appreciate all their efforts.

                                                In terms of the main findings, some of us might look at this data and say, well it's not surprising that those are the characteristics, or the features, of the top performing hospitals, but I felt like it was great, in terms of how the data were presented. Encouraging hospitals to adopt this. Giving them almost like a checklist of what they need to be doing to improve the outcomes of their in-hospital cardiac arrests, in terms of ensuring that they have designated resuscitation teams.

                                                The whole idea about diversity of participants in these arrests, and making sure everyone has a clear role and responsibility. The whole idea of making sure that somebody takes leadership and you have clear and very good communication among the different people who are doing this and great training. In fact, these people were doing in-depth mock codes. I think that spells it out very nicely and gives a lot of the hospitals, hopefully, action items that they can implement to improve the outcomes these patients. I love this paper.

Dr Carolyn Lam:                Sana, I love the way you put that. Checklist, and you know what I was thinking as Brahmajee and Steve were talking earlier? I was thinking blueprint, almost, of the things that we should have. So Steve, could I ask your thoughts. I mean, are you going to put some of these things into practice in your own committee and how?

Dr Steven Kronick:           There are a variety of things we can do. Some of these things are a pretty high-functioning place, but still looking at recommendations that have been laid out and how we help modify those things. Though the example is the roles that people play at an arrest. We can certainly improve on assigning those roles, how people work together as a team, and then also, getting to work more as a team, so that when they are called upon to perform those duties, they can do it in a more coordinated way.

Dr Carolyn Lam:                How beautifully put. I'm going to steal a couple of minutes at the end of this podcast. I really have to because it's so rare to have Brahmajee on the line today and he's the Editor-in-Chief of Circ: Cardiovascular Quality and Outcomes. Brahmajee, could I ask you to say a few words to our worldwide audience about your journal?

Dr Brahmajee Nallamothu:          We are a kind of daughter journal to Circulation. We are a bit more unique than the others, in the sense that we aren't disease or subspecialty focused. We deal with, broadly, the issues around outcomes research, health services research, quality of care research, and really health policy. We publish an issue once a month. We have a broad interest in things that are really relevant to the community around outcomes research and health services research.

                                                I will say that I really appreciate this because of the worldwide audience and reach, one of the big issues we've been very interested in is expanding our reach, from the United States to other parts of the world, and in fact, last fall, we had a global health issue, which was well received, and we received papers from across the world.

                                                In fact, every paper in that issue was a non-US-based paper, and it touched on a number of things from issues around healthcare utilization in Asia to demographics and disease registries in Africa, and it was a wonderful experience, so I think it's a journal that we're excited about.

                                                It was first launched by Harlan Krumholz, who has set a high bar and standard for us, and I think that my editorial team, which has been fantastic, has continued with that work. We would love to see papers from your readers and your listeners from across the world and excited about what that journal is going to be doing in the next five years.

Dr Carolyn Lam:                Oh wow! That's so cool! Well listeners, you heard it right here, first time on Circulation on the Run. Thank you so much for joining us today. Don't forget to tune in again next week.


Jul 2, 2018

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week features Circulation Global Rounds, a brand-new series of papers from all across the world that you are going to want to hear about, coming right up after these summaries.
The first original paper this week tells us that community trends and acute decompensated heart failure may differ by race and sex. Dr Patricia Chang from University of North Carolina in Chapel Hill and colleagues examine the 10-year rates and trends of hospitalized acute decompensated heart failure in the Atherosclerosis Risk in Communities or ARIC study, which sampled heart failure–related hospitalizations in four US communities from 2005 to 2014, using ICD-9 codes. They found that acute heart failure with reduced ejection fraction was more common in black men and white men, whereas acute heart failure with preserved ejection fraction was most common in white women.
Rates of hospitalized acute decompensated heart failure increased over time, with higher rates in blacks, and rising cases of preserved ejection fraction heart failure. Mortality rates were 30% at one year with a more pronounced decrease over time in blacks but generally did not differ by heart failure types. Whether racial differences may be related to age of onset comorbidities, or other community level and social economic factors, deserve further study.
The next paper is a population-based study identifying long-term outcomes and risk factors and children with hypertrophic cardiomyopathy. Dr Alexander from Boston Children's Hospital and colleagues examine the National Australian Childhood Cardiomyopathy Study, a long-term national cohort study with a median follow-up duration of 15 years. They found that the greatest risk of death or transplantation for children with hypertrophic cardiomyopathy was in the first year after diagnosis, with 14% of patients achieving this combined end point compared to 0.4% per year thereafter.
Risk factors for death or transplantation included symmetric left ventricular hypertrophy at diagnosis, Noonan syndrome, increasing left ventricular free wall thickness, and lower fractional shortening during follow up. The majority of surviving patients had no symptoms. Thus, children with hypertrophic cardiomyopathy who are alive one year after diagnosis have a low long-term rate of death or transplantation. Deaths from heart failure usually occur soon after diagnosis, whereas the risk of sudden cardiac death is ongoing.
The next paper is the first demonstration of a peripheral clock in the perivascular adipose tissue that could contribute to the homeostatic regulation of circadian blood pressure variation. Co-corresponding authors Dr Chang and Chen from University of Michigan and their colleagues used a novel brown adipose specific aryl hydrocarbon receptor, nuclear translocator-like protein 1 or Bmal1 and angiotensinogen knockout mouse model to demonstrate that local Bmal1 in perivascular adipose tissue regulated angiotensinogen expression
and the ensuing increase in angiotensin II, which acted on smooth muscle cells
in the vessel walls to regulate basal activity and blood pressure in a circadian
fashion during the resting phase. In fact, deletion of Bmal1 or angiotensinogen
in the perivascular adipose tissue resulted in a superdipper phenotype with
exacerbated hypotension during the resting phase. These findings imply that it
is possible that obesity could alter the perivascular adipose tissue peripheral
clock, thus promoting abnormal dipper phenotypes and increasing
cardiovascular risk. The results therefore inform the design of novel therapeutic
approaches for hypertension by targeting the perivascular adipose tissue
peripheral clock.
What is the net clinical benefit of oral anticoagulation for very elderly patients
with atrial fibrillation? Well, the next paper by first author Dr Chao, cocorresponding
authors, Dr Chen from Taipei Veterans General Hospital and Dr
Lip from University of Birmingham, addresses this question. These authors use a
nationwide cohorts study in Taiwan to compare the risks of ischemic stroke and
intercerebral hemorrhage between patients with and without atrial fibrillation,
all aged 90 years and above, from 1996 to 2011, and they also compared
patients treated with warfarin and non-vitamin K antagonists oral
anticoagulants, or NOX from 2012 to 2015 when NOX were available in Taiwan.
They found that even among these very elderly patients aged 90 years and
above, atrial fibrillation was associated with an increased risk of ischemic stroke
compared to patients without atrial fibrillation. Warfarin use was associated
with a lower risk of ischemic stroke, with no difference in intercerebral
hemorrhage risk compared to nonwarfarin treatment. The use of warfarin was
associated with a positive net clinical benefit compared to being untreated or to
antiplatelet therapy. Compared to warfarin, NOX were associated with a lower
risk of intracerebral hemorrhage, with no difference in the risk of ischemic
stroke. Thus, oral anticoagulation may still be considered for
thromboprophylaxis in very elderly patients with atrial fibrillation, with NOX
being a favorable choice
The final paper provides insights into the mechanisms linking obesity and
cardiovascular diseases. Co-corresponding authors, Dr Kong and Wang from
Peking University Health Science Center and colleagues use a combination of
animal models and human adipose biopsies to characterize a new adipokine
named family with sequence similarity 19, member A5 or FAM19A5. This novel
adipokine was capable of inhibiting post injury neointoma information via
sphingosine-1-phosphate receptor 2 and downstream G12/13-RhoA signaling.
Thus, down regulation of FAM19A5 during obesity and loss of its vascular
protective function may trigger cardiometabolic diseases.
Well, that wraps it up for our summaries. Now for our feature discussion.
I'm just so excited about today's feature discussion, because we're talking about
Circulation going global. And I am just absolutely delighted to have with us, our
Editor-in-Chief himself, Dr Joe Hill from UT Southwestern, as well as our Senior
Advisory Editor, Dr Paul Armstrong from University of Alberta. So Joe, could you
start by telling us a little bit more about your vision for the global outreach of
Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global
journal with a global footprint. We have editors distributed around the world in
16 countries and 10 time zones. And importantly, those editors all have an
equivalent role at the leadership table. Part of the reason for this is because
cardiovascular disease is now, as we are all aware, a global scourge. There are
no more final frontiers for cardiovascular disease. That said, the manifestations
of cardiovascular disease differ in different parts of the world. In the developed
world, and the developing world, for example, the way cardiovascular disease
manifests itself can be very different. And at the same time, the way in which
the disorders are tackled are different. The way we tackle heart disease in the
West can be different than it is in the East, for example. And there are
important initiatives that have emerged in different pockets of the world, best
practices that we need to understand better. What can we all learn from the
way in which cardiovascular disease manifests itself around the world and it's
being addressed around the world?
Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in -
Chief and I heard you say this, I was just floored, because coming from
Singapore and all our listeners out there in Japan and China, we just really
appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit
more about this new initiative then for the journal.
Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from
Canada, who is a household name in the cardiovascular world, he and I cooked
up a scheme that Paul will describe, where we will reach out on a regular basis
for insights from various different countries, ultimately, circling the globe
progressively over time. And I will defer to Paul to tell us more about the
Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but
still believing that you can teach an old dog new tricks, I would point out that
Circulation is almost 70 years old, and it has staying power. And one of the
reasons that it has staying power is because it is capable of reinventing itself,
and so I was attracted to help out again, from the editorial process, given Joe's
vision and leadership and the excitement around the reinvention that you've
described, to get involved with this initiative. And I was inspired, of course, by
the fact that those of us who do clinical trials appreciate that a lot of different
ideas, a lot of different cultures and perspectives are brought to a collaborative
table. And I'm thinking back now, Carolyn to three years ago, when you and I
first met enjoying courses as part of a trial in heart failure, which involves 43
countries, 800 sites, it will be 5000 patients centers, we've traveled separately
and together around the world, convincing people that there are unmet needs
in heart failure and other parts of cardiovascular disease, we learned that the
approach to standard of care, the rigor which is applied, the exquisite
sensitivities around differences that are meaningful, and the tricks that some
investigators and countries use that we can all I think, learn from has been very
So I think in this initiative, we want to have thought leaders. And we've already I
think, commenced and have two outstanding leaders from Japan and India to
come forward in the first two quarters of this initiative. Tell us about the
regional epidemiologic features, cardiovascular disease in their regions, what
the most important challenges are, what their best practices are, that you're
alluded to, who provides cardiovascular care and what the impediments are to
progressing because we think if we listen and learn as essentially knowledge
brokers, because welcome to Circulation, we can facilitate raising the level of all
of the boats in the water and potentially make new partnerships and do a better
job. So I'm excited about this. I'm delighted that Joe was receptive and really
look forward to working with him and some of these terrific people around the
world, you included who brings such a unique and important perspective from
which we can all learn.
Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International
knowledge brokers, that's what we hope to be. Isn't that fabulous, just an
opportunity to learn from each other, everybody having stuff to bring to the
table? Tell us a bit more though, what are you looking for in these papers?
Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic.
We're going to allow diversity of approaches. We're going to invite a thought
leader and hope that that thought leader might invite one or two others, we
want to limit it to three co-authors. We want obviously some insights into how
cardiovascular health professionals are being trained, what research
infrastructure exists, and how they access the literature, how do they read
Circulation, how do they read other journals, and are there collaborative ideas
that they've developed to their neighbors to the East and West that may be
could be broadened? Are there unmet needs that they've indicated similar or
different from those in Western Europe, South America? We've got about seven
or eight points of light that we hope to illuminate in the course of this exercise.
And the prospectus that's laid out in an editorial that Joe and I collaborated on
that I believe, Joe, is going to come out in early July.
Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just
the opposite of a formulaic, cookie cutter approach. We want to leverage the
beautiful diversity of our world. The different approaches that people take to
attack this scourge that is keeping a humble approach to tackle instead of the
visas that is humbling bar none. There is nothing that is more globally important
than the continued growth and expansion of cardiovascular disease. And
importantly, we can all learn from each other. There are exciting initiatives that
I've learned about in South America and in pockets of Europe and in Asia, and in
the Middle East that we can all benefit from, and we want to shine a bright light
on that. These pieces will be relatively short. They will be in our Frame of
Reference section, so 1200 words or so, so that they are accessible so that
people, you know, feel that they can carve out, you know, four minutes in their
busy day to read what cardiovascular disease looks like, as Paul said, our first
ones will be from Japan and India, and we plan to reach out to South America
and to the Middle East, and just continue on around until over the course of the
next number of years, we've touched virtually every country in the world.
Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that
you might be looking to focus on?
Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is
that in the West, in the developed world, cardiovascular disease increasingly has
become a chronic disorder where more and more people, over the course of the
last six years are surviving their acute coronary syndrome, their tachyarrhythmia
events, and they are developing chronic disorders like heart failure, whereas in
the East, it is the atherothrombotic manifestations that have both MI and stroke
that are expanding rapidly. So given that the face of cardiovascular disease is
different in different parts of the world, different strategies have to be
leveraged to address that, and we want to learn about that.
Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these
papers and just reflect on the things that we're learning. Paul, did you have
anything else that you wanted to add?
Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes
and obesity and the expanding epidemic that seems to effect some regions such
as India, in the Middle East, even more than other areas, but I think this is going
to be great. We're gonna have some fun and learn and exciting and hopefully it
will catalyze better care and better thinking around this enemy that we all face.
Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited
as I am about this. You have to read the editorial. It's a fantastic read.
Thanks for joining us today. And don't forget to tune in again next week.

