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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Now displaying: August, 2019
Aug 26, 2019

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

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                In just a moment, we will be discussing further results from the CREDENCE trial. That's canagliflozin in patients with type 2 diabetes and chronic kidney disease, this time focusing on the cardiovascular outcomes as well as both primary and secondary prevention groups. Really exciting stuff, huh, Greg?

Dr Greg Hundley:             Absolutely, Carolyn. Got any papers you want to have a coffee chat about?

Dr Carolyn Lam:                Absolutely. So my first pick really tells us that allele-specific RNA silencing of human alleles may be effective in treating inherited cardiomyopathies. Want to hear more?

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                So, this is a study from Dr Ashley and colleagues from Stanford University School of Medicine who performed a selective allele-specific silencing of the human restrictive cardiomyopathy, a specific mutation of asparagine to lysine in the regulatory light chain, which is encoded by MYL2. So they did this in a humanized transgenic mouse model using an adeno-associated virus RNA interference approach. Using this approach, they showed that an interfering RNA treatment ameliorated disease phenotypes by specifically reducing the cardiac expression of the mutated allele, hypertrophic carb biomarkers and intramyocardial fibrosis. In fact, isolated cardiomyocytes from the treated animals showed normalization of contraction and relaxation dynamics with partial restoration of calcium re-uptake dynamics.

Dr Greg Hundley:             Boy, Carolyn, sounds like improvement in cardiovascular function, but were there any adverse effects?

Dr Carolyn Lam:                Great question. Well, they also performed cardiac genome-wide transcriptome profiling, which showed a reduction in the hypertrophic program without significant off-target effects, so that's important. So in summary, these results show the feasibility, efficacy, and safety of RNA interference therapeutics directed at human restrictive cardiomyopathy. A really promising step towards targeted therapy for a prevalent disease.

Dr Greg Hundley:             Very nice. Carolyn. So I'm going to start my discussion also with a basic science paper that's going to focus on ischemia reperfusion injury and looking at the mechanism by which mitochondrial dysfunction can be avoided. So, the paper emanates from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital Medical University in Beijing. The study from Dr Li identifies an important mechanism of this myocardial ischemia-reperfusion injury in a mouse model and found, in human subjects, a biomarker that was predictive of adverse cardiovascular events after those individuals had sustained an MI.

Dr Carolyn Lam:                Oh, interesting. So tell us more, Greg.

Dr Greg Hundley:             Yeah, so the authors utilized a dynamic transcriptome analysis of mouse hearts exposed to various myocardial ischemia-reperfusion periods to identify a new inflammatory molecule that they termed S100A8/A9, and it was an early mediator. And then they measured this new inflammatory molecule level in patients, human subjects, after myocardial infarction, before and after they had undergone percutaneous intervention. So this S100A8/A9 was identified as the most significantly up-regulated gene during the early reperfusion stage and knockout of that molecule markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of the molecule exacerbated myocardial ischemia-reperfusion injury.

                                                The authors then demonstrated that the levels in patients significantly increased day one post-PCI in anterior MI patients and elevated molecule levels were associated with the incidents of future MACE. So perhaps, in the future, targeting this molecule-initiated signaling may represent a novel therapeutic intervention for myocardial ischemia-reperfusion injury.

Dr Carolyn Lam:                Interesting and very nicely explained. Now my next paper, the title says it all. Three Public Health Interventions Could Save 94 Million Lives in 25 Years. So we know that preventable noncommunicable diseases, which are mostly cardiovascular diseases, are responsible for 38 million deaths annually. So, these authors who are Dr Danaei and colleagues from Harvard T.H. Chan School of Public Health in Boston, Massachusetts, quantified the global mortality impact of three high-impact and feasible interventions. One, scaling up treatment of high blood pressure to 70%, two, reducing sodium intake by 30% and, three, eliminating the intake of artificial trans fatty acids.

                                                So, they used global data on mean blood pressure levels and sodium and trans-fat intake by country, age and sex from a pooled analysis of population health surveys and regional estimates of current coverage of antihypertensive medications as well as cause-specific mortality rates in each country, along with projections from 2015 to 2040. They used the most recent meta-analysis of epidemiologic studies to derive the relative risk reductions for each intervention.

                                                And, in summary, they found that the combined effect of the three interventions delayed 94.3 million deaths during 25 years. Increasing the coverage of antihypertensive medications to 70% alone would delay 39.4 million deaths, whereas reducing sodium intake by 30% would delay another 40 million deaths and eliminating trans-fat would delay an additional 14.8 million deaths.

Dr Greg Hundley:             Aha. So controlling blood pressure, cutting salt, eliminating trans fats, but are there any regional differences around the world, Carolyn, your part of the world versus United States?

Dr Carolyn Lam:                Good question as always. So the authors also estimated the impact in different parts of the world and found that the estimated impact of trans fat elimination was largest in South Asia. Sub-Saharan Africa had the largest proportion of premature delayed deaths out of all delayed deaths. National and international efforts therefore need to scale up these interventions and this should be a focus of cardiovascular disease prevention programs.

Dr Greg Hundley:             Oh, my. Really interesting. Well, I'll tell you what, Carolyn, my next article is going to take us to space, the unified efforts of all these countries in the world trying to examine the effects of prolonged space flight. So this article, it's headed up by Dr Ben Levine at University of Texas Southwestern Medical Center, but it has a very large group of coauthors and examines the impact of prolonged space flight on orthostatic tolerance as those astronauts return to earth.

                                                So, as we know, astronauts returning to earth usually demonstrate reduced orthostatic tolerance, especially when you assess them on a tilt table. But no studies to date have evaluated sort of the post-flight return to earth effects of orthostatic on activities of daily living, and those are most clinically relevant. So in this study, ambulatory blood pressure variability, that's already been known to be associated with orthostatic intolerance in other patient populations and can capture clinically significant orthostatic hypertension during activities of daily living. So, in the study, ambulatory beat-to-beat blood pressure was recorded using a portable device for multiple 24-hour time periods before, during, and after six months of space flight in 12 astronauts, four women, age averaged 48 plus or minus five years.

Dr Carolyn Lam:                Fascinating. What a clever study. So what did happen to the astronauts when they returned to earth?

Dr Greg Hundley:             So, in contrast to previous studies which employed the tilt tables or the stand test, no astronaut experienced orthostatic intolerance or hypertension during activities of daily living before or after space flight. 24-hour systolic blood pressure decreased in space as we might expect, but it returned to normal upon landing and diastolic blood pressure was unchanged during and following space flight. Systolic and diastolic blood pressure variability remained the same before, during, and after space flight. Given the current countermeasures that include exercise, training in flight, volume resuscitation on return, no astronauts experienced orthostatic hypertension or intolerance during routine, for landing day, activities in the initial 24 hours after landing, following six months in space. And prolonged exposure to space fight, therefore, had little impact on systolic blood pressure variability and its distribution. Though the latter showed just a transient change in space and that might be expected. It returned, however, to preflight values when we got back to earth. Very nice work.

