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Circulation on the Run

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!