Jun 26, 2018


Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. And I am joined today by our Editor of Digital Strategies, Dr. Amit Khera from UT Southwestern, as well as three wonderful fellows in training. Yes, you've guessed it, it's our FIT Podcast and I'm just so thrilled to be here again.

Dr Carolyn Lam:                Amit, any words of introduction before we start?

Dr Amit Khera:                  Thank you Carolyn. I think, for both of us, this is our favorite podcast, or two podcasts, that we do, a year. It reminds us of how bright the future is, with superb cardiology fellows in training around the country, and it really is a testament to how important we find fellows in training, to Circulation, to our mission, and how much we learn from them.

                                                So we're really excited about this group, today, and thank them for participating.

Dr Carolyn Lam:                Absolutely. So, why don't we start, now, with ladies first? Let's hear from Dr. Elizabeth Hill.

Dr Elizabeth Hill:                Thanks for having me today. My name is Beth Hill, and I'm a first year cardiology fellow at Scripps Clinic, in La Jolla, California. I've a particular interest in sports and exercise cardiology, which brings me to the article I picked today about sudden cardiac death and hypertrophic cardiomyopathy, hot topics in the field and in general.

                                                And so, today, I'm excited to be discussing the EVIDENCE HCM study, looking at the hypertrophic cardiomyopathy of risk, sudden cardiac death model.

Dr Carolyn Lam:                Nice. So tell us a little bit about what really struck you about the paper and, perhaps, how that may apply to where you practice?

Dr Elizabeth Hill:                What I really liked about the paper is that, when I see patients in clinic with hypertrophic cardiomyopathy, prior to having this risk stratification tool, we didn't really have a way to objectively risk stratify our patients with hypertrophic cardiomyopathy and really guide the discussion about who may benefit from an implantable cardiac defibrillator or ICD. And so, I've been using this a little bit with my patients. While it hasn't made it fully into the AHA or ACC guidelines yet, I'm using it as a tool.

Dr Carolyn Lam:                Great. You know, these are seven risk factors, isn't it? I'm always struck by that survival curve that really shows that those with a predicted 6% risk stand out. Is that what you use, as well, to guide your decisions?

Dr Elizabeth Hill:                Yeah. I think, as the authors noted, they picked this somewhat arbitrarily so that they could study their risk model. But I think what they found is that it seemed to fit well with the observed high risk of sudden cardiac death cohort, such that those that were seen and observed, about 9% risk of sudden cardiac death in five years, were in that greater than 6% cohort. So I think that population should receive ICDs, and that is one factor that I used to guide my decision making as well.

Dr Amit Khera:                  Beth, this sort of interest that you've had for a long time, in sports cardiology, I've noted you've done some prior work in EKG screening and other screenings. In terms of this article specifically, as you pointed out, this is a really helpful tool because I still remember back when I was a fellow in training, there was, sort of, this thought that everyone was high risk with hypertrophic cardiomyopathy, and I think we realized that's not true at all. The overall incidence of sudden death was only 2.4% in this cohort.

                                                The question I have for you, in terms of application, is, as Carolyn pointed out, these are reasonably simple variables, but as we sometimes are now using cardiac MRI and genetics and other more advanced tools, where do you think they fit in, in the current paradigm, since this is a bit of a more simplistic score?

Dr Elizabeth Hill:                The seven risk factors they put into this tool were noted to be independently associated with an increased risk of sudden cardiac death, and those are well known factors, entricular tachycardia, maximum wall thickness. But I really do think that other factors will come into play soon and are part of my discussion, and colleagues' discussions, including the late gadolinium enhancement on MRI, genetic factors, and I really think this may be a place for tools like machine learning. These authors, O'Mahoney and colleagues, they really did, kind of a tour-de-force, going back to the 1970s, but there is still a decent amount of data missing. So maybe we can partner with the machines and help them go back into these records, a little bit more effortlessly, and look at genetics, maybe some wearable device data, and really refine our risk stratification tool moving forward. But that's definitely something I use in risk stratification in some of my intermediate risk patients.

Dr Amit Khera:                  Those are great points. I think your point about machine learning and novel algorithms will definitely take foot in the future.

                                                Maybe a follow-up, again, given your background interest, I think it's a trade-off where we're trying to, of course, avoid sudden death, but you also don't want to overtreat. Especially, when you think about athletes getting ICDs and how that changes, or anyone, for that matter, about maybe telling someone they're at high risk, or giving them an ICD when perhaps they don't need it. I guess that comes to, what's the threshold? Here they use 6%, but that ends up being a bit arbitrary, in terms of what threshold we use. And how do we decide, when we talk to our patients, about what threshold's a right threshold to apply an ICD?

Dr Elizabeth Hill:                Yeah. That's a great question. Like you mentioned, these devices come with inherent risks, such as unnecessary shocks, increased risks for infection, and sometimes there's restrictions with athletic sport, although that's been changing recently.

                                                But, I think that's where the shared decision-making process comes into play, where you put current data on the table with the patients and, perhaps, their families as well, and have a risk-benefit discussion. Perhaps gather a little bit more data about the patient, maybe follow them over time, but I guess I wouldn't jump to put an ICD in, in every patient and, especially, the lower-risk cohort. And what number that is, I'm not quite sure. Here they say maybe less than 4%, but, again, somewhat arbitrary, I think.

Dr Carolyn Lam:                Thanks Beth. I mean, as Amit said, it's just so inspiring to see how the papers are being used in practice. Really loved those perspectives.

                                                Now, from sunny San Diego all the way to snowy New Zealand. We have Dr. Mesfer Alfadhel. And Mesfer, tell us a little bit about yourself, and the paper that you've chosen?

Dr Mesfer Alfadhel:        Thank you very much. I'm thrilled to be part of this podcast. I'm a second-year cardiology fellow-in-training at the Needham Hospital, in Needham City, New Zealand, where it's snowing at the moment. I'm also a clinical lecturer at the University of Otago School of Medicine. I do have great interest in general cardiology, as the rest of my colleagues, but also am passionate about interventional cardiology and structural heart disease.

                                                The paper I've chosen is really quite relevant to everyone in cardiology, and perhaps extends to other colleagues in other health professions impacted by automated external defibrillator use on survival and functional outcomes in shockable observed public cardiac arrest. The aim of the study was to determine the association of bystander automated external defibrillator use, the survival and function of outcomes in shockable observed out of hospital cardiac arrests. The study was from 2011 to 2015 and the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at nine regional centers, six in the United States and three in Canada.

                                                They also found that among nearly 50,000 out of hospital cardiac arrests, 8% were observed public out of hospital cardiac arrest, of which 61% were shockable. Overall, a remarkable one in five of shockable observed public out of hospital cardiac arrest were bystander shocked. Now the bystander automated external defibrillator observed, shockable observed public out of hospital arrests were associated with increased odds of survival and full or near full functional recovery almost 2.6 and 2.7 odds ratio than when compared to emergency medical service defibrillation. What's also interesting is that the longer the wait for the emergency services, the higher the benefits from a bystander observed shock.

Dr Carolyn Lam:                You know, Mesfer, I appreciate that you chose this one as well. What struck out to me immediately was that more than 60% of out of hospital cardiac arrests were shockable. And when we think about the number of lives that could potentially be saved, therefore, that's quite astounding, isn't it? But can I ask you something? So these are in the US and Canada, how applicable do you think this is to New Zealand?

Dr Mesfer Alfadhel:        We do have a small population, just over four million. The number of cardiac arrests here is around 2,000 out of hospital cardiac arrests. And I think probably half of them in the latest reports were shockable. The emergency response time in the urban areas is around six minutes, which I think is acceptable, but we have about 20% of population living in rural areas. And the emergency response time exceeds 10 minutes almost all the time. I think that probably a group that we need to direct intervention to in New Zealand.

Dr Amit Khera:                  It's really an important article. I should say that June for the American Heart Association is AED and CPR month so great choice to remind us of the value of these and especially, the one thing that was amazing, obviously this is an observational study, but the absolute change, not relative, was about 14% meaningful recovery and so that's quite impressive in terms of the number needed to treat if you will. Maybe an adjunct to Carolyn's question is, when we think about strategies to enhance bystander AED use for strategies, essentially get the AED there faster. As you know if the EMT time was not delayed it wasn't necessarily better for the bystander.

                                                We had a paper in Circ sometime last year looking at drones and then also geocoding and other people in some countries have looked at apps where you essentially can train a group of people and then they can be texted for a sudden cardiac arrest in their area. I'm curious about any creative things, there's always training and AEDs, I think in this place it was public areas in industry, but what do you think are some creative things or things that we need to be doing to help enhance the ability for bystander or early AED use.

Dr Mesfer Alfadhel:        I think this is one area in medicine in general that where technology is really going to advance how we deal with this problem. There's an app that's available, it was launched in the UK a few years ago and it’s become available in New Zealand in the last two weeks called, the Good SAM. SAM stands for smartphone activated medics. And it's become available in New Zealand two weeks ago and I downloaded it and still yet wait for it to be activated. And the way it works is you can activate a medical emergency using the app and it dials the emergency response but what it also does is it activates the nearest three people with CPR training nearest to you and it tells you how far they are from the emergency. Now if you don't have the app and you call 911 or the equivalent, the operator can activate it to the nearby personnel who have that experience. And I think it's going to reduce the time markedly.

                                                Now the other end of the question where some of what strategies could be used I think we had a good report from Denmark where they made changes in 2007 in Denmark and then followed by the rest of the country in 2010 where they made CPR or resuscitation education as compulsory at school but also when getting a driving license they made courses available for free that increased the number of defibrillators available in public places and they shared that information with public. They’ve redone, audited their work, and compared to prior to intervention prior to 2007 and after that and they found an increase number of using the AEDs increased from somewhere around 2% to 15%, which is really encouraging. I think we are following Denmark in that regard probably at slower rate.

Dr Amit Khera:                  Thank you those are excellent insights.

Dr Carolyn Lam:                Amit, don't you see that I just love learning from these fellows during these podcasts. We should do more of these. This is awesome.

Dr Amit Khera:                  I completely agree.

Dr Carolyn Lam:                Thank you Mesfer, enjoy the skiing. But now from snowy New Zealand we're going all the way to Nashville Tennessee. Welcome Dr. Vineet Agrawal. So tell us a bit about yourself and your paper.

Dr Mesfer Alfadhel:        So my name is Vineet Agrawal. I'm a second-year cardiology fellow at the Vanderbilt University Medical Center. My background is as a physician scientist and as a general cardiologist. My long-term goals are in understanding mechanisms underlying heart failure with preserved ejection fraction.

                                                With that in mind I was really taken by an article that was recently by Margaret Redfield's group from the Mayo Clinic in Circulation, titled “Global Pulmonary Vascular Remodeling and Pulmonary Hypertension Associated with Heart Failure and Preserved or Reduced Ejection Fraction.” I found this article to be a very interesting, hypothesis-generating article.

                                                In a nutshell what they did was they took an autopsy cohort of patients in the Mayo Registry and those who had heart failure with both preserved and reduced ejection fraction, normal controls, and those who had a primary pulmonary venous occlusive disease, and looked at the lung specimens of these patients. And interestingly what they found was there was a significant amount of pulmonary venous remodeling that had occurred in patients who had both preserved and reduced ejection fraction. This correlated not only with their right heart cath findings, so those who had elevated pulmonary pressures and elevated transpulmonary gradients, but also differed from the primary pulmonary venous occlusive disease in the sense that the histologic appearance of these vessels was quite different.

                                                And while as an autopsy study this is not necessarily an article that would immediately change practice, what I think it does do though is it forces us to think about these conditions in a different context and particularly with an eye towards future therapeutics. Heart failure with preserved EF as a disease, as I'm sure we all know, is sorely missing therapies that could alter the disease progression and potentially even alter mortality in these patients. And this article in my opinion really sheds light on at least anatomically a new location for us to think about as a therapeutic target when we try to better understand this disease and find therapies for these patients.

Dr Carolyn Lam:                Vineet, can I just say you're singing to the choir here. I'm such a fan of this work as well for obvious reasons. But hey, could I ask you, in your clinical practice, do you see a lot of these patients with HFpEF and pulmonary hypertension and wonder how to treat them? And along those lines, how has this paper helped you think about these patients more?

Dr Mesfer Alfadhel:        I would say when I first started residency as a medical student this was not necessarily a condition that was really something that I had learned much about or felt like I had been exposed to; however, as a resident I felt like most of the patients, or at least half of the patients, I was seeing with heart failure had a component of diastolic heart failure or they had a preserved EF but very symptomatic from the standpoint of heart failure. And I struggled to treat them, particularly in some part due to the fact that many of the risk factors that contribute to HFpEF, diabetes, uncontrolled hypertension, obesity, are chronic problems that are difficult to manage as a clinician regardless.

                                                And second because I feel that there just weren't any data to support any treatments that we were pursuing at the time and so we would try and apply what we had learned in other types of heart failure to these patients with limited results. If I could talk about what I think this article may change in terms of my practice today, one thing that we've always thought about in terms of pulmonary vascular remodeling in heart failure is that it's just a passive process that as fluid builds up you back up into the lungs and as the fluid builds up and backs up into the lungs you get remodeling.