Dr Carolyn Lam:                Yes, indeed. Very clever. But let's carry on with our feature discussion, shall we?

Dr Greg Hundley:             You bet. Welcome everyone to our featured article discussion, and we're going to learn more about primary and secondary cardiovascular-related events from the CREDENCE trial and we have with us, Dr Ken Mahaffey from Stanford Medical Center in California and our associate editor, Professor Naveed Sattar from Glasgow in the United Kingdom. Welcome to you both and we feel very honored to be able to discuss this paper today with you, Ken.

                                                Can you just refresh our memories a little bit about the CREDENCE trial? What were its primary results? I understand they had patients with diabetes and chronic kidney disease. Maybe tell us a little bit about how that was defined and then transition to what were the hypotheses in your study that you were going to test?

Dr Kenneth Mahaffey:   So, the CREDENCE trial was a trial of an SGLT2 inhibitor, canagliflozin, in patients with diabetes who had chronic kidney disease with albuminuria. And it was the first of any of the SGLT2 inhibitor trials that was done in a dedicated renal population with a primary outcome that was a composite of renal outcomes along with cardiovascular death, and the trial was stopped early by the data safety monitoring board on an interim analysis when they found overwhelming efficacy. And, at the end of the day, the final results showed that canagliflozin compared with placebo showed a 30% reduction in the composite renal outcome as well as important reductions in cardiovascular outcomes without any evidence of increase in amputations.

                                                Now, the study that we're talking about today is a pre-specified, pre-planned subgroup analysis from CREDENCE where we wanted to look at how canagliflozin worked in people or participants who had known cardiovascular or cerebrovascular or peripheral vascular disease and those who did not. And one of the reasons this was an important analysis was that in previous studies of SGLT2 inhibitors, there has not been a consistency in the message about whether the drug worked in both primary and secondary-prevention populations.

                                                And what we found here in this analysis was that in the primary-prevention participants, which actually was 50% of the overall trial recruitment, had very similar reductions in renal outcomes and cardiovascular outcomes compared with those who were a secondary-prevention cohort. So a very different results and a very important result in this patient population.

Dr Greg Hundley:             Really interesting. So in terms of the patients that you evaluated in this sub study, were they any different than the whole cohort and, in terms of participants and compliance with the therapy, was there any difference with the placebo versus the study drug that you noticed and can you infer from that any particular groups of patients that may benefit more or be able to take the therapy more? Just more about compliance.

Dr Kenneth Mahaffey:   First of all, you asked how the primary and secondary-prevention groups in the study were different and they were, as one would expect. Those participants who did not have prior atherosclerotic cardiovascular disease tended to be younger. They were more often women. They had shorter durations of diabetes and they were less often treated with cardiovascular preventive medications, in terms of staph and antiplatelet therapies. All the patients were on an ACE or an ARB.

                                                In terms of overall compliance with canagliflozin, it was very good. Now, the SGLT2 inhibitors, as a class, have a number of important side effects including genital mycotic infections in both men and women. They do cause some hypovolemia and volume depletion, but we found overall in the CREDENCE trial that fewer participants stopped the study drug prematurely in the canagliflozin arm than in placebo arm. So we feel that we had a very, very good comparison of the two therapies in the overall trial and in the primary and secondary-prevention analyses.

Dr Greg Hundley:             And so just general thoughts of how do you think this might impact the results of your study, or treatment, when we see patients with diabetes and chronic kidney disease?

Dr Kenneth Mahaffey:   I think there's potentially a big impact moving forward. Now, the SGLT2 inhibitor classes were approved based on the early cardiovascular outcome trials, did not enroll participants with lower EGFRs. So once these data are reviewed by the FDA and if they accept these findings and change the label, then the proportion of patients with diabetes who also have EGFRs down to 30 would be potential candidates for this therapeutic intervention. And it's important to point out that the CREDENCE trial that showed this reduction in renal events in patients with type 2 diabetes and chronic kidney disease, this is the first positive trial in 20 years of an intervention and 20 years ago we had both ACEs and ARBs based on large outcome trials, but we've had nothing since then that could be a therapeutic intervention to improve outcomes in this very important patient population.

Dr Greg Hundley:             Thank you so much, Ken. And, Naveed, I would like to just turn to you and ask you a couple things. One, can you put this study on the SGLT2 inhibitors with all the other information that's coming out related to potential benefits, not only in controlling blood sugar, but impacting cardiovascular disease-related events? How does this fit in to all of the other studies that we're learning about in such rapid fashion?

Dr Naveed Sattar:            This comes on the back of the three major trials and extends the evidence based so that, yes, I think we now show clear evidence that these drugs work in people with impaired renal function down to a level of 30 which I think is very important, so that will extend the guidelines. Yes, they seem to work in primary prevention. Of course. I think Dr Mahaffey would accept that these are probably high-risk primary prevention individuals because you also have evidence for chronic kidney disease and I suspect a lot would probably have subclinical cardiovascular disease if we went to look for it.

                                                Nevertheless, I think it will extend the guidelines in the sense that physicians are not only going to be potentially using these drugs in people with existing cardiovascular disease but also patients like those in CREDENCE with chronic kidney disease or a very high risk of cardiovascular disease without having had an event. So I think that's also very reassuring as well and exciting. And I think also the benefits of kidney outcomes is, as we said beautifully, that this is a game changer. Over the last few decades we've not really had any major trials to excite the renal community. But now we have. This trial extends the promise that we saw in the three previous trials and takes it a bit further, that these drugs have substantial and meaningful benefits in prevention of important kidney outcomes in our patients with diabetes. It looks like those benefits appear across the spectrum of diabetes. Whether they've existing disease, chronic kidney disease, or even a primary prevention when previous colleagues looked at it in a meta-analysis.

                                                So, I think that's exceptionally exciting and I think, therefore, given the profile of these drugs and as we're improving our safety in the sense we're able to use these drugs better in groups and also advise how to reduce side effects. I think really they're changing the paradigm of how we care for many of our patients with diabetes and I'd be interested to see what Dr Mahaffey thinks about those comments. My sense is this is really exciting.

Dr Greg Hundley:             Ken, any thoughts?

Dr Kenneth Mahaffey:   I think it was nicely articulated, some of the important observations here. I do agree that the patient population here that has chronic kidney disease but no known atherosclerotic disease and therefore primary prevention, it had higher risk. The event rates in CREDENCE were much higher than event rates in the CANVAS trial where the mean eGFR was much higher and so I agree that these patients may have some subclinical atherosclerotic disease, but they are clearly at higher risk of developing it.

Dr Naveed Sattar:            Again, this would be interesting to take Ken's take. But if people have chronic kidney disease, they are, in a sense, revealing themselves to have evidence of end organ damage or be at the level of the kidney but not necessarily the heart. So my sense is there's still people with evidence of disease and it's just that we're seeing it in a different way. I don't know what Ken thinks about that as a kind of interpretation.

Dr Kenneth Mahaffey:   Again, I think they're at high risk and we know that people who have kidney disease often are at higher risk of having cardiovascular disease during their lifetime and where we are in the spectrum of those new disease processes. We don't necessarily have the data in CREDENCE to understand that at a very granular level, but I think it's an important area that we need to evaluate sooner and it raises that issue of treatment for primary prevention should occur earlier and what we're seeing now is that when people develop type 2 diabetes and we notice that they have chronic kidney disease with microalbuminuria, that is the time to intervene, intervene soon. We now have a single therapy that's safe and effective and reduces the metabolic derangements with improved glucose control, improved blood pressure control, improved weight. It also has an important impact on the renal outcomes and important impact on cardiovascular outcome. So it's really a trifecta from a single therapy that can be prescribed easily.

Dr Naveed Sattar:            I agree. And all those means of treatments were very, very favorable as well across the board, which I think is also important.

Dr Greg Hundley:             So, Ken, what are some key clinical aspects related to your study that you feel we need to address?

Dr Kenneth Mahaffey:   What we need to think about carefully is we now have a new therapy. These types of patients are actually seen by a whole host of clinicians in our healthcare systems, at least in the United States. They're seen by diabetologists, cardiologists, nephrologists, and primary care. And we need to think of ways that we can educate all four of those groups of clinicians about these important data and provide learning and other mechanisms to integrate these therapies into clinical care. It's a message I've been trying to get out.

Dr Greg Hundley:             Well, listeners, what a great discussion between Ken and Naveed on this very important topic, the emergence of SGLT2 inhibitors and the results of these primary and secondary cardiovascular prevention group analyses from CREDENCE.

                                                We want to thank each of you for listening with us this week. Carolyn and I look forward to talking with you next week. Take care now.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Aug 19, 2019

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

Dr Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

                                                Well, Carolyn, this week's feature is from Professor Carl Lindstrom from Helsinki University Hospital and the University of Helsinki and evaluates whether administration of simvastatin via nasogastric tube in brain-dead individuals prior to cardiac transplant donation improves transplant recipient cardiac-related outcomes. It is a randomized trial using an inexpensive therapy, and I look forward to that discussion with Professor Lindstrom. How about we grab a cup of coffee and start off our discussion today.

Dr Carolyn Lam:                All right, so here goes. The first paper that I want to discuss really looks at the question, is DNA methylation related to incident coronary heart disease? Well, Dr Agha from Columbia University in New York and colleagues looked at this and profiled epigenome-wide blood leukocyte DNA methylation in 11,461 individuals from nine population-based cohorts in the United States and Europe using the Illumina Infinium 450K microarray and prospectively ascertained coronary heart disease events.

Dr Gregory Hundley:       So Carolyn, what did they find?

Dr Carolyn Lam:                Well, they found that differences in blood leukocyte DNA methylation at 52 cytosine phosphate guanine sites were associated with incident coronary heart disease or myocardial infarction with a false discovery rate of less than 0.05. Several of the differentially methylated loci mapped to genes related to calcium regulation and kidney function. Exploratory analyses with Mendelian randomization supported a causal effect of DNA methylation on incident coronary heart disease at loci in active regulatory regions with links to noncoding, RNAs and genes involved in cellular and tissue structural components.

                                                Very nice Caroline. So what's the summary for us clinically?

Dr Gregory Hundley:       So, these findings really provide the first evidence that genomic regulation via epigenetic modifications in kidney function and calcium homeostasis related pathways may be involved in the development of coronary heart disease. The findings of epigenetic, loci related non-coding RNAs highlight pathways that have not immersed in genome-wide studies of coronary heart disease and therefore represent novel therapeutic targets, which thus far have not been explored.

Dr Carolyn Lam:                Very good, Caroline. Well, I've got a basic paper that I want to present and it's from professor Xander Wehrens from the Baylor College of Medicine. And this study addresses factors that promote atrial fibrillation. The investigators found that reduced levels of protein phosphatase-1 regulatory subunit R3A in human atria are causally linked to abnormal calcium handling and atrial fibrillation pathogenesis.

                                                In the absence of protein phosphatase-1 regulatory subunit R3A reducing binding of PP1 catalytic subunit increases phosphorylation levels of the ryanodine receptor, R2 calcium release channel, and phospholamban. Complex zone, profiling, a technique that combines native gel electrophoresis with mass spectrometry to obtain the composition of multi protein assemblies revealed that PP1 R3A is part of a macro molecular protein complex containing the ryanodine calcium release channel and the circuit 2APLN calcium uptake transporter.

Dr Gregory Hundley:       Wow. Complex zone profiling. That's so cool, but what does it all mean for us clinically, Greg?

Dr Carolyn Lam:                Well reduced levels of PP1 regulatory subunit contribute to abnormal calcium release and re-uptake and atrial monocytes, thereby promoting atrial fibrillation pathogenesis. And thus normalizing levels of PP1R3A phosphatase sub unit may represent a novel therapeutic approach to manage atrial fibrillation.

Dr Gregory Hundley:       That's so cool. I next have a preclinical paper which contributes really to the understanding of molecular basis of pathological myocardial remodeling in heart failure. And this is from co-corresponding authors, doctors, Jung, Liu, and Lin-Jung from Shanghai East Hospital Tongji University School of Medicine in China. And the paper really focused on Forkhead box transcription factor P1 or Foxp1 in endothelial cells.

Dr Carolyn Lam:                So Foxp1 Carolyn, tell me a little bit more about that.

Dr Gregory Hundley:       Is it good that you asked before I asked you. Forkhead box proteins P or Foxp are large modular transcription repressors that bind to DNA via their highly conserved Forkhead DNA binding domains. Fox p1 is highly expressed in vascular endothelial cells and it's essential for normal cardiac development.

                                                So, these authors found significantly down regulated Fox P1 expression in cardiac endothelial cells during cardiac remodeling induced by to angiotensin 2. Endothelial cell Fox P1 loss of function resulted in cardiac dysfunction following angiotensin 2 infusion and in the transverse aortic constriction model with severe cardiac fibrosis and mild adaptive cardiac hypertrophy.

                                                Whereas endothelial cell Foxp1 gain of function protected against pathological cardiac remodeling and improved cardiac dysfunction transforming growth factor beta 1 signals were identified as Foxp1 direct target genes in endothelial cells which mediated the pathological cardiac fibrosis through cardiac fibroblasts proliferation and myofibroblast formation and maladaptive cardiac hypertrophy through TGF beta 1 promoted endothelial one expression during pathological cardiac remodeling.