                                                I think one thing that this article shows is that it may actually be a bidirectional process, which would suggest that perhaps we may need to reconsider looking at pulmonary-specific therapies in this population. But more importantly I think it does confirm that chronic elevating filling pressures do have an effect and a deleterious effect on the pulmonary vasculature. Particularly when you look at other trials such as the CardioMEMS trial, the CHAMPION trial in which the data pretty convincingly showed that as clinicians we don't do the best job of reducing left-sided filling pressures in our patients with heart failure as much as we think we do. This article really drives home the point to me that I really need to make sure that when I see these patients that I'm doing everything I can to reduce their left-sided filling pressures because the consequences of not doing so can affect the lungs, which can then in turn affect the heart as well.

Dr Carolyn Lam:                Vineet, that's really words of wisdom. Couldn't agree more. And these are the first sort of autopsy, histological evidence that we have, which is so important. I think if I could just add a couple of perspectives too, it makes me think about making sure that I rule out PVOD in these patients sometimes. We now keep thinking about HFpEF we forget that we need to also rule out PVOD and the other thing much as we now think about not just the filling pressures but the remodeling it's good to note that they found it more in the venous than the arterial system, which also comes therefore with a warning message that we can't just extrapolate I suppose all the PAH therapies that we know about. What do you think about that?

Dr Mesfer Alfadhel:        I absolutely agree with that. It's really interesting that all of our therapies from heart failure standpoint and from a PAH standpoint have focused on the myocardium, the neural hormonal cascade, and then the arterials. The pulmonary main artery and arterials. I don't think anyone really understands the biology of pulmonary veins and yet they're actually a pretty significant part of our everyday practice in cardiology. Pulmonary veins are thought to be the source of atrial fibrillation. We look at pulmonary vein inflow when we evaluate patients with echoes. And yet we understand so little about the biology and the mechanisms by which pulmonary veins are affected in both diseased and healthy patients.

                                                I think this article for that reason raises a number of very interesting questions and may potentially change the way we think about these patients.

Dr Carolyn Lam:                I keep learning, Amit, this is awesome. I could go on forever so you better stop me.

Dr Amit Khera:                  I should probably just be a fly on the wall. You must know Carolyn is a HFpEF, HFrEF aficionado and you guys should have a side call for another hour after this. But I do have one, maybe orthogonal question which is, it's interesting because if you look at how insights were made, they're made off areas I would argue at least that we don't, modern environment uses much which is the autopsy and probably to a large degree hemodynamics as much as probably in the old days although that's changing. I'm curious in a fellowship training program your exposure to autopsy and kind of current in-depth hemodynamic-type training, what's your experience?

Dr Mesfer Alfadhel:        Our experience with looking at pathological slides, getting under the microscope, seeing tissue first hand, is somewhat limited in our fellowship training program. I would say in certain subspecialties like our heart failure, advanced heart failure subspecialties we do get a chance to see more myocardial biopsy specimens, but I think increasingly the focus has been on noninvasive methods by which we can assess some of these same things that we used to do, use the microscope for. Invasive hemodynamics I think similarly we get a lot of experience in terms of spending time in the cath lab but I do kind of wonder if we don't have the same in-depth training that we used to have in understanding all the nuances of hemodynamics that used to exist in the past.

                                                Certainly, I think that while that's partially a reflection of the way and the direction in which medicine is heading, there is a little bit that's potentially lost there. That said, while we have the benefit of manuscripts like this that does do in-depth hemodynamics and looks at autopsy samples from a clinical standpoint, if we were to ever try and understand this in a larger population I think we would be required to try and find a way to noninvasively or maybe through potentially invasive hemodynamics better study this in live patients.

Dr Amit Khera:                  Appreciate that answer and I'm just for all of you, this has been outstanding. You all have served as incredible expert discussants. I know Carolyn already said it multiple times but we've learned a ton about each of these articles and great to see how they come alive and are used in practice and how they're applied in your own thinking and specifically as fellows in training with these have meant to you. We thank you all for joining us and it's really been a fantastic experience.

Dr Carolyn Lam:                Amit, I can only echo your thanks and thank you listeners for joining us today. Fellows out there you are so important to us. Please, please apply to join us on the next FIT podcast as you can see it's really fun.

                                                Don't forget to join us again next week.

Jun 19, 2018

Dr Carolyn Lam:                Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue is so special. It is an autopsy issue. I think it's actually the first of its kind in the history of Circulation. I am so pleased to have with me today Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center, who's the content editor for Pathology for Circulation and the guest editor for this entire autopsy issue. Welcome, Jeff.

Dr Jeffrey Saffitz:             Thank you.

Dr Carolyn Lam:                We also have Dr Lee Goldman from Columbia University Medical Center who wrote a beautiful perspective piece on autopsy. Thank you and welcome, Lee.

Dr Lee Goldman:              Morning.

Dr Carolyn Lam:                Jeff, could you start us off? I mean, an autopsy issue. How in the world did this come about?

Dr Jeffrey Saffitz:             I think it really began by coincidence. The journal received submissions from several authors, each involving studies of autopsies, and the editors approached me and asked if we might consider grouping them together in a special issue focused on the role of the autopsy and cardiovascular medicine. I thought that would be a very interesting idea and this evolved into actually something much greater. Two additional papers came in focusing on the autopsy and I think looking at these papers in the aggregate, they represent what we can now consider to be the contemporary utility of the autopsy in understanding the way cardiovascular disease works. So I was particularly pleased that the editors agreed to group these papers into a single issue focused on the autopsy. We were really delighted that Lee Goldman agreed to write a perspective. He has had a longstanding history of studying the role of the autopsy and I hope the readers will find this to be a really interesting and useful issue which will, I hope, chart the course for future discovery.

Dr Carolyn Lam:                Just listening to you, I love the way you say it's a contemporary look at autopsy. I mean, we covered things like molecular genetic, proteomic, autopsies, even like electronic autopsies using device. That's really cool. Lee, thank you again for sharing your time and incredible perspectives with us. The long history of autopsy. Do you think it's still necessary now?

Dr Lee Goldman:              Maybe give some perspective. I first got involved in this a number of decades ago, when as a junior faculty member, I was assigned to be on the medical audit committee of the hospital where I saw patients as a cardiologist. And two of the senior people in the committee got into a debate about whether autopsies were still important given the advent of CT scans and other modern diagnostic technology. And to listen to them debate for 15 or 20 minutes, I finally had the temerity to pipe in and say we can actually study this, and so we did. We looked at autopsies in three different decades: 1960, 1970, 1980, and much to everyone's surprise, I think found, A. that the rate of which autopsies found diagnoses that doctors had missed and for which treatment would almost certainly have prolonged life was about 10 percent, and it was 10 percent, 1960, 10 percent, 1970, 10 percent, 1980.

                                                But the difference was that doctors were missing different diagnoses. The things that got missed in 1960, and where autopsies showed there were being missed led to better diagnostic approaches and those things were rarely missed in 1980. But since people stayed alive longer, they got new things that we didn't really know much about in 1960. A big difference, fewer people missed heart attacks, pulmonary emboli, and things of that sort, but far more people had missed infections, especially fungal infections that were complication of multiple antibiotics or immunosuppressive therapies.

                                                And so, as I followed this in 1980, if you will, to now, 2018, we find this gets recapitulated over and over again. Medicine moves forward, things we used to miss, we no longer miss, but people still die, and they still die from things that we don't always diagnose. We've done statistical analyses to show that probably the rate of misdiagnosis is going down a little bit, but it's still substantial and we still estimate that thousands of people each year die in the U.S. from things that are not what the doctors thought they had, and if that diagnosis had been made, the patient would have lived longer.

Dr Carolyn Lam:                Lee, I just love that perspective. I have to say, it's really humbling. I mean, 1960s and so on would predate me as well, so I'm really humbled, and I love that reminder. Jeff, in fact, quite a number of our papers illustrate exactly what Lee said. We have four papers just dealing with sudden cardiac death, and that is still what diagnosis was struggled with. Could you tell us a little bit more about those?

Dr Jeffrey Saffitz:             Yes, of course. I think we all recognize that sudden death remains a huge public health issue. We also realize that most people who die suddenly and unexpectedly don't do so in the hospital when they're being followed and monitored; rather, they die out in the community, and in many cases, these are individuals in whom major risk for coronary disease or other potentially lethal cardiovascular conditions was really not known. So I think it remains a major public health issue, and we still have a great deal to learn. So perhaps it's not surprising that four of the five papers involved autopsy studies of sudden death victims of individuals who died out in the community. A couple of them focused on sudden death in young people.

                                                We know that these individuals often will have familial diseases, and the autopsy has been one mechanism for studying these individuals, so one of the papers from Michael Ackerman at Mayo Clinic, advanced the concept that they started many years ago, the so-called molecular autopsy in which they apply a whole exome sequencing in cases of sudden unexpected death in young people defined here as age under 40, and they identified some rare variants which were likely to be of potential pathogenic significance in sudden death. A related paper from Junttila et al in Finland looks at the finding of myocardial fibrosis in young victims of sudden death. They identified several cases in which that was the only structural change in the myocardium, and when they applied next gen sequencing, the identified variance that we typically associate with the familial non-ischemic cardiomyopathies, arrhythmogenic, dilated, and hypertrophic cardiomyopathy. But the key insight here is that we traditionally think of these diseases as having rather characteristic structural changes which we can recognize at autopsy. What they showed is that those structural changes might be limited to nothing more than some fibrosis. And so the key here is that this expands our potential opportunity to recognize these familial cardiomyopathies, and the overarching idea is we use the autopsy to serve the living. This is a way to gain information at autopsy that we can then use to help family members and other individuals by virtue of the insights gained at autopsy.

Dr Lee Goldman:              When we did the estimates in my editorial, and I estimated that roughly 28,000 people die each year in America with diagnoses that doctors missed and for which treatment would have been different if they hadn't missed it, that's really based on, I'll call traditional autopsy methods, which are anatomical, include microscopic evaluation, include culture, but it's not historically included genetic testing. I believe, as these articles show, that the advent of genetic testing, which you could argue could have been done while the patient was alive, but we're not quite there yet in terms of testing everyone's genome, now help you autopsies find even more things that might've been missed. And as you just heard, also can have important information for the family. So, one of the issues you often get into in autopsies is what's in it for the family, and one of the problems here is that the pathologists don't get paid. For the family members, it's mostly an aggravation. The doctors are worried they're going to get sued if something that gets found. And so, to make this work you need to bring in some incentives. Doctors not getting sued if they find things because they should get credit for trying to learn more, some way to reimburse reasonably pathologists and hospitals who do the autopsies, and the understanding of family members that they not only will perhaps be more reassured about what happens to the loved one, but also may learn things that will affect their future, because certainly, these cardiomyopathies, instead of them being diagnosed, are familial and oftentimes will lead to testing and hopefully interventions in family members that'll be to their benefit.

Dr Carolyn Lam:                Lee, what great comments about bringing this into the clinical perspective and I just love what you said, Jeff, about autopsy for the living. That is just a quotable quote. That's so cool. I noticed that you did ask Dr Judge to write an editorial specifically about bringing autopsies into the molecular genetic era. So I just want to encourage all our listeners to make sure you read that as well. But Jeff, back to you about the other two papers.

Dr Jeffrey Saffitz:             Well, I think one that I found particularly significant is this idea that nowadays, patients come to autopsy with implantable cardiac electronic devices, and the point of this paper is that interrogation of these devices postmortem can provide really important information about the cause and timing of those deaths. I think the reality is that most pathologists who do these autopsies are entirely unprepared or ill equipped to do such interrogations, and so I think the point of this paper is simply to encourage pathologists who do these autopsies to develop partnerships and relationships with cardiologists who are able to get this type of information from these devices. And again, it not only provides information about what happened to that one individual and what the death was all about, but it provides important information to the family and potentially information that allows the family to recognize particular risks that might impact the living members. So I thought this was just another really interesting example of how information that is potentially available at autopsy may not be fully utilized, and I hope that this paper will have an impact in that regard.

Dr Carolyn Lam:                That's great. Lee, did you have any perspectives on devices and its role in autopsy now?

Dr Lee Goldman:              I guess that the point that I would just reinforce would be that diagnostic technologies, including the ability to monitor someone's heart rate, have helped us diagnose things that were missed in previous eras, but medicine is always pushing the frontier forward, and as long as we develop new therapies, develop new devices, there'll be new things to learn. I want to make one other point about what I'll call overconfidence in diagnoses. The published statistics for the accuracy of most diagnostic tests are based on what doctors think the diagnosis ends up being, not the autopsy, which is the ultimate gold standard. So, if you actually go through some not-so-complicated arithmetic, you'll find that many of the tests that we think are almost perfect at finding things really aren't because the people who die with those things found that autopsies that the test missed. There's something called a virtuous circle, there's also a vicious cycle. There's a bit of a vicious cycle here that if you don't do autopsies to be sure you aren't missing things, you become overconfident in the tests that you think are finding them, and therefore think you already know everything and don't need to do an autopsy. To me, in some ways, that's the most perverse result of the plummeting autopsy rate, which, by the way, can be linked directly to changes in how hospitals get accredited, that in prior years there was a minimal autopsy rate required for accreditation. When that was removed, not surprisingly, autopsy rates plummeted, and now, most autopsies done in the US are not done in hospitals because doctors aren't sure what's going on. They've done by medical examiners as part of the laws for autopsies least being considered and people who die without having had a medical attention to some degree.