Dr Carolyn Lam:                Wow. Carolyn, this was very sophisticated work. What do we take away from it clinically?

Dr Gregory Hundley:       These data really identified endothelial Foxp1 mediated TGF beta 1 signal pathway involvement in the promotion of cardiac fibrosis and cardiac hypertrophy via TGF beta 1 induction of the endothelin one pathway. So targeted delivery of TGF beta 1 silencing RNA or small interfering RNA to inhibit endothelial cell specific TGF beta 1 for the improvement of pathological cardiac remodeling may actually represent a future novel therapeutic strategy in managing this maladaptive cardiac fibrosis and hypertrophy during progression of heart failure.

Dr Carolyn Lam:                That was an excellent summary of a very technical but informative basic science paper. I'm going to shift gears a little bit and talk a little bit about a study relating to clopidogrel and aspirin from the point study.

                                                This study comes from Claiborne Johnston at the Dell Medical School and University of Texas. And in patients with acute minor ischemic stroke or high risk transient ischemic attack enrolled in the point trial. The combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. This current paper is a secondary analysis of Point and involves 4,881 subjects in which the investigators assess the time course for benefit and risk from the combination of clopidogrel and aspirin.

                                                The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction or ischemic vascular death, and the primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left truncated models.

Dr Gregory Hundley:       So, what did the study show Greg?

Dr Carolyn Lam:                Well through 90 days, the rate of major ischemic events was initially high, then decreased markedly while the rate of major hemorrhage remained low but stayed constant throughout the study. Using a model based approach the optimal change point for major ischemic events was 21 days with a hazard ratio of 0.65 for clopidogrel aspirin versus aspirin at a P value of 0.0015 compared to later at 22 to 90 days. Where that hazard ratio was 1.38 and the P value only 0.24.

                                                And the models showed benefits of clopidogrel aspirin for treatment delayed as long as three days after symptom onset. So Carolyn, the authors conclude that the benefit of clopidogrel aspirin occurs predominantly within the first 21 days and outweighs the low but ongoing risk of major hemorrhage. When considered with the results of the CHANCE study, a similar trial treating with clopidogrel aspirin for 21 days and showing no increase in major hemorrhage. The combined results suggest limiting clopidogrel aspirin use to 21 days may maximize benefit and reduce risk after TIA or minor ischemic stroke. Very practical paper.

Dr Gregory Hundley:       Indeed. Thanks Greg. That was nice.

Dr Carolyn Lam:                You bet.

Dr Gregory Hundley:       Welcome everyone to our podcast and we're very pleased today to have Dr Antti Nykänen from Helsinki University in Finland as well as an associate editor, Justin Ezekowitz from Edmonton, Canada to discuss a very interesting randomized clinical trial related to the administration of simvastatin in those that are donors for heart transplantation and looking at subsequent outcomes in the patients that received the transplants. Antti, we're very excited for you to bring this to circulation. This particular paper and I wonder if you might outline for us what were your hypotheses that you are trying to test and what was your overall study design.

Dr Antti Nykänen:            These things are routinely admitted to heart transplant recipients starting one to two days after transplantation. As previous clinical studies show that recipient that treatment has beneficial long-term effects on mortality and cardiac allograft vasculopathy. So in this clinical study, we basically tried to answer the question whether having the statin effect on the board even earlier before the transplant procurement by giving statins to the organ donor, if that would protect the transplanted hearts.

                                                And this question was based potential rapid vascular and cardioprotective effects of statin and when our previous experimental study showing that treating the organ donor with statins will decreases vascular profusion injury in a heart transplant model. So basically we went on the test donor simvastatin clinically and randomize brain dead heart transplant donors either to a control group or to receive a signal 80 milligram dose of simvastatin before organ procurement.

Dr Gregory Hundley:       I'm imagining that you would administer the simvastatin through either an intravenous mechanism or perhaps an NG tube, something like that. Maybe tell us a little bit about how you accomplish this and then what were your study results?

Dr Antti Nykänen:            So, the simvastatin was administered to the donor via a nasogastric tube so there is no intravenous simvastatin formulation available. It needs to be absorbed and then activated through the liver so that can form. So, what we did in our previous experimental study was that we included a few clinical human brain-dead donors and basically investigated whether by giving simvastatin through the nasogastric tube would be metabolized and if you could detect that in in the donor plasma.

                                                And that was actually the case. So in a few hours we saw up-regulated levels of simvastatin and also the active form in the donor or so basically showing off that treatment in a clinical brain dead donor of situation would be feasible. So we went on to use that method, clinical study and basically our primary outcome was plasma levels of cardiac injury biomarkers after transplantation.

                                                And interestingly by treating the donor with simvastatin decreased and recipients for troponin INT levels six hours after transplant's profusion. Therefore, it seems that organ donor’s statin treatment reduces biomarkers of myocardial injury after transplantation in a clinical setting.

Dr Gregory Hundley:       And did you examine any other functional measures of these patients? For example, ejection fraction by echo or anything, or was it primarily a biomarker study? That's the first question. Second question. Do you have any other information on other organs that also may have been donated? Would the statin have impacted, for example, liver transplantation?

Dr Antti Nykänen:            That's a good question. So we did follow up cardiac function and the routine and serial measurements with the echocardiographic and we did not find any changes in the left ventricle. It took some traction after transplantation.

                                                We did however find the decrease in proBNP levels into recipients. And that was maybe then at one week after transplantation and then it's leveled out after that.

                                                And then regarding the next question about other transplanted organs. So once he was in a multi organ donor situation, so the same donor could have donated kidneys or livers, lungs, pancreas. So we did a follow up of the close recipients also. And I can say that there was no adverse effects, no decline in the survival or primary function of the transplanted organs. And interestingly we did find in the liver recipient that if the recipient received the liver from a donor simvastatin treated the liver function tests were better at day seven post-transplant.

Dr Gregory Hundley:       Very interesting. And then lastly, just another outcome related question. Sometimes I know these patients undergo assessments for rejection by biopsy. Any information that you can share with us on outcomes related to biopsies.

Dr Antti Nykänen:            We took routine biopsies, myocardial biopsies from the recipients and we did not find any significant differences in the biopsy program rejections either at 30 days or one year after transplantation. We did also monitor, we checked some treatments, so during the first 30 days there was significant decrease in the amount of rejection treatments for hemodynamically rejects it about not for the first year.

Dr Carolyn Lam:                Wow. Just fabulous results. Thank you so much Antti. So Justin, I wanted to turn the conversation over toward you. Tell us about post-transplant management of these patients and then how do you see these study results integrating into our current standards of care.

Dr Justin Ezekowitz:        Thanks Greg and Dr Nykänen and thanks for also letting us look at your work, which is terrific and extremely hard to do from the translation of your original 2011 circulation publication in animals and moving forward into the current publication years later. And thinking forward into the next few years of how we translate this into practice so that the current management after transplantation obviously involve multiple anti-rejection medications and many activities around detecting rejection is one of the key ways in which patients are managed other than their hemodynamics and other things that happen early.

                                                What I was interested in is the generation of the idea where the simvastatin will really affect the clinical outcomes on the recipient and thinking that into the practice environment is, it's a very simple intervention to think about that would be easily applicable in, I think, most hospitals that do transplantation as either the recipient or the donor.

                                                And Dr Nykänen, when you think about translating this into practice over either Europe or in Finland, I don't sense that this is going to be very difficult. Statins are well tolerated. The cardiology and other communities are very familiar with using a statin. But do you anticipate any barriers to translating this into practice as I think the guidelines may pick this up as something of interest.

Dr Antti Nykänen:            Yes, I think we can show that it's feasible and we did a result on the biomarkers, so indicating that the damage the heart undergoes during the transplantation was smaller after donor statin treatment, so it is feasible, it's very cheap and it generally has a good safety profile. The timeframe for the treatment also feeds into the window of creating a brain dead organ donor. So in that sense it would be applicable in a donor treatment situation.

Dr Justin Ezekowitz:        Right. And so I think this is the key point is even though it's a smaller trial in terms of the cardiology thinks about its trials. This is an area that doesn't have a lot of clinical trials were randomized clinical trials and so any evidence of benefit with a known, generally considered safe medication such as a statin, you would think that we should be able to broadly apply pretty quickly even on what are often not hard outcomes that are softer outcomes.

                                                Because the benefit to risk ratio is generally favorable here. Dr Nykänen, my only other question to you is to think about the team getting this done must have been incredibly hard, but do you think there is a need for a larger trial to test this hypothesis on clinical outcomes or do you think this is really as far as you can go in the transplant world for an RCT.

Dr Antti Nykänen:            So, it's been a long road from artery to single center clinical trial, which took time, so the patient numbers are fairly small in our study. We had 42 in the control group on 42 in the treatment group. I agree the risk benefit ratio is probably beneficial. But for sure it would be very nice to see larger studies that would look at the biomarker effects, but also would look at the other clinical end points.

Dr Justin Ezekowitz:        Right, and that's a great point. It's only 84 patients, but a continued study of the area's important while perhaps implementation studies could go on to take what you found in both an animal translation into humans in a single center RCT and now translation into a larger population of recipients and their donors. I think that's probably the key next step in the transplantation world which has a tougher time getting larger number of patients into clinical trials for a variety of reasons.

                                                So, congratulations to you and your team in getting this one to the point where we could probably apply this in a reasonable way with reasonable safety and an expected benefit to a broader group of patients.

Dr Gregory Hundley:       Well this has been a fascinating discussion, Antti as well as Justin and what a relatively simple, clever idea that could have profound outcomes for this transplant population. We certainly want to thank you Antti for bringing this to circulation and sharing it with our readership. Are there any few last words you'd like to share with us before we close today?

Dr Antti Nykänen:            Very nice to see how things evolve after this. We will for sure try to look more closely at the mechanisms and follow up the patient population for a long term follow up. And I hope this will stimulate some other experiments in the field.

Dr Gregory Hundley:       Justin, any parting comments from the editorial team?

Dr Justin Ezekowitz:        This is a great example of a full clinical trial that is mechanistic, but also has MR outcomes, and I just want to congratulate the authors on providing a very full picture of all the pieces that it takes to do in a clinical trial environment. Plus also collecting genetic and other biomarker material and imaging material. So, my compliments to the authors both to yourself, Dr Nykänen, but also the team that you assembled over the last six or eight years of doing this project, which we know was a huge task and my congratulations to you and your team.

Dr Gregory Hundley:       We want to thank Dr Nykänen and his team from Finland and Justin Ezekowitz. We look forward to chatting with you next week.

Dr Carolyn Lam:                This program is copyright American Heart Association, 2019

Aug 12, 2019

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

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia. Carolyn, oh, this is going to be an exciting featured article today, and we're going to discuss the combination of agents or their administration et al that are best suited for managing both anticoagulation and antiplatelet therapy and those with coronary disease, peripheral arterial disease and heart failure. And, we'll speak with Dr Kelley Branch from the University of Washington.

Dr Carolyn Lam:                And me!

Dr Greg Hundley:             Yes. How am I going to interview you? And, we'll discuss the utility of Rivaroxaban with or without aspirin in patients with heart failure or peripheral arterial disease from the compass trial.

Dr Carolyn Lam:                Well, I'm not going to let you get there until I tell you about this first basic paper I've chosen because it focuses on the unfolded protein response.

Dr Greg Hundley:             What's that?

Dr Carolyn Lam:                Well, Greg, I was really hoping you'd ask. The unfolded protein response is a cellular adaptive process to cope with protein folding stress. Now, approximately 40% of human proteins are predicted to be either transmembrane or secretory. The synthesis, the folding, the cellular transportation and location of these proteins rely on proper functioning of this secretory pathway. Numerous studies have established that the unfolded protein response plays versatile roles during development and under physiologic and pathophysiologic conditions. However, the role of this unfolded protein response in the regulation of cardiomyocyte growth is unclear.

Dr Greg Hundley:             That's fantastic, Carolyn. I've already learned something here. So, what did this paper show?

Dr Carolyn Lam:                This is from Dr Wang and colleagues from UT Southwestern, and basically, they use both gain and loss of function approaches to genetically manipulate spliced X-box binding protein one or XBP1, which is the most conserved signaling branch of the unfolded protein response in the heart. In addition, primary cardiomyocyte cultures were employed to address the role of XBP1S in cell growth in a cell autonomous manner. They found that XBP1S expression was reduced in both human and Rhode and cardiac tissues with heart failure deficiency of XBP1S lead to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac restricted over expression of XBP1S prevented the development of cardiac dysfunction. Mechanistically, they found that XBP1S stimulated adaptive cardiac growth, your activation of mechanistic target of rapamycin or MTOR signaling which is mediated via the FK-506 binding protein 11, which is a novel transcriptional target of XBP1S. So in conclusion, this study really showed a critical role of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in coupling the unfolded protein response and cardiac cell growth regulation.

Dr Greg Hundley:             Boy Carolyn, you explained that so well, and I learned a lot from that. I hope I can do as well with this next article from Professor Johann Backs from the University of Heidelberg. Now paradoxically, some glucose lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling, and this study from his group focused on one of the class two histone deacetylases or HDAC's namely HDAC-4, which functions as an important epigenetic regulator by responding to upstream stress signals, and linking them to downstream gene regulatory programs involved in among other things, metabolic regulation.