Dr Jeffrey Saffitz:             You are exactly right on all of these points. I'll just say this is the point of one of the other papers from Tseng et al. This was a prospective autopsy study of sudden death in the city and county of San Francisco, and what they showed here is that only about half of the deaths that were considered to be sudden cardiac deaths as defined by the conventional criteria actually turned out to be deaths due to a rhythmic disorder. So Lee's point is exactly right. Doctors think they know a lot of things, but they're not always right about that, and the autopsy is probably one of the best ways to bring some quality control to this, and to really provide, I think, objective data that often is the case flies in the face of what the previous thinking was, and I think this paper in this issue of Circulation really brings that point home very clearly.

Dr Carolyn Lam:                Yikes. OK, so here I am, I practice in Asia, and I think the autopsy rates are even lower, so this is a great wake up call for me just listening. Let's switch gears a little bit. How about the paper by Dr Herrington? Now this goes to a proteomic bisection almost of maybe preclinical disease and atherosclerosis. Would you like to comment on that on, Jeff?

Dr Jeffrey Saffitz:             In the perspective that I wrote with Gaetano Thiene, in addition to looking at the history of the autopsy, we looked to the future and just considered briefly what role will the autopsy play going forward, and I think the paper by Herrington is a great example of how we can use the autopsy to learn so much more about the way human disease works. The basic idea here is that something like coronary artery disease or atherosclerosis, we think of as being a disease that only involves the blood vessels, and we tend not to recognize it until it is rather advanced and clinically manifest, but we recognize that these diseases begin decades before they become clinically manifest. We really don't know how to identify the earliest antecedents, and without knowing that we really, I think, very much limit our ability to identify the disease way early before it becomes clinically manifest, and then be able to practice preventive measures and intervene to prevent the disease from occurring.

                                                So, what this paper showed is that it's an application of high-throughput proteomics looking at coronary artery and aortic samples obtained at autopsy, and these authors identified particular changes in proteins that they then were able to show in a prospective independent clinical cohort were able to predict the development of coronary artery disease. So I think going forward, we are going to redefine our understanding of human disease by learning about its earliest expressions and its full systemic distribution, and in doing so, we'll be much better prepared to diagnose earlier and intervene and prevent disease. So I think this was a great example of how the autopsy can help in that effort.

Dr Carolyn Lam:                I feel like we are going full circle in history and going back to learn about how to go forward. I don't know if I expressed that well, but I am just in awe of what I've learned from both of you. Thank you so much, Jeff, for putting together this amazing issue, and thank you so much, Lee, for sharing your perspectives. Thank you, audience, for joining us this week. You've been listening to Circulation On The Run. Don't forget to tune in again next week.


Jun 11, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today's feature discussion revolves around important hemodynamic and echo data from the reprise three trial, comparing the lotus and core valve transcatheter aortic valves in patients with high surgical risk. Can't wait? Well it's coming right up after these summaries.

                                                The first original paper this week provide experimental data showing that the endothelium controls cardiomyocyte metabolism and function via notch signaling. Corresponding author, Dr. Fischer, from German Cancer Research Center in Heidelberg, Germany, and colleagues, studied fatty acid transport in cultured endothelial cells and transgenic mice with endothelial specific notch inhibition, or wild type mice treated with neutralizing antibodies against the Notch ligand. They showed that notch signaling in the endothelium controlled blood vessel formation and fatty acid transport in the adult mouse heart. Inhibition of Notch signaling in the vasculature led to expansion of the cardiac vasculature and impairment of fatty acid transport to cardiomyocytes. This resulted in metabolic reprogramming and heart failure.

                                                Together, these data provide compelling evidence for a central role of Notch signaling at the coordination of nutrient transport processes in the heart. These findings help to explain how pharmacological inhibition of Notch signaling, for example, in oncology could lead to heart failure. The findings also help to identify the signals and molecules involved in endothelial transport capacity and show how these could offer new targets for the treatment of heart failure.

                                                The next paper raises the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure. Ischemic injury to the myocardium is known to trigger a robust, inflammatory response, which is an integral part of the healing process, although much effort has been directed at tempering the inflammatory response in hopes of achieving clinical gain. Major efforts have focused on individual cytokines, the complement cascade, and antibodies to adhesion molecules preventing leukocyte invasion.

                                                In contrast, relatively little effort has focused on macrophages. Although macrophage transformation is known to be crucial to myocardial repair, the events governing this transformation are poorly understood. In today's paper, co-corresponding authors of the trial in Hill, from UT Southwestern Medical Center, performed an elegant series of experiments and showed that release of DNA from necrotic tissue during myocardial infarction, triggered in macrophages a recently described innate immune response known as the GMP-AMP synthase-stimulator of interferon genes pathway or cGAS-STING pathway.

                                                This response in turn promoted an inflammatory macrophage phenotype. Suppression of the pathway promoted emergence of reparative macrophages, thereby mitigating pathological ventricular remodeling. These results therefore reveal for the first time, that the cytosolic DNA receptor, GMP-AMP synthase, functions during cardio ischemia as a pattern recognition receptor in the sterile immune response.

                                                Furthermore, this pathway governs macrophage transformation, thereby regulating post injury cardiac repair. As modulators of this pathway are currently in clinical use, these findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.

                                                Cigarette smoking is a well-known risk factor for atherosclerotic cardiovascular disease. However, less is known about the risk for heart failure. First author, Dr. Kamimura, corresponding author, Dr. Hall, from University of Mississippi Medical Center, and their colleagues investigated 4129 black participants without a history of heart failure or coronary heart disease at baseline in the Jackson Heart Study.

                                                They examined the relationship between cigarette smoking and left ventricular strength and function by using cardiac magnetic resonance imaging. They found that current cigarette smoking status, smoking intensity in terms of cigarettes per day, and smoking burden in pack-years, were independently associated with higher left ventricular mass, lower left ventricular strain, higher brain natriuretic peptides, higher BNP levels and higher risk of incident heart failure hospitalization in blacks.

                                                These relationships were significant after adjustment for coronary heart disease, suggesting mechanisms beyond atherosclerosis may contribute myocardial dysfunction and increased risk of heart failure in smokers. In summary, these findings suggest that smoking is associated with structural and functional left ventricular abnormalities that lead to heart failure in blacks and that smoking cessation should be encouraged in those with risk factors for heart failure.

                                                What happens to the risk modifying effects of exercise in individuals with increased genetic risk of cardiovascular disease. Drs. Tikkanen, Gustafsson, and Ingelsson from Stanford University School of Medicine performed the study in about 500,000 individuals from the UK Biobank and reported and compared the association's objective and subjective measures of fitness and physical activity with prospective cardiovascular disease events and all-cause death.

                                                They found consistent and robust inverse association, particularly between objective measures of fitness and physical activity and six cardiovascular outcomes and total mortality. Using genetic risk scores for coronary heart disease and atrial fibrillation, they showed that these inverse associations were present in each genetic risk category, suggesting that elevated genetic risk for these diseases can be compensated for by exercise.

                                                The knowledge that lifestyle choices have substantial effects on disease risk could encourage individuals to initiate a healthier lifestyle to reduce their overall risk. In the longer term, identifying subgroup space on genetic risk that benefit most from lifestyle interventions, could help personalize preventive strategies for chronic diseases.

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

                                                Today's featured paper deals with transcatheter aortic valve replacement, which we are all going to recognize has rapidly emerged as a treatment of choice in inoperable patients and, it's a reasonable alternative to surgical aortic valve replacement in high- and intermediate-surgical-risk patients. However, the success of this technology is in large part due to the rigor with which quantitative echocardiography by core laboratories has been used to assess the native and prosthetic aortic valve function.

                                                Today's feature paper gives us such important data from the REPRISE III trial, which compares the Lotus and the CoreValve transcatheter aortic valve in patients with high and extreme surgical risk. I'm so pleased to have the corresponding author, Dr. Federico Asch, from MedStar Washington Hospital Center, as well as our associate editor, Dr. Dharam Kumbhani from UT Southwestern. All right Federico, please help me here, so as a noninterventionist and a person who doesn't deal with all these different types of valves every day, please tell us what was the motivation of looking so closely at the echocardiographic data from REPRISE, because the REPRISE III trial results were already published?

Dr Federico Asch:             The most interesting aspect of this analysis is really that there is a very methodic, blinded comparison of two different valves. The valve that is being tested and that the reason why Boston Scientific has sponsored the study, is the Lotus valve, the Lotus System is, if you want, a new valve that is not clinically approved in the United States yet, that basically, it's a completely repositionable bovine pericardial valve that comes in different sizes.

                                                The three sizes that were tested in here are what we would call the small, or 23 millimeters, the medium, 25 millimeters, and the large, 27 millimeters. Each patient, at the moment of randomization, or at the moment of inclusion, were randomized to the small, medium, or large Lotus valve vs the clinically approved CoreValve, which is a Medtronic product. Obviously, this is taken as the control group because this is one of the valves that is widely clinically available nowadays in the United States and worldwide.

                                                This is exactly the motivation here. On one side, to prove whether this valve was as good as CoreValve or not and whether it was as safe as the CoreValve as well, and that, the study was about. Every three patients that were randomized, two were randomized to the new valve, the Lotus, and one was randomized to the CoreValve.

                                                An important note to make here is because the control arm included clinically available valves at the beginning of the study, the previous generation of CoreValve was used and then about halfway through the trial, the Evolut valve was the one being used, so there's two different valves on the CoreValve system that were tested in this trial while Lotus was a single earlier generation valve.

We focus here on the hemodynamic implications, that meaning, the gradients and the degree, if you want, of obstruction that these valves could have over time, and the amount of regurgitation that these two valves and how they compare to each other.

Dr Carolyn Lam:                That's great. Could I ask if you had any hypothesis going in, because as I recall, the Lotus valve actually met the non-inferiority comparison, but it did have significantly higher rates of new pacemaker implantation and valve thrombosis, right? So, was that perhaps a hypothesis going in and what did you find?

Dr Federico Asch:             So, the initial hypothesis of the trial overall was that this new valve was one that was designed to have less paravalvular regurgitation, which is something as you probably know, has been of significant concern in the cardiology world ever since the initial clinical trials for Tyler with Partner and CoreValves.

                                                Patients with more significant paravalvular leak did have worse outcome over time, so, one of the main goals of this valve itself, was to prevent that paravalvular regurgitation. So, that was the initial idea behind this product I would say, not just the clinical trial and obviously, this clinical trial tried to prove that, indeed, as I mentioned before, the primary effectiveness end point was mortality, disabling stroke, and paravalvular leak, the main driver on the difference between the two valves there was indeed a much lower paravalvular regurgitation on the Lotus valve compared to CoreValve.

                                                There was also lower stroke rate, but the most important difference was on the paravalvular aortic regurgitation. Of course, when you think of any of these devices, for them to be able to prevent paravalvular leak, they have to have some kind of skirt or cushioning around the valve, an adaptive seal, which in the case of the Lotus valve, that would prevent any flow around the stent, but one of the risks of that of course is that by trying to seal the valve, you're actually, you may be decreasing a little bit the effective orifice area, so it was actually very important to understand whether gradients with this valve were higher and whether the potential differences in the gradients did turn into any difference in clinical outcomes.

Dr Carolyn Lam:                That is super clear now. What did you find?

Dr Federico Asch:             I would say, the findings from a hemodynamic standpoint, we can briefly summarize them in two aspects of it. No surprise, the paravalvular leak was significantly lower for Lotus compared to CoreValve, and that was true for any of the three sizes, for the small, medium, and large size in all of them, the rate was significantly lower for Lotus. It was actually under 1% of the patients with moderate or higher paravalvular leak, as opposed to an average of 6.7% on the CoreValve, but on the other side of the spectrum, the gradients and the effective orifice area, and the dimensional index were all significantly better on the CoreValve compared to the Lotus.

                                                The bottom line is, we have two valves that each of them has a specific strength. On one side, Lotus has less paravalvular leak. On the other hand, CoreValve has a better gradient profile than Lotus. I would say in two lines, that's the findings of this study. We did take these findings further and compared among different valve sizes and we saw that these differences were consistent at each of the valve size, so if we would compare the small Lotus with the small CoreValve or the large Lotus with CoreValve, the findings were very similar.

                                                They were always significant, and what is important is that while there was a difference, both for paravalvular leak and for gradients and other hemodynamic parameters, the reality is that when it came to clinical outcomes, there was no significant difference among the two.

Dr Carolyn Lam:                Dharam, you have to weigh in now as an interventional cardiologist, what does this mean to you.

Dr Dharam Kumbhani:   First of all, Federico, congrats to you and Ted and the rest of the group. I think this is obviously a very important trial and I think this hemodynamics paper, I think definitely moves, helps understand the differences a little bit better, so I think this is a very valuable contribution. I think you said it exactly right. I think what is really interesting is that you have a significant introduction into the paravalvular leak, but yet you have, because of difference in valve design, one being annular vs the other being super annular, you have higher gradients with the Lotus valve compared with the CoreValve, so you wonder if the two differences can cancel themselves out in some way, because you don't see any difference in clinical end points at one year, and also, I guess, what we've learned from the Partner data and other CoreValve data is it would be really helpful to see how this evolves over time, whether there will be any late separation of the curves or just a long-term follow-up, whether that will still be important.