Dr Carolyn Lam:                Very interesting. So what did they find?

Dr Greg Hundley:             What they found is that HDAC4 acts as an important maintenance factor of cardiac function in diabetes and O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the production of cardio-protective HDAC F-end terminal fragment and attenuates cardio detrimental Cam kinase two mediated phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase two mediated phosphorylation of HDAC4 at searing 632 attenuates HDAC-4 n terminal production. Thus, these findings lay the ground for the development of novel therapeutic strategies for diabetic patients with heart failure by inhibiting Cam kinase phosphorylation at CIHR 632 or enhancing o-glycine and escalation at searing 642.

Dr Carolyn Lam:                Fascinating, Greg. Well, my next paper is a subgroup analysis of EUCLID and is the first to assess acute limb ischemia in the context of a large-scale clinical trial studying a primary peripheral artery disease population.

Dr Greg Hundley:             So Carolyn, reminded us what was the EUCLID trial.

Dr Carolyn Lam:                Okay, so EUCLID stands for Examining Use of Ticagrelor in Peripheral Artery Disease, and this was a randomized clinical trial that included acute limb ischemia as an adjudicated outcome in a primary peripheral artery disease population randomized to ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not superior to Clopidogrel for the prevention of cardiovascular events in patients with stable peripheral artery disease. However, a EUCLID subgroup analysis of patients with and without prior limb revascularization demonstrated significantly higher risk for acute limb ischemia hospitalization in patients with prior low extremity revascularization.

Dr Greg Hundley:             So Carolyn, that's interesting. So, what did they find related in this study that focused on the acute limb ischemia?

Dr Carolyn Lam:                Right. So, today's paper is from Dr Hess and colleagues at University of Colorado School of Medicine and CPC, clinical research in Aurora, Colorado. And, they found that acute limb ischemia occurred in 1.7% of almost 13,900 randomized patients with a median time to hospitalization for acute limb Ischemia of 320 days after randomization. In this population, prior lower extremity revascularization, atrial fibrillation and lower ankle brachial index identified patients at higher risk for acute limb ischemia. Hospitalization for acute limb ischemia was associated with subsequent cardiovascular and limb ischemic events. So, the take home message is providers should monitor for signs and symptoms of acute limb ischemia in patients with stable symptomatic peripheral artery disease, particularly those with prior lower extremity revascularization, atrial fibrillation, and lower ankle brachial index.

Dr Greg Hundley:             That's very instructive, Carolyn. Fantastic message. So, I'm going to ask you if you could select one lipid biomarker to forecast future adverse cardiovascular events, which would you select? Total cholesterol, HTLC, non-HTLC, direct and calculated LDLC, APO-A1, or APO-B?

Dr Carolyn Lam:                Well, I'm traditional. I would have chosen LDL.

Dr Greg Hundley:             Okay. Well, the authors of this study led by Dr Paul Welsh at the University of Glasgow attempted to answer this question by studying participants from the UK Biobank without baseline cardiovascular disease and not taking statins with relevant lipid measurements. They had 346,686 participants. An incident fatal or nonfatal cardiovascular event occurred in 6,200 participants of which 1,656 were fatal, and they occurred over a median time of 8.9 years. So, the associations of non-fasting lipid measurements, total cholesterol, HDLC, non HDLC, direct and calculated LDLC, APO-a1, and APO-B with cardiovascular disease were compared using Cox models, adjusting for classical risk factors and predictive utility was determined by the C-index and net reclassification index. Also, prediction was tested in 68,649 participants taking a statin with or without baseline cardiovascular disease, and that group experienced 3,515 cardiovascular events.

Dr Carolyn Lam:                Okay, so drum roll. What did they find?

Dr Greg Hundley:             So, measurement of total cholesterol and HDLC in the non-fasted state is sufficient or was sufficient to capture the lipid associated risk in the cardiovascular disease prediction with no meaningful improvement from addition of APO lipoproteins, direct or calculated LDLC. And, similar findings were reproduced in those taking a statin at baseline.

                                                As such, the authors feel like calls for widespread use of APO lipoproteins are not warranted given the negligible difference in risk prediction beyond total cholesterol in HDLC. And, direct LDLC is also not required for risk prediction. Non HDLC is a cheaper or equivalent predictor of risk on and off statins without the requirement of one of us being fasting. This is an excellent article for our listeners to review or download.

Dr Carolyn Lam:                Wow, that is so cool. So, from one excellent paper to another excellent paper in our feature discussion. Let's go, shall we?

Dr Greg Hundley:             Welcome everyone to discussion of our featured article. We have Dr Kelley Branch from the University of Washington and our own Carolyn Lam, and they're going to be discussing the compass trial. So Kelley, could you tell us a little bit about the rationale for compass as opposed to the previously published commander study?

Dr Kelley Branch:              So, in order to understand compass and compare it to commanders, we're going to have to go back a little bit in time here. And recall, you know well over 20 years ago that when we used anticoagulants in coronary artery disease, that was actually shown to be more beneficial than aspirin alone, but because of the excess bleeding risk, warfarin or vitamin K antagonists not used, and aspirin won. Fast forward a number of years, and now we have the non-vitamin K anticoagulants, and the was potentially that we could find the goldilocks, if you will, the good balance of benefit as well as less bleeding maybe used to these new agents. So, the compass trial was really born from an atlas ACS one and Atlas ACS two, which found that a low dose of, in this case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams VAB were shown to be beneficial in patients after acute coronary syndrome.

                                                And then, it was thought what happens if we treat these patients with now chronic coronary disease as well as arterial disease? And from this 27,000 patients, 47,395 patients were tested, and our study very specifically looked at patients with a baseline or a history of heart failure when they answered compass. Compass were shown to be beneficial with specifically the use of aspirin plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test this in patients with this baseline or history of heart failure. Now, this is in real contradistinction to what the commander tried to do. And the reason why encompass, we actually excluded patients with severe heart failure. This was defined as a New York Heart Association class three or four or an ejection fraction less than 30%. Now if you looked at patients with commander, these patients had ejection fraction less than 40%. That was a criteria to get in. And of course, these patients had to have a recent hospitalization for heart failure. So, these are very different patient populations. Well, both of them, yes, they did have coronary artery disease, but really very different patient populations.

Dr Greg Hundley:             Very good. So Kelley, tell us specifically, what were your treatment group assignments and the doses and the outcomes that you were going to follow, and then lead us into what did you find? What were the outcomes of your study?