                                                I think that is the really interesting insight that we glean from this analysis. I want to make two other points. I think the other interesting thing about the design of the Lotus valve, and probably having such a great seal for the paravalvular leak reduction and having higher radial strength, I would think, at the annulus, I suspect that that's probably also the reason why the pacemaker rate is higher with this, compared with CoreValve, so it's almost 30% in this trial. About 20%, 18% already had an existing pacemaker, so particularly I guess, as we move to lower-risk population, I think that will certainly, balancing the two and deciding probably one valve doesn't fit everybody and we may have to have strategies to figure out which may be the best valve for a given patient based on this.

                                                The other point I'd like to make is the question about stents or valve thrombosis and I know that your group has been heavily invested in that research, because I know in the JAMA paper, there was a report of few valve thrombosis events and you also bring that home here in this hemodynamics paper. Is there anything you want to elaborate on that or any insights that you feel would be helpful for the next set of trials and next generation of the Lotus valve?

Dr Federico Asch:             Yeah, you're bringing two very, very important points. Let me address the thrombosis one first. As you very well described, we have been working a lot on multiple different valves and understanding why this is happening. It's clearly something of concern. In this study in particular, we did not have data collected to detect subclinical thrombosis, which is what most of us have been talking mostly about over the last few years. The diagnosis of thrombosis here was not so clinical. These were patients that mostly, because gradients were going up, were detected. They were image ... there was one or two cases with TE and the other ones with CTs and then they were given anticoagulation and those results, and based on that is that the diagnosis of thrombosis was made. All those cases, nine cases, indeed, happen on the Lotus group. The CoreValve is one in that overall has shown to have lower rates of thrombosis in general and I'm not just talking about our own report. Our report was consistent with that.

                                                That may be something related to the fact that it's a super annular valve and the flow through the valve may be better, if you want, but we don't know that. The rate of thrombosis, again, clinical thrombosis, in this case, for the Lotus valve was 1.5%, which is still low, but it's impossible to compare to all those new reports that are coming out because those are mostly subclinical, which is not the case here.

                                                One could argue that if would have done CTs on every patient here at 30, 45 days, we would have found much higher rates in both valves, but we don't know that. We don't have the data to address that.

Dr Dharam Kumbhani:   As I remember, almost all of them, I think seven out of eight of those reported, were in the 23 valve, right? They were not ... I think the larger valves ...

Dr Federico Asch:             Exactly. There were nine cases overall, eight of them were on the small valve, on the 23 millimeters, and one was in the middle size, on the 25 millimeters. You are completely right.

Dr Dharam Kumbhani:   I don't know what to make of that, but that was an interesting observation as well.

Dr Federico Asch:             Yeah. It's interesting because when you look at reports of subclinical thrombosis, actually some of the reports suggest that this is more common in bigger valves than in smaller valves. Registries, I'm talking about, but that didn't seem to be the case here, but again, we need to understand the limitations. This was not a study geared towards detecting sub clinical thrombosis or thrombosis overall. These are just clinically reported cases that were analyzed thoroughly but they were triggered by some kind of clinical event, what's mostly an increase in the gradient.

                                                That's all that I would make out of the thrombosis. I think there is definitely more that we need to learn about it. We know that both CoreValve and Lotus have been reported to have cases of thrombosis, but in general, CoreValve seems to be of all the type of devices, the one with the lowest incidents.

Dr Dharam Kumbhani:   Maybe your studies will help in understanding the influence of hemodynamic profile, patient-prosthesis mismatch, to the risk of thrombosis. I think the interactions are not well understood. I think that will be very interesting going forward.

Dr Federico Asch:             Exactly. And the other comment that I wanted to make, Dharam, regarding your first impression about the pacemakers and the gradients, a couple of observations that I want to make out of that, one is that the difference in gradients between Lotus and CoreValve seem to be the highest early and then over months, that difference seemed to get smaller and smaller, still significant though, even at one year, but one could argue that if, as we continue following up these patients, maybe the difference starts getting smaller and smaller to the point that to become irrelevant, but we don't know that. That is just the impression that we get at looking at the curves over time.

                                                The pacemaker, obviously, as you can imagine, this is something that is of concern for everybody. It's a high rate, the newer Lotus generations are geared towards having lower paravalvular leak, like the head Lotus Edge and so we would expect that in the future that would be the case, but we don't know. The same way that it is important to mention that CoreValve has been addressing their initial concern, which was paravalvular leak.

                                                I mentioned before that the control arm in this clinical trial included CoreValve classic, earlier generations from roughly half of the patients, and the paravalvular leak in that group was a little bit over 10%, while the second group, which was the Evolut R had already a much lower rate of paravalvular leak, but was still significantly higher than Lotus, but was definitely better.

                                                I think what this points out to, is that all these devices are so early in their life, in their history, that all the efforts that each of these companies are making into fixing the specific problems that each of them have, really turn into a next generation that addresses more aggressively all these things. In the case of CoreValve, definitely the paravalvular leak is one and they are making very good progress in the care of Lotus, the permanent pacemaker is one and we expect in subsequent generations to improve as well.

Dr Carolyn Lam:                It's been very enlightening for me and I'm sure for all our listeners. Thank you for joining us today listeners. Don't forget to tune in again next week.

Jun 4, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associated editor from the National Heart Center and Duke National University of Singapore. This week's feature paper reports results of the SWAP-4 study, which is the first study to evaluate the pharmacodynamic impact of the timing and dosing of clopidogrel administration when de-escalating from ticagrelor therapy. Extremely important take-home messages for clinicians looking after patients with coronary artery disease and a must listen to. Coming up right after these summaries.

                                                In the first original paper this week, chondroitin sulfate, well known in the context of the monogenic disease mucopolysaccharidosis type 6 may actually represent a novel therapeutic approach for the treatment of general heart failure. First author Dr Zhao, corresponding author Dr Foo, from Genome Institute of Singapore studied changes in myocardial chondroitin sulfate in non-mucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. They found that failing human hearts display an abundant accumulation of chondroitin sulfate proteoglycans in the extracellular matrix largely localized to fibrotic regions.

                                                The main component of chondroitin sulfate glycosaminoglycan chains in human hearts was chondroitin 4 sulfate. TNF alpha was a direct binding partner of glycosaminoglycan chains rich in chondroitin 4 sulfate. Modification of the chondroitin sulfate chain with the recombinant human arylsulfatase B, which is an FDA-approved treatment for mucopolysaccharidosis type 6 that targets chondroitin 4 sulfate, actually ended up reducing myocardial inflammation and overall fibrosis in vivo. In two independent rodent models of pathological cardiac remodeling, this recombinant human arylsulfatase B treatment prevented cardiac deterioration and improved functional recovery. Thus, targeting extracellular matrix chondroitin sulfate represents a novel therapeutic approach for the treatment of heart failure.

                                                The next paper focuses on the subcutaneous ICD, which is an entirely subcutaneous system that does not require intra-procedural vascular access or endovascular defibrillator leads or coils. Now the subcutaneous ICD has a novel mechanism of defibrillation and is associated with an increased energy requirement for defibrillation when compared to traditional transvenous ICDs. Thus, ventricular fibrillation or VF conversion testing at the time of subcutaneous ICD implantation is a class 1 recommendation.

                                                Yet, what is the current adherence to this recommendation? Well, today's paper addresses this question from first and corresponding author Dr. Friedman from Duke Clinical Research Institute. He and his co-authors studied first time subcutaneous ICD recipients between 2012 and 2016 in the National Cardiovascular Database Registry ICD Registry to determine the predictors of use of conversion testing, predictors of an insufficient safety margin during testing and in-hospital outcomes associated with the use of conversion testing.

                                                Results show that use versus non-use of VF conversion testing after subcutaneous ICD implantation in the US was more related to physician preference than patient characteristics. The study also identified several patient characteristics associated with an insufficient defibrillation safety margin. That included increased body mass index, severely decreased ejection fraction, white race, and ventricular pacing on the pre-implantation ECG. Use of VF conversion testing after subcutaneous ICD implantation was not associated with a composite of in hospital complications or death. These data may inform ICD system selection and a targeted approach to conversion testing.

                                                We know that elderly patients are at elevated risk of both ischemic and bleeding complications after an acute coronary syndrome and display higher on clopidogrel platelet reactivity as compared to younger patients. Does prasugrel at five milligrams compared to clopidogrel reduce ischemic events without increasing bleeding in the elderly? Today's paper addresses this question from corresponding from corresponding author Dr Savonitto from Manzoni Hospital Italy and his colleagues.

                                                These authors performed a multicenter randomized open label blinded end point trial comparing a once daily maintenance dose of prasugrel five milligrams with the standard clopidogrel 75 milligrams in patients more than 74 years old with acute coronary syndrome undergoing percutaneous coronary intervention. The primary end point was a composite of mortality, myocardial infarction, disabling stroke and re-hospitalization for cardiovascular causes or bleeding within one year. Enrollment was interrupted due to futility for efficacy according to pre-specified criteria after a planned interim analysis when 1,443 patients had been enrolled with a median follow-up of 12 months.

                                                At this point of interruption, there was no difference in the primary end point between reduced dose prasugrel and standard dose clopidogrel. The results of this Elderly ACS 2 study therefore could not show overall clinical benefit of prasugrel five milligrams versus clopidogrel in elderly ACS patients undergoing early PCI.

                                                The final study is the first to define the cellular and molecular mechanisms of cardiac valve inflammation and fibrosis occurring in the setting of systemic inflammatory disease. First author Dr. Meier, corresponding author Dr Binstadt from University of Minnesota used T-cell receptor transgenic mice which spontaneously developed systemic auto antibody associated autoimmunity leading to fibro inflammatory mitral valve disease and arthritis.

                                                They identified a critical population of CD301b/MGL2 expressing mononuclear phagocytes that orchestrated mitral valve inflammation and fibrosis in this mouse model. They further demonstrated an analogous cell population was present in human inflammatory cardiac valve disease. Finally, they defined key inflammation molecules that drove mitral valve disease in this model, thus providing multiple potential therapeutic targets that are required for mitral valve inflammation and fibrosis.

Dr Carolyn Lam:                That wraps it up for your summaries. Now for our feature discussion.

                                                Searching between different classes of P2Y12 inhibitors including de-escalation from ticagrelor to clopidogrel commonly occurs in clinical practice. However, what are the pharmacodynamic profiles of this strategy? Well, today's feature paper is going to provide a lot of insights. I am so pleased to have the corresponding author of the SWAP-4 study, Dr. Dominick Angiolillo from University of Florida College of Medicine Jacksonville, as well as our associate editor Dr. Gabriel Steg from Hôpital Bichat in Paris, France. Dominick, now this is SWAP-4. That means there was a SWAP 1, 2, 3. Could you just paint the background and rationale for SWAP-4 and tell us what you found?

Dr Dominick Angiolillo:   We performed this study on the background of a line of research that we've been conducting over the past number of years of switching antiplatelet therapies. There's so many different types of switches that can occur and one of them is that which is defined as a de-escalation which is that from a more potent P2Y12 inhibitor to a less potent and one of those that occur frequently in clinical practice is the switching from a ticagrelor to clopidogrel and this was essentially the rationale for conducting the SWAP-4 study.

                                                Now I want to start off with saying that the reason for doing this study is not to advocate switching because we always recommend that individuals follow guideline recommendations but we performed this study because we wanted to provide clinicians with some additional insights that if you're going to switch particularly from ticagrelor to clopidogrel, which would be the modality which is associated with, put it this way, with the smoothest transition one drug to another.

                                                This is the rationale. What we did was do a pharmacodynamic, conduct a pharmacodynamic study taking patients who were on standard treatment with dual antiplatelet therapy aspirin and clopidogrel and they had a run-in phase with ticagrelor. And the reason why we took patients on the back part of aspirin and clopidogrel is because we then wanted to look at the effects after switching to compare it with a baseline. There have been some discussions about drug-drug interactions. And patients were randomized to either continue with treatment with ticagrelor to switch with a loading dose of clopidogrel, 600 milligrams 12 hours after last dose of ticagrelor. 24 hours after last dose of ticagrelor or directly switch with a maintenance dose. So, the randomization was into four groups.

                                                Essentially to keep a long story short, what we observed was that when de-escalating from ticagrelor to clopidogrel we did see an increase in platelet activity obviously as expected. But the use of a loading was not able to mitigate this increase but there were no differences according to timing of administration of the loading dose clopidogrel 12 or 24 hours. We had anticipated in our study design that with the administration of the loading dose 24 hours after last maintenance dose we could have achieved a smoother transition, but this was not the case.

                                                Nevertheless, the overall conclusions of our study are supported by the pharmacodynamic data in terms of you still achieve a better transition when you give a loading dose than without a loading dose. I was also want a little bit cautious and I think during the review process of the journal and feedback from the editors we kind of phrased in a very cautious way the suggestion for a drug-drug interaction, in fact we suggested because there are other ways to look into this phenomenon in more detailed manner. For example, doing some specific pharmacodynamic analysis which was not done in this study. Nevertheless, the take-home message from a clinical perspective remains unchanged.

Dr Carolyn Lam:                Thanks so much, Dominick. That was a very important framing of the paper that you gave us at the start that this trial was not designed to try to say who should be de-escalated or not and that should be in line with the guideline recommendations and yet such an important just take-home message that if there is a need that the 600-milligram loading dose of clopidogrel should be used. You know, Gabriel, you've thought a lot about this and especially the drug-drug interaction question. What are your thoughts there?

Dr Gabriel Steg:                Yeah, well first of I think this is an extraordinary, important study even though it's a pharmacodynamic study, which many clinicians might look at and then quickly read the abstract and turn the page I think this is actually one of the most interesting papers we've published in recent months. The reason for this is this is tackling a very common clinical scenario, which is having or desiring or wanting to de-escalate the intensity of platelet therapy after a PCI or ACS from a potent agent such as ticagrelor to a less potent agent such a clopidogrel. And as nicely explained in the paper, there are multiple reasons why this can occur.

                                                A common clinical scenario is that cost is a major issue. Because of the cost patients or physicians may want to switch to clopidogrel, a generic drug as opposed to a branded drug. Another scenario which is fairly common is side effects. Either nuisance bleeding or maybe dyspnea with ticagrelor may prompt some physicians and patients to want to deescalate to clopidogrel. To a less intensive therapy which may not have dyspnea or may not cause as much nuisance bleeding. And finally, sometimes it's done on purpose because some believe that within a few weeks or months following PCI or ACS the benefits of more intensive patient therapy is less, the risk remains the same and therefore maybe we could proposedly de-escalate therapy to clopidogrel and get away with it and there have been a number of randomized studies and observational studies that suggested that this might be feasible although these studies have weaknesses. They're often open label. They're often fairly small and somewhat underpowered.

                                                So, we don't have a definitive answer. Nevertheless, this happens on an everyday basis in most large clinical centers and we don't know exactly how to do it and what the best way to do it and I really want to credit Dominick's team for doing a rigorous series of investigations, including this one, which is the latest one but not the only one in trying to really map out how exactly we should as clinicians manipulate these agents to achieve the best safety and efficacy for our patients. And I think the message here is very clear. Yes, you can de-escalate but you have to be careful on how you do it. And I think you really need to use a loading dose, a 600-milligram loading dose of clopidogrel if you're going to deescalate from ticagrelor to clopidogrel to avoid a gap in protection that might be deleterious to patients.

                                                That does not address all of the questions that are raised by de-escalation and as I pointed out I think outcome trial data are really of paramount importance here, but I think this really important because it has major practical implications for clinicians worldwide on how to do this. So, I think this is a great study. I really want to congratulate Dominick.

Dr Dominick Angiolillo:   Thank you.

Dr Carolyn Lam:                You looked at the genetic status as well. Could you tell us about your findings there?

Dr Dominick Angiolillo:   We in the spirit of trying to perform the most comprehensive possible assessment we have also looked at the genetic background of our patients and in particular looking whether the presence of a loss of function allele for CYP2C19, which is involved with clopidogrel metabolism, could have affected the outcomes. And the reason why we did this there've been a lot of studies clearly showing that if you have a loss of function allele for CYP2C19 you do have higher levels of platelet reactivity. Therefore, we want to see if those carriers would have had even a greater increase in platelet reactivity. And again, we did all this in the spirit of really trying to define again this from a pharmacodynamic standpoint, if there could be any potential safety hazards with such an increase in platelet reactivity with the de-escalation.

                                                When we did our analysis, we did not find any impact of a CYP2C19 on our data. However, I think it's important to underscore that we did not have too many patients with a loss of function allele so clearly the study was not designed or nearly closely powered to look into this assessment. So, I think that aspect does need to be interpreted with caution.

Dr Carolyn Lam:                Thanks so much, Dominick. Were there perhaps caveats that clinicians listening in should pay attention to? For example, this study was conducted in stable patients with coronary artery disease. What about patients with recent acute coronary syndrome?

Dr Dominick Angiolillo:   That's a great point. The reason why we conducted this study in a more stable setting was largely driven by two aspects. Well first of all, we wanted to have a run-in phase of patients switching from clopidogrel to ticagrelor to have some sort of baseline to reference to after the switch. And this would have been mostly ACS patients that would be less likely to be on clopidogrel. The second is purely a safety issue. We know that patients with acute coronary syndromes are associated with higher levels of platelet reactivity and in the context of a study where we do not know the pharmacodynamic profiles associated with de-escalation or better off we don't know the details.

                                                And so, there was a safety consideration there which is why we did it in stable patients. But what we can say is tied with Gabriel's comment before in all the studies out there are not powered or do not have the rigor of a mega trial. Although we give our suggestions and recommendations, practical recommendations on how to switch, there is an increase in platelet reactivity and we stress in our manuscript that if you are going to switch, please try to delay this as much as possible because those increases in platelet reactivity for example, in a patient with an ACS for example, immediately after PCI, something that we probably would not want for our patients. I'm very happy actually that we conducted the study in the more stable cohort because we had less confounders. This is kind of the reason behind all this.

Dr Gabriel Steg:                The last question maybe I would ask Dominick is whether he believe that results would be different if we had the patients on a maintenance therapy for longer with clopidogrel, do you believe that the risk of rebound or drug-drug interaction are the same early on after institution of therapy or later on? Is there any reason to expect a difference?

Dr Dominick Angiolillo:   That's a great question. My personal opinion would be that with longer duration the platelet reactivity would have gone back down to baseline. We actually continue to study out up to around 10 days following the switch which we thought would have been sufficient time to get back to baseline and it was not the case particularly in the patients whose switch was a 75 milligram. The answer's probably yes. Probably yes. To redesign the trial again maybe having that 30-day time point as well would have been obviously of added value.

Dr Carolyn Lam:                Thank you so much, Gabriel and Dominick. This has been extremely insightful. Fun as always.

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


May 29, 2018

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

                                                What do salty, Chinese meals, neurotransmitters, cancer, and pulmonary arterial hypertension have in common? Well, you are not going to want to miss this week's feature discussion. It's going to reveal a new therapeutic approach to pulmonary arterial hypertension that may just surprise you, coming up right after these summaries.

                                                Do congenital heart defects signal a familial predisposition to cardiovascular disease? Well, this question was addressed in this week's first original paper from first and corresponding author, Dr. Auger, from University of Montreal Hospital Research Center in Quebec, Canada. Dr. Auger and colleagues aimed to determine whether the risk of cardiovascular disorders later in life was higher in women who had newborns with congenital heart defects. To answer the question, they studied a cohort of more than one million women who had delivered infants between 1989 and 2013 in Quebec. They showed for the first time that congenital heart defects in offspring were associated with increased risk of maternal cardiovascular morbidity later in life, including atherosclerotic disease, cardiac hospitalization, and cardiac transplantation. The association with subsequent cardiovascular morbidity risk was present for both critical and noncritical congenital heart defects. Thus, women who have given birth to offspring with congenital heart defects may benefit from early attention to traditional cardiovascular risk factors and more aggressive primary prevention strategies.

                                                Acute myocardial infarction, or AMI, is a major cardiovascular complication of non-cardiac surgery, but what are the outcomes following perioperative AMI? This question was answered in the next paper from co-corresponding authors, Dr. Smilowitz and Berger, from New York University School of Medicine. The authors identified more than 8,000 patients who were diagnosed with AMI during hospitalization for major non-cardiac surgery using the 2014 US Nationwide Readmission Database. They found that perioperative AMI after non-cardiac surgery was associated with a high in-hospital mortality and a 19% risk of 30-day hospital readmission among survivors. The majority of hospitalizations after perioperative AMI were because of infectious, cardiovascular, or bleeding complications. Recurrent AMI occurred in 11% of patients re-hospitalized after perioperative AMI. At six months after perioperative AMI, more than 36% of patients were re-hospitalized, and the overall risk of in-hospital deaths was almost 18%. Thus, hospital readmissions and mortality among patients with perioperative AMI pose a significant burden to the healthcare system. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted.

                                                What is the recent status of hypertension in China? Co-corresponding authors, Dr. Wang and Gao, from Fuwai Hospital, Peking Union Medical College, and Chinese Academy of Medical Sciences in China used a stratified, multistage, random sampling method to obtain a nationally representative sample of more than 450,000 residents from 31 provinces in mainland China from 2012 to 2015. The authors found that more than 23% of Chinese aged 18 years or old had hypertension, and that's equivalent to an estimated 284.5 million individuals. The prevalence of hypertension was similar in rural and urban settings, whereas three municipalities, mainly Beijing, Tianjin, and Shanghai had the highest prevalence of hypertension. Almost half the hypertensive population was aware of their hypertension. About 41% were treated, and only 15% achieved a blood pressure control. Among treated patients, barely 32% were prescribed two or more antihypertensive medications. Thus, this study revealed a considerable prevalence of hypertension in Chinese adults, as well as low awareness and control rates, representing an urgent public health message in China.

                                                Patients with systemic sclerosis-associated pulmonary arterial hypertension have a far worse prognosis than those with idiopathic pulmonary arterial hypertension. But why is this the case? In the next paper, from co-corresponding authors, Dr. Hsu and Dr. Kass, from Johns Hopkins University School of Medicine, these authors tested whether the disparity involved underlying differences in myofilament function. They studied cardiac myocytes isolated from the right ventricular septal endomyocardial biopsies from patients with systemic sclerosis-associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, or systemic sclerosis with exertional dyspnea but without pulmonary arterial hypertension. They also looked at control right ventricular septal tissue obtained from non-diseased donor hearts.

                                                They found that right ventricular myofilaments isolated from humans with systemic sclerosis-associated pulmonary arterial hypertension exhibited diminished contractile force and abnormal calcium sensitivity versus control myofilaments. This is in sharp contrast to the hypercontractile compensation in idiopathic pulmonary arterial hypertension. Systemic sclerosis patients with dyspnea and only exercise-induced pulmonary hypertension exhibited an intermediate right ventricular myocardial filament phenotype. These myofilament contractile abnormalities correlated strongly with in vivo right ventricular function at rest and right ventricular contractile reserve during exercise, suggesting a central role of right ventricular myofilament dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.

                                                In summary, these findings uncover key deficiencies in the right ventricles of systemic sclerosis-associated pulmonary arterial hypertension, and these findings suggest that therapies targeted at right ventricular myofilament contractile dysfunction may prove particularly useful for this vulnerable subpopulation. That wraps it up for our summaries. Now, for our feature discussion.

                                                Today's feature paper promises a new therapeutic approach in pulmonary arterial hypertension. We know that pulmonary arterial hypertension is a rare disease, but nonetheless it casts a large shadow because it most commonly afflicts young women and remains a disabling disease. Despite treatment advanced in the last 20 years, high-risk patients still succumb at a rate of 15% annually. Moreover, our most effective therapy is a continuous infusion of parenteral prostacyclin, which is both cumbersome and expensive. Thus, there remains an urgent need for better therapies to improve survival and quality of life. Today's feature paper introduces a novel approach to this.

                                                I'm so pleased to have the corresponding author, Dr. Sylvia Cohen-Kaminsky, from Inserm, Paris, France, as well as associate editor Dr. Charlie Lowenstein, from University of Rochester, to discuss today's special paper. You know, I'm gonna start with Charlie, because you have a way of explaining things and just putting the background to mechanistic papers so well. Could you do that for us, please?

Dr Charlie Lowenstein:  Sure. When I started in research, I worked in a neuroscience laboratory. One of the things we studied was glutamate and its class of receptors. Glutamate, as you know, is one of the major neurotransmitters in the brain. The brain releases small amounts of glutamate, which acts as a messenger, neurons talking to other neurons. But when there's a stroke, the brain releases huge amounts of glutamate, and it's actually toxic and can cause damage, and mediate neuronal damage and cell death. Glutamate is a hot topic in the world of neuroscience. But in the cardiovascular field, people don't know much about glutamate. They don't appreciate glutamate as being important at all. So, I have a question for you, Sylvia. How did you start to get interested in glutamate and its family of receptors?

Dr Sylvia Cohen-Kaminsky:          It started around 2000, and since 2000 we are having some clues about peripheral glutamate receptor in different cells in different organ. But basically, for vascular cells and for the topic of PAH, there was two things that make me thought about it. First of all, it was shown that the NMDA receptor contributes to the proliferation of different cancer cell types. Human tumor cells express the NMDA receptor, then an NMDA-receptor antagonist may inhibit cancer cell growth and migration. We know that pulmonary vascular cells from PAH patients have cancer-like properties. They are also proliferative and resistant to apoptosis, and they have several properties of cancer cells, such as metabolic shift and so on.

                                                In addition, not only neurons in the brain express the NMDA receptor, but also brain microvascular endothelial cells that respond to an NMDA receptor activation by gross production, disruption of endothelial cell barrier, and monocyte transmigration. All these three processes are relevant to PAH development. That's why I thought that perhaps an NMDA receptor is expressed on microvascular cells from the lung, and perhaps we could have a process involving an NMDA receptor in this vascular remodeling.

Dr Charlie Lowenstein:  As you know, there are three flavors of glutamate receptors. How did you discover that there was one particular kind, the NMDA receptor, that was really important for smooth muscle cells?

Dr Sylvia Cohen-Kaminsky:          You are right. We did analysis of mRNA expression, and most of the known receptor in the brain, either metabotropic or ... ionotropic, sorry, indeed expressed in vascular cells and they may cooperate to activate this NMDA receptor exactly as it happens in the brain. We didn't work that on these other receptor, but we are pretty sure they are at work in cooperation with the NMDA receptor. Why though an NMDA receptor? Because it's an ion channel permeable to calcium, and the calcium is an event which can be important in cell proliferation. In addition, the first thing we have shown in these remodeled vessels when we did mass spectrometry imaging was increased level of glutamate and glutamine, its precursor. That was also an additional element that makes us think about this NMDA receptor.