Dr Kelley Branch:              Sure, so compass was actually developed as a partial three by two factorial. The arm that we're going to be talking about is the rivaroxaban arm. There was also another arm that tested the use of Proton pump inhibitors, and that actually was shown to not be as beneficial as we thought to decreased bleeding. But specifically for rivaroxaban, the baseline was aspirin, and this was on top of guideline based medical therapy. And then patients were randomized to either aspirin alone plus placebo or Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5 milligrams BAD. Those were really the three treatments. Patients were going to be followed for about three to four years. That's what we expected to get our 2200 events , an event-driven trial. But, because of the overwhelming benefits at 23 months median follow up, this trial was actually stopped early, so we only had a little over 1300 events at that time.

                                                And with that we saw substantial reduction in major adverse cardiovascular events, about 24% mortality was reduced 18%, and there was a bleeding risk along with this, major bleeding, little different way of actually measuring major bleeding, but that was increased by about 70%, and that was the overall trial results. So, looking at the patients with heart failure, though, there was actually a relatively large proportion of patients, so 5,902 patients, about 22% of patients, actually had either baseline heart failure or had a history of heart failure coming in. Now, this was defined specifically by the PI's. These were not rigorously defined as compared to say commander, but these were patients where the PI said this patient has history or has chronic heart failure. So, with these 5,902 patients, we looked specifically at the outcomes of major adverse cardiovascular events similar to what we saw with compass and that is cardiovascular death, myocardial infarction, or any stroke, that combination. And then, looked at some others exploratory analysis like mortality.

                                                And, what we found is that in patients with heart failure, the baseline rate was substantially higher for a mate's. Not too surprising because this tends to be a higher risk patient population. But, what we found is that the hazard ratio was about 0.68, so pretty similar to what we've seen the 24% relative risk. In this case, this was a 32% relative risk reduction in those patients with heart failure. Now, if we looked at a patients without heart failure, the hazard ratio is 0.79, so fairly similar and the [conference intervals 00:16:33] overlap. No statistical heterogeneity or no difference between those, but what we did see if we looked at the absolute risk reduction, was an absolute risk reduction in heart failure of 2.4% reduction. That means a number needed to treat of about 42. If you look at the absolute risk reduction for those patients without heart failure, that was 0.9 to 1.0 depending on what the rounding was. We took 1.0 so that means the number needed to treat of 103. So, these were slightly different relative risks, but overall, what we saw is that the hazard ratio is very consistent with the overall effect of compass in the same direction.

                                                Interestingly, and actually I think even for me it was surprisingly, we actually looked at the hazard ratios for bleeding, and when we looked at the hazard ratios for bleeding, we fully expected that because it's the higher risk patient population, we actually expected that to go up. What we saw is that the bleeding actually was no difference at all, and if anything in the heart failure population was slightly lower. And, this was fairly surprising to us because we thought that the patients with heart failure, the bleeding would actually trend up because this was a higher risk patient population. So it looks like it's something can be used and really no substantial increase in bleeding.

Dr Greg Hundley:             Very good. Well Carolyn, as someone that's managing patients with heart failure, what do you see are the clinical implications of this study?

Dr Carolyn Lam:                That is a beautifully simple, direct question but is not as easy to answer as I may have thought. And, that's because the commander trial that Kelley did describe a bit earlier was neutral on its primary outcome. And, the commander trial is what we would traditionally think of as a heart failure trial. And why? Because those were patients that we rigorously define heart failure, including a naturally acid peptide inclusion criteria. And, because we really wanted these to be severe heart failure patients, we recruited them very close to their hospitalization or decompensation event. So, I just want to reiterate what Kelley has already so beautifully described that commander was neutral, whereas this heart failure subset of compass showed very impressive results that were consistent with the very impressive positive results of the overall compass trial.

                                                So, how do we reconcile all of it? Well, first of all, I have to humbly remind myself that this heart failure subset of compass, the entire subset was actually bigger in numbers than the entire of the commander trials. So, this is not a small little subgroup analysis. This is a huge subgroup analysis. And that's why a paper like this, we're so proud to be publishing in circulation.

                                                So, how do I apply it? Well, when I have a compass like patient, which means it's a stable coronary artery disease or peripheral artery disease patient who happens to have some mild heart failure. I think of this patient as a compass patient and I think that the combination of aspirin and low dose Rivaroxaban has been shown to be effective in these patients. So, in such a patient, I continue the aspirin rivaroxaban combination. However, if I have a new patient coming in with decompensated heart failure, a very low ejection fraction and has some coronary artery disease, by the way, I see that as a commander patient, and I just want to make sure that in such a patient I'm not trying to reduce their overall mortality by treating them with a combination of aspirin Rivaroxaban because commander has shown that I don't impact their overall survival with this combination, even though we may still have beneficial effects on their thromboembolic thrombotic events.

                                                Kelley, would you agree?

Dr Kelley Branch:              I would completely agree. That was actually born out very, very well by Barry Greenberg who had a really a wonderful sub analysis which he looked at the thrombotic events published in Jama cardiology and really showing that yes, you can affect the thrombotic events, but I mean really what it comes down to is we want to save lives. We want people to be better. There's just an overwhelming risk for these patients with heart failure that is really non thrombotic, primarily. And so, you're really not going to move the needle very much. You may prevent a stroke here, you may prevent some cardiovascular death from a thrombotic problem, but overwhelmingly pump failure, arrhythmia, et cetera. Those are really going to be the drivers for the commander like population.

Dr Carolyn Lam:                But Kelley, this comes up a lot when we've chatted, but if you have a compass patient who has heart failure and then gets admitted with heart failure, what would you do then?

Dr Kelley Branch:              That's a really interesting question, right? It depends on what the overall goal is. So, if the patient gets admitted for heart failure, now has it decreased ejection fraction sick. So has an MI, now decreased the ejection fraction. What's the end game? Right? Well you know, you may not be affecting mortality in this case because there's now competing events. However, if the goal was to decrease stroke, we've seen that. Still this goal is to decrease MI to some extent than we see that also. So, it would be reasonable to continue in order to prevent those events. But, just knowing full well that there's many other medications which actually do much better for the patients with decreased ejection fraction. And, those would probably be considered first line, but it's reasonable to continue. But, I would never start it.

Dr Carolyn Lam:                Kelley, I couldn't agree more. And here I think the, your data showing that the bleeding risk is not significantly increased in this patient matters a lot. So, if I had a patient, a compass patient who was already on the combination and then gets admitted with heart failure, I too, if there's no additional bleeding risk, I would continue the combination as well.

Dr Kelley Branch:              Couldn't agree more.

Dr Greg Hundley:             Well listeners, this was a fantastic discussion, and we look forward to seeing you next week. Have a great week.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Aug 5, 2019

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

Dr Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Our feature article today really invokes thought regarding LVAD bridging to heart transplantation. I really look forward to the conversation with Dr Veli Topkara from Columbia University, the corresponding author and our associate editor, Dr Mark Drazner from UT Southwestern. And it's regarding the outcomes from their study, evaluating patients waiting for transplant that are bridged with an LVAD versus not. But before we get to that, let's dive into some of our other original articles with our little coffee chat. Do you have an article that you'd like to discuss?