Dr Charlie Lowenstein:  I want to go from the receptor to glutamate. There are three or four amazing things about your paper. One of them is that you suggest that cells in the vascular are releasing glutamate, which is a neurotransmitter. Do you think those are the smooth muscle cells that are talking to other smooth muscle cells by releasing these messenger molecules?

Dr Sylvia Cohen-Kaminsky:          Yes. Smooth muscle cells are talking to other smooth muscle cells. But we also did some work on endothelial cells, and they are also able to release this glutamate. So we think that vascular cells in the vascular wall are discussing together through glutamate, although we don't know yet the normal function of this NMDA receptor in the vascular system. However, in the pathology it's very clear that there is this release. What is very interesting is that this release can be triggered by pathways which are already down-regulated in PAH, such as the endothelin-1 pathway.

Dr Charlie Lowenstein:  Another remarkable part of your observation is that the signaling with glutamate and glutamate receptors is hyperactivated in the setting of a major human disease, pulmonary artery hypertension. How did you figure out that glutamate is so important in this special disease?

Dr Sylvia Cohen-Kaminsky:          Because we showed, as I already told you, this glutamate accumulation in the remodeled vessel. We used this mass spectrometry imaging which allows analysis of metabolites directly in the remodeled vessels from sections performed from extended lengths. We saw this glutamate accumulation together with glutamine accumulation, so the ligand was overexpressed. In addition, when doing western blots from these remodeled tissue dissected from ongoing arteries, we have shown that we have a particular phosphorylation of this receptor which is very well-known in the CNS. This phosphorylation is involved in sending the receptor to the membrane and stabilizing the receptor to the membrane. Having this phosphorylation means that NMDA receptor is engaged, activated in the remodeled vessels in situ.

Dr Charlie Lowenstein:  In an experimental model, you explored the role of glutamate in two very nice, complementary ways. One is with a genetic approach, the NMDA receptor deficiency. The other is using drugs. What were the drugs, what were the pharmacology that you used to block glutamate's transmission, and how did that affect the mice?

Dr Sylvia Cohen-Kaminsky:          We used drugs that are very well known in the CNS. We used two drugs. One is memantine, which is already commercialized for the treatment of Alzheimer's disease. The other one is MK-801, which has been produced initially as a potential pharmacological drug but it was too potent to be used in the CNS. Therefore, this drug is only used in research at the moment. But these two drugs were able to act on this vascular remodeling and a number of PAH parameters. We have explored at least 12 parameters involved in this animal model of PAH, and hemodynamic stable parameters of hemodynamics including intra-arterial pressure, vascular remodeling, right ventricular remodeling with different parameters that shows a certain index. The cardiomyocyte hypertrophy, the fibrosis, the inflammation inside the right heart and around remodeled vessels, all these parameters were modified by the drug.

                                                In addition, in vivo we have shown the destruction of the NMDA receptor glutamate axis with decreased engagement of the NMDA receptor in pulmonary arteries by following this phosphorylation I mentioned, decrease of apoptosis resistance and also proliferation. This was shown also after the treatment with the drugs, and also decrease of endothelial cell dysfunction that could be followed in the blood through selecting those H.

Dr Charlie Lowenstein:  Your results with this drug were really impressive. I love that part of your study. You showed when you block glutamate signaling, first of all, the blood vessels looked much better in a model of pulmonary artery hypertension. In an experimental model, blocking glutamate transmission really improved the way the vessels look. But secondly, what was really amazing was, normally in humans one of the big problems with pulmonary artery hypertension, as you said, is the right ventricle gets inflamed and fibrotic, and a lot of patients die from complications of right ventricular dysfunction. In your model, when you treat with MK-801, blocking glutamate receptor, the right ventricle looks a lot better. It was really an impressive part of your study.

Dr Sylvia Cohen-Kaminsky:          I think that this is view on the effect of the vessels themselves, then the right heart can recover. But we may have a direct effect in the heart. If you remember this Chinese restaurant syndrome, when you eat too much Chinese food, which is full of glutamate, you have some cardiac involvement, arrhythmia, and so on. Initially, toxicologists thought that it passed through the central nervous system. But then they realized that maybe the NMDA receptor is expressed in cardiac cells, and indeed it is expressed and is colocalized with the ryanodine receptor, meaning that it could have a function in the heart as well. But this has, of course, to be explored precisely. We know from the transplantation that, when we transplant on with the lung, the heart can recover very well. We may have these two effects. One due to the relief on vascular remodeling, and the other perhaps a direct effect on the heart.

Dr Carolyn Lam:                You know, I have to chime in now. That cuts too close to home with the Chinese food and glutamate. First and foremost, I just really have to say, Charlie and Sylvia, it's people like you who make basic science come alive and simply extraordinarily exciting. Taking glutamate, something that we've talked about in the context of Chinese food and neurotransmitters, and therefore showing the potential to even repurpose perhaps some drugs for pulmonary arterial hypertension. So let me just round up by asking you, what do you think our next steps, how far are these findings away from clinical application? Perhaps, Charlie, your thoughts?

Dr Charlie Lowenstein:  While I think that the use of MK-801 to treat excess monosodium glutamate during a Chinese meal, maybe that's a little bit premature. I'm much more excited about the idea of using glutamate-receptor antagonists to treat or prevent or even reverse pulmonary artery hypertension, both its vascular and cardiac complications. I'd love to ask Sylvia, do you think these medications in this class, do you think NMDA-receptor antagonists are ready for clinical trials?

Dr Sylvia Cohen-Kaminsky:          In fact, they are not ready as they are. We have a program in which we have designed hypothesized new NMDA-receptor antagonist that do not go to the brain, because we want that treating PAH has to be safe, and we don't want to interfere with brain system. So we created this new NMDA-receptor antagonist that do not go to the brain. At the moment, we are in the process of the documentation. We have two patents for two series of molecules, and we expect the drug conjugate by the end of this year. To reconjugate means that we have a number of properties on this drug, the pharmacokinetics, metabolism, selectivity profile, toxicity, and so on. We are doing all this physical chemical properties, and of course validation of these new molecules in the animal models as therapy alone and also as add-on therapy with existing therapies, such as these vasodilators. We hope that we can have an additive effect between an NMDA-receptor antagonist and current PAH drugs.

Dr Charlie Lowenstein:  Sylvia, as you know, drug companies about 10 or 20 years ago invented all these amazing glutamate-receptor antagonists to treat central nervous disease like stroke. One of the amazing things about your discovery is you're suggesting that glutamate receptors in the periphery are great targets as well. The exciting thing about your observation is you're really opening up new therapeutic approaches for targeting neurotransmitters in the periphery. I think your discoveries are tremendously exciting and could open up new avenues in treatment of a disease, pulmonary artery hypertension, for which there really aren't effective therapies right now.

Dr Carolyn Lam:                I couldn't have said it better. Thank you so much, Charlie. Thank you so much, Sylvia.

                                                See, listeners? Aren't you glad you heard it here right on Circulation on the Run? Don't forget to tune in again next week.


May 22, 2018

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on the challenges of cardiovascular disease risk evaluation in people living with HIV infection, an important discussion coming right up after these summaries.

                                                The first original paper this week provides experimental evidence that nicotinamide riboside could be a useful metabolic therapy for heart failure. First author Dr. Diguet, corresponding author Dr. Mericskay, from University Paris-Sud investigated the nicotinamide adenine dinucleotide or NAD homeostasis pathways in the failing heart. They found that an expression shift occurs in both murine and human failing hearts in which the nicotinamide riboside kinase two enzyme, which uses the nucleoside nicotinamide riboside was strongly up-regulated for NAD synthesis.

                                                Nicotinamide riboside supplemented diet administered to murine models of dilated cardiomyopathy or pressure overloaded induced heart failure restored the myocardial NAD levels and preserved cardiac function. Nicotinamide riboside increased glycolysis as well as citrate and Acetyl-CoA's metabolism in these cardiomyocytes. Thus, nicotinamide riboside supplemented diet may be helpful in patients suffering from heart failure and may help them to cope with the limited myocardial ATP supply by restoring NAD coenzyme levels and its associated signaling.

                                                In the single ventricle reconstruction trial, one year transplant-free survival was better for the Norwood procedure with the right ventricle to pulmonary artery shunt compared with the modified Blalock‒Taussig shunt in patients with hypoplastic left heart and related syndromes. In the paper in this week's journal, authors compare transplant-free survival and other outcomes between these groups at six years. First and corresponding author Dr. Newburger from Children's Hospital Boston and her group showed that the right ventricular pulmonary artery shunt group had similar transplant-free survival at six years, but required more catheter interventions before the Fontan procedure.

                                                Right ventricular ejection fraction, New York Heart Association class and complications did not differ by shunt time. Cumulative incidences of morbidities by six years included 20% with a thrombotic event, 15% with a seizure, and 7.5% with a stroke. These data therefore emphasize the importance of continued follow-up of the cohort, and the need to find new strategies to improve the long-term outlook for those with single ventricle anomalies.

                                                The next paper presents results of the CREATIVE trial, which stands for Clopidogrel Response Evaluation and Anti-Platelet Intervention in High Thrombotic Risk PCI Patients). First and corresponding author Dr. Tang from Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College conducted a head-to-head comparison of the safety and effectiveness of intensified anti-platelet therapies either a double dose clopidogrel or adjunctive cilostazol and conventional strategy in 1078 post-PCI patients at high thrombotic risk as identified thromboelastography, which is a platelet function test.

                                                The primary outcome was the incidence of major adverse cardiac and cerebral vascular events at 18 months post-PCI they find as a composite of all cause death, myocardial infarction, target vessel revascularization, or stroke. The authors found that the primary end point occurred in 14.4% of those in the conventional strategy. 10.6% in those given double dose clopidogrel alone. And 8.5% in those also given adjunctive cilostazol. Now, although both intensified anti-platelet strategies achieved increased platelet inhibition, only the triple strategy with adjunctive use of cilostazol significantly reduced adverse events in the long-term follow-up.

                                                No increased rates of major bleeding was found with the intensified anti-platelet therapy regimes. Thus, in patients with low responsiveness to clopidogrel as measured by thromboelastography, the intensified anti-platelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding.

                                                The final original paper sheds light on the prevalence and predictors of cholesterol screening awareness and statin treatment among American adults with familial hypercholesterolemia or other forms of severe dyslipidemia. First and corresponding author Dr. Bucholz from Boston's Children's Hospital and their colleagues used data from the National Health and Nutritional Examination Survey, and showed a high prevalence of screening and awareness above 80%. However, there were relatively low rates of statin use among individuals with familial hypercholesterolemia at 52.3%.

                                                And even lower rates among those with severe dyslipidemia at 37.6%. The discrepancy between the prevalence of cholesterol screening and treatment was most pronounced in younger patients, uninsured patients, and patients without a usual source of healthcare. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.

                                                And that brings us to the end of our summaries. Now for our feature discussion. The natural history of infection with HIV has completely changed with the use of potent antiretroviral therapies. We now know that people living with HIV actually have morbidity and mortality patterns that really resemble the general population, especially with regards to cardiovascular disease, which is very prominent in this population. And I suppose it's this that has led to the assumption perhaps that risk prediction tools and intervention strategies that we apply in the general population may be used in patients living with HIV.

                                                Is this the case however? Well, this week's feature discussion is going to be so enlightening. And it's so important we are talking across the world here, from South Africa to the United States, and of course with me here in Singapore. I am so pleased to have the authors of this week's feature paper and they are none other than Dr. Virginia Triant from Massachusetts General Hospital, Dr. Ralph D’Agostino from Boston University. And our associate editor, Dr. Bongani Mayosi from University of Cape Town. Thank you so much for joining me for today's exciting discussion. Virginia, could I ask you to first describe your study?

Dr Virginia Triant:             As you mentioned in the introduction, we have found that patients infected with HIV have an increased risk of cardiovascular disease. That includes both myocardial infarction and stroke compared to age-matched controls in the general population. And extensive data has suggested that the etiology of this increased risk is related both to traditional cardiovascular risk factors, as well as novel risk factors that are specific to HIV infection. And these include chronic inflammation in the immune activation. So consequently, it remains relatively unknown whether established cardiovascular risk prediction functions are accurate for patients with HIV because they include only risk factors that are traditional factors and they don't reflect the complete mechanism that we know is at play in cardiovascular disease associated with HIV.

                                                So in our study, we assess the performance of three established cardiovascular risk prediction functions, two Framingham functions, and then the ACC/AHA pooled cohort's equations and we applied this to a longitudinal HIV infected cohort that was comprised of men. And we investigated the performance of the risk scores in terms of comparing regression coefficients, discrimination and calibration, which are standard metrics in cardiovascular risk prediction. So I'll briefly summarize our overall results as a start. We found that overall, the risk prediction functions underestimated risk in our group of HIV-infected men.

                                                We found that discrimination was modest to poor, and this was indicated by low c-statistics for all of the equations. And we also found that the calibration or the agreement between observed or predicted risk was also poor across the board for all three risk prediction functions. So our results suggests that simply taking the risk prediction functions and transporting them to an HIV infected group may actually result in mis-classification in terms of patient risk. And in underestimation of cardiovascular risk.

Dr Carolyn Lam:                Well, Virginia, beautifully summarized of a beautiful paper. But perhaps at this point, we should take a step back and ask ourselves how exactly were these risk prediction scores originally developed. And I can't imagine asking a better person than Ralph. Ralph, could you take us on a jaunt along history and tell us how were those Framingham risk scores developed in the first place? Who are they supposed to be applied to? And did these results surprise you?

Dr Ralph D’Agostino:      After the second World War, what was becoming quite clear is things like cardiovascular disease were becoming very prominent. Things like infections and what have you, we were developing all sorts of ways of handling them with medicines and so forth. But with cardiovascular disease, it's a thing that progresses slowly over the years and it starts wiping out people. And back in those days, one out of three men between the ages of 30 and 60 had some kind of cardiovascular event. Women weren't that bad off, but they were pretty bad off also. And so what happened is the American government and the American Heart Institute set up this study in Framingham, where they took a third of the individuals between the ages of 30 and 60 and actually followed them. They took values of variables like blood pressure, cholesterol, things they thought might be useful.

                                                And took values on them. And they had to come back every two years and after as time went on, they took the data after six years, after 10 years they took the data, and started to look at how each individual's blood pressure related to cardiovascular disease. Does cholesterol, and the answer was yes. And then I started getting involved and we were developing these cardiovascular functions where you could actually take an individual, take their measurements now, and make a prediction that had a lot of validity, good discrimination, high predictability over what was going to happen in ten incidents and then the government, the US Government, started having guidelines and what we did is we ran a study where we took a number of different studies in the US, different cardiac studies, the ARIC studies, number of 'em, and we thought applying our functions how well would they do. And it turned out that for whites in the country, the Framingham functions did very well.

                                                But Japanese-Americans in the country, it over-predicted. Then we found out that you could make a calibration adjustment and what we've gone to, like in China, we have a big study where we had a function and Framingham function it over-predicted but calibration adjustment would make enough corrections and so now with Jeanne and the HIV, our hope was that you could take these functions and see how they work on the HIV population. When we did it we were quite well aware, because people have been looking at different things, there's something beyond the original cardiovascular risk. And what the paper shows, quite nicely, these cardiovascular risks do have some relationship but they don't explain enough. The HIV population have a much bigger burden and a simple calibration adjustment just isn't going to work. We need new variables, we need new insights on what to add to these functions.

Dr Carolyn Lam:                Thank you so much for that. That's just such important part of history because I have to thank you for those equations. We apply those definitely in our Asian cohorts with that calibration factor. But I was just reflecting as you were telling that story of how we've come full circle now to actually talk about an infection again. It's the midst of an infection, like HIV infection, that we're now testing these equations once again. What better than to ask than Bongani, you're in the epicenter, if I may, of HIV infection. What do you think of the applicability of these findings to the patients you see?

Dr Bongani Mayosi:         Yes. These findings are clearly of great interest to us here in the Sub-Saharan African region because it is really the epicenter HIV pandemic. We found population, in terms of risk factors for arteriosclerosis disease still remains low although there clearly derives, for example, in the incidence of myocardial infarction that's being detected in a number of the leading centers now. And with HIV we have observed cases of myocardial infarction while they tend to be younger men who almost always smoke and who get a lot more of a thrombotic episodes.

                                                When you catch them on a thrombotic load, you do not find arteriosclerosis disease. It's going to be important, I think, as we move forward to make sure that as we develop risk functions that will predict cardiovascular disease in patient HIV that the African epidemiological context is completed teaching that HIV affects younger people, affects large numbers of women, but that, quite clearly, is associated with decreased cardiovascular event and stroke and stroke is well demonstrated. But in terms of actually looking at the risk factor this population was still in the early day and certainly in future studies would have to have a major contribution of the African cohort.

Dr Carolyn Lam:                That's true, Bongani, but may I ask how would you, perhaps, advise your African colleagues now to look at these data? Then I'd also like to turn that same question over to you, Virginia. What do we do? What's the clinical take home message of these findings?

Dr Bongani Mayosi:         I think the message is true that HIV infection is associated with the increased risk of cardiovascular event, there's no doubt about that. That there are some risk factors that can carry through, such as the smoking population but it's important for all clinicians to be aware of that. The ordinary risk you find in using Framingham and other established risk functions is not going to give us all the information that we need. So that recommendation should come through we need to know that risk factors are unknown, that they're important and we need to learn more about these patients in order to give us a perfect prediction of what will happen in the future.

Dr Virginia Triant:             I think the findings have a lot of clinical relevance. This suggests, I think, that there are a lot of clinical implications for any patient who has novel cardiovascular risk factors that may not be accounted for in heart functions. And what our findings suggest is that if functions don't reflect the actual composition of risk factors in the population, that can result in misclassification and thus we underestimate risk, we might miss high-risk individuals, high-risk patients who would benefit from aggressive risk reduction but are not currently receiving it. This is a real clinical challenge as sit in clinic and we pull up the scores and calculate them for our patients, whether that is a trustworthy number or whether we should, perhaps, thinking that it's higher, thinking that it's different than what we're seeing for predicted 10-year risk. I think what this suggests is that the functions may need to be further tailored to different populations and sub-populations to reflect the actual composition of risk factors in that population. Even within HIV patients and populations, the risk factors in South Africa might be different than those in Boston, with different relative contributions.

                                                One of the next stepped planned for our team is to actually look at developing, new risk functions which are tailored to HIV and incorporating both HIV itself as a risk factor, as well as HIV specific variables and to attempt to see if we can improve the performance of these functions for HIV populations. Perhaps HIV or HIV related factors might become sort of a new cardiovascular risk equivalent and we can serve patients in this population as higher cardiovascular risk baseline. I also just wanted to mention, briefly, that I think that there are important clinical implications beyond HIV that extend to other chronic inflammatory conditions. Inflammation is increasingly recognized as important in cardiovascular risk and this way HIV can serve as a prototype population. But these results are likely to extend to a lot of different populations who have chronic inflammation for different reasons.

Dr Carolyn Lam:                That's a great point, Virginia. As I'm listening, I'm wondering is there no end to this because now we say HIV and then we put other inflammatory diseases, then we say, "Well, women may be different from men," and then different ethnicities may be different. I think gonna be going closer and closer to precision risk prediction, if I might say. Could I just pick your brain here? What do you think the future is? Where's the room for machine learning approaches for risk prediction, individual almost down to that level? What do you think?

Dr Ralph D’Agostino:      I think you're right on target. In some sense, the functions we have there's a sort of massiveness about it, when you come to view this population, back in the 50s and 60s and so forth, cardiovascular disease was such a major ... it still is a major problem ... such a major problem you identify some of the real items like the blood pressure and cholesterol, and you attack and develop functions on that and you'd find that you're affecting positively a huge number of individuals, but now as, like Jeanne was saying, and others have been saying, you start focusing, you've got this massive group of individuals who should have their blood pressure controlled and what have you, but if you go into HIV, you go into a number of other populations and so forth, there are other things that are driving these disease and driving the manifestations of the disease. It isn't that blood pressure isn't important, it's that there's other things that are important. And so it's machine learning and so forth and deep learning that you're gonna have to be dealing with manifestations on very high levels and maybe even get into genetics.

                                                Look in the cancer field ... I do a lot of work with the FDA ... look at the cancer field now; how it's so genetically driven in terms of a lot of the drugs the so-called biomarkers, which are basically driven by uniqueness in populations. I think that's definitely going to be, or is the future of these cardiovascular functions.

Dr Carolyn Lam:                Okay audience. You heard it, right here. These are exciting times. In the meantime, thank you so much for this precious, valuable piece of work. Virginia, Bongani, Ralph, it was great having you on the show.


May 14, 2018

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

                                                Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.

                                                Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.

                                                They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.

                                                The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.

                                                From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.

                                                The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.

                                                The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.

                                                The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.

                                                RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.

                                                Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.

                                                The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.

                                                They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.

                                                That brings us to the end of our summaries. Now, for our featured discussion.

                                                Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.

                                                I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.

                                                Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find?

Dr Robin Mathews:         The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?

                                                We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.

                                                ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.

                                                What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.

                                                We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.


                                                What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.

                                                When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.

                                                We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant.

Dr Carolyn Lam:                What a detailed summary. Thanks so much.

                                                Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful?

Dr Jeptha Curtis:               It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.

                                                I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.

                                                What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.

                                                As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.

                                                All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.

                                                What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals.

Dr Carolyn Lam:                Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that?

Dr Sandeep Das:               Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.

                                                One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."

                                                I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems.

Dr Carolyn Lam:                Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US?

Dr Robin Mathews:         Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."

                                                Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.

                                                In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.

                                                At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts.

Dr Sandeep Das:               One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?

                                                The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive.

Dr Robin Mathews:         Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.

                                                I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.

                                                At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them.

Dr Carolyn Lam:                Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.

                                                Thank you so much for listening today, and don't forget to tune in again next week.

May 7, 2018

Dr Joseph Hill:                    My name is Joe Hill. I'm the Editor-in-Chief of Circulation and I'm very pleased today to be here today with Professor Daida from Juntendo University in Tokyo, Japan, as well as one of our associate editors, Professor Shinya Goto from Tokai University in Kanagawa, Japan. Dr. Daida is one of the senior authors on a very exciting clinical trial that we're publishing in Circulation. The first and largest trial comparing high-dose versus low-dose statins in Asia. Dr. Daida, would you please tell us more about the study?

Dr Hiroyuki Daida:            Yes. Thank you. The trial, called REAL-CAD, is a randomized trial. We compare high-dose statins with low-dose statins in Japanese patients with stable coronary artery disease. The number of the patients is 13,000. It's the largest trial ever comparing high-dose and low-dose statins. We found that with that reduction of the primary end point, which is a composite end point, including cardiovascular death, non-fatal MI, non-fatal stroke, and unstable angina requiring hospitalization.

                                                That is very exciting result because it is the largest trial ever and also the very first trial in Asia.

Professor Shinya Goto: Congratulations, Professor Daida, for that great achievement, in the REAL-CAD trial. Could you explain a little bit about the background and that the dose of statins in Japan is generally low, and what was the reason why we kept using low-dose statins, and is care to try change the standard of care in Japan and also East Asia? Could you give a comment on those two topics?

Dr Hiroyuki Daida:            Our trial is quite similar to that of PNP trial of comparing Western extensive statin treatment and the Asia statin treatment. However, that extensive statin treatment, intensive statin treatment, is not popular in Asia, so we did that maximum clinical dose of statin, we use this dose in Japan. It is the maximum dose of statin approved in Japan.

Dr Joseph Hill:                    So as I understand it, the rationale was the thinking that Asians, East Asians, are unable to tolerate high-dose statin therapy. In this case you used pitavastatin. And, in fact, what you found was there were no increase in serious adversive events in high dose patients. And, just like Caucasians, they derived considerable benefit at multiple points in atherosclerotic cardiovascular disease metrics.

Dr Hiroyuki Daida:            Actually, they didn't experience a really high-dose of statin in Japan so government approval is up to 4 mg of pitavastatin, a dose of that about 20.

Dr Joseph Hill:                    So, this is not what we would call high-intensity statin therapy but nonetheless, there was a dramatic benefit including an all-cause mortality, irrespective of the starting LDL level at the beginning of the trial?

Dr Hiroyuki Daida:            That is right. We found that the effect is similar that the patient, the LDL is greater than 95 or less than 95. So, the effect is independent of the basal based on LDL level.

Professor Shinya Goto: The one thing, very exciting just like Joe mentioned, all cause of mortality, especially known cardiovascular caused mortality reduced with the use of high-intensive care of the statin. If any kind of speculation, what is the cause, reduce the inflammation or maybe reduce cancer, something like that. They have any kind of advance to an analysis?

Dr Hiroyuki Daida:            We didn’t have further analysis but we are not so keen to emphasis the total mortality because maybe that is a chance of the effect but this is the largest trial, so the result is really exciting in this kind of aspect.

Dr Joseph Hill:                    So, I would reiterate Shinya’s congratulations. This is a monumental piece of work. The largest clinical trial comparing high dose versus low dose statin. The largest ever. The first in Asia. You found a benefit that makes total sense across what we know from other trials and this will change practice. Your work, I believe, will change the way patients with atherosclerotic cardiovascular disease is handled in Japan.

Dr Hiroyuki Daida:            Yes, actually the current guideline in Japan for the secondary condition. The condition is LDL less than 100 and for the really high-risk secondary condition listed seventh. We didn't recommend high-dose statin initially, so, this trial result is kind of like this, changing.

Dr Joseph Hill:                    I can't resist asking, what comes next? What's your next project?

Dr Hiroyuki Daida:            Maybe we need to have a further reduction of LDL. We have another drug, other potent drug recently. We need to investigate all of the new drug such as PCSK9 inhibitor in secondary prevention.

Professor Shinya Goto: That's wonderful. Do you have any time to extend observation of the trial? I think the trial is relatively still superior as compared to the global long-standing trial. Really, that's fine, that effect of statin on the cholesterol and even it's different from Japan and other regions of the world. There ought to be intriguing thing, I would like to know, what are you waiting to extend that observation now?

Dr Hiroyuki Daida:            Fortunately, we do not intend to extend the follow-up. The whole thing is about four years but we do not plan to extend. We will further analyze the data for some group and our kind of CRP and effect of the baseline.

Dr Joseph Hill:                    Lots of secondary analysis underway, undoubtedly. Let me thank both of you for being here, Professor Daida and Professor Goto, I congratulate you again. It's not often that you make a practice-changing intervention in modern-day medicine. I salute you and we are honored and thrilled to publish your outstanding work in Circulation. Thank you both.

Dr Hiroyuki Daida:            Thank you very much.

Professor Shinya Goto: Thank you very much.


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