Dr Carolyn Lam:                You bet I do Greg and I have my coffee here. Have you ever wondered, does microvascular disease, in any location in the body, increase the risk of lower limb amputation? Well, this was looked at in the paper that I chose first today. It's from Dr Beckman from Vanderbilt University Medical Center in Tennessee and his colleagues, and they basically examined 125,674 participants in the Veterans Aging Cohort Study from 2003 to 2014 and analyzed the effect of prevalent microvascular disease defined as retinopathy, neuropathy and nephropathy and peripheral artery disease status on the risk of incident amputation events, of which there were 1,185 amputations over a median of 9.3 years.

Dr Gregory Hundley:       Wow, Carolyn. What did this study find? What did Josh and his colleagues find?

Dr Carolyn Lam:                They found that the presence of microvascular disease increases the risk of amputation significantly in the absence of peripheral artery disease. As many as one in six below knee amputations may result from microvascular disease, even without peripheral artery disease. Microvascular disease also potentiates the amputation risk in persons with peripheral artery disease to more than 20-fold, compared to persons with neither peripheral artery disease nor microvascular disease. Further research is really needed to understand the mechanisms by which this occurs. And in the meantime, clinicians should bear this increased risk in mind when screening for and managing lower extremity disease.

Dr Gregory Hundley:       Ah. Well Carolyn, my first paper is somewhat related because we're going to talk about triglycerides. And this paper is from Zahid Ahmad from UT Southwestern Medical Center. He's the corresponding author. And can you imagine Carolyn an antibody that could correct elevations in serum triglycerides?

Dr Carolyn Lam:                Tell us about it, Greg.

Dr Gregory Hundley:       Well, I'm going to give you a little background first. Low levels of triglycerides and other lipids are observed in individuals with loss of function mutations in angiopoietin-like protein 3 which inhibits lipoprotein lipase activity, increasing triglycerides and other lipids, and providing a rationale for development of a monoclonal antibody therapy.

Dr Carolyn Lam:                Interesting. What did this study do Greg?

Dr Gregory Hundley:       It evaluated evinacumab. They looked at the safety of this. This is a fully human angiopoietin-like protein 3 antibody, and it was compared with placebo, with no serious treatment emergent adverse events, no events related to death or treatment discontinuation was reported. They did two phase one studies evaluating single and multiple ascending doses. In addition, substantial and sustained percent reductions from baseline versus placebo were observed and triglycerides with absolute levels reaching about 50 milligrams per deciliter for several of the evinacumab doses at specific time points in both studies. And therefore, the data from these two phase one studies in this one paper support further clinical evaluation of this new antibody in larger studies of hypertriglyceridemic individuals.

Dr Carolyn Lam:                Definitely a space to look out for. Well Greg, my next paper is a basic paper. Genome wide association studies have identified chromosome 14 Q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterized gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the function of this gene and its role in atherosclerosis has previously been unknown, well, until today's paper. But Greg, here's your quiz. What do you know about the hedgehog proteins?

Dr Gregory Hundley:       Well, I know hedgehogs are friendly little animals and I know they must have great proteins because they're so friendly.

Dr Carolyn Lam:                Why did I expect that? Oh, let me tell you a little bit about them. The mammalian hedgehog proteins like sonic hedgehog, desert hedgehog, and Indian hedgehog are secreted molecules that exert a concentration and time dependent effect on target cells following binding and complex signal transduction pathways. They induce the transcription of target genes, primarily involved in cell proliferation, survival, and fate specification.

                                                Now in adults, the hedgehog signaling is involved in the maintenance of adult vasculature and ischemia induced neovascularization, including after myocardial infarction. Today's authors, however, including Tom Webb from University of Leicester and colleagues, report the first experimental investigation of HHIPL1 and the present evidence that it is a secreted proatherogenic protein that regulates smooth muscle cell proliferation and migration. So, that's novel.

                                                Through a series of experiments involving coronary artery disease, relevant human cells and mouse models, they showed that HHIPL1 is a secreted protein that interacts with sonic hedgehog and is a positive regulator of hedgehog signaling. In murine models, HHIPL1 deficiency attenuates the development of atherosclerosis by reducing smooth muscle cell proliferation and migration. The clinical implications are two-fold. First, this study supports HHIPL1 as the causal gene at that 14 Q32 coronary artery disease locus that we did not really understand previously. And secondly, HHIPL1 is a promising therapeutic target that affects a pathogenic mechanism not addressed by current mechanisms for coronary artery disease. Room for novel development.

Dr Gregory Hundley:       Very interesting Carolyn. Well, I've got another basic science paper, and this is from Dr Kenneth Walsh at University of Virginia and it's going to look at the role of neutrophils, not necessarily macrophages but neutrophils and their role in pressure overload induced cardiac dysfunction. While the complex roles of macrophages in myocardial injury is widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. This study examined the regulation and function of neutrophils in pressure overload induced cardiac hypertrophy as mice underwent treatment with Ly6G antibody to deplete neutrophils and then subjected them to transverse aortic constriction or TAC.

Dr Carolyn Lam:                Huh? What did they find?

Dr Gregory Hundley        Caroline, the study revealed that neutrophils played a critical role in the hypertrophy of the left ventricle that results from pressure overload in this murine model of heart failure and identified that a non-canonical Wnt protein is essential for the recruitment of neutrophils to the injured myocardium.

Dr Carolyn Lam:                Hmm. What do you think are the clinical implications of this?

Dr Gregory Hundley        This study demonstrates how neutrophils contribute to the hypertrophy of the left ventricle under conditions that do not involve ischemia or myocardial necrosis. Also, since cardiac hypertrophy is a risk factor for the development of heart failure, this study implicates WnT5a mediated neutrophil infiltration as an early step in the progression of this disease.

Dr Carolyn Lam:                Wow, thanks Greg. That was so cool. But let's hurry on to our feature discussion, shall we?

Dr Gregory Hundley        You Bet.

Dr Carolyn Lam:                Bridge to transplant with left ventricular assist devices is a mainstay of therapy for heart failure in patients awaiting heart transplantation. The criteria for heart transplantation listing does not differ between patients medically managed versus mechanically bridged to heart transplant. However, are there differences in post-transplant outcomes between medically managed and mechanically bridged patients? Well, today's paper provides important data to address this question. So pleased to have with us the corresponding author, Dr Veli Topkara from Columbia University Medical Center, New York Presbyterian as well as Dr Mark Drazner, associate editor from UT Southwestern. Welcome gentleman. Veli, this is an important question. Could you please tell us how you addressed it and what you found?

Dr Veli Topkara:                We decided to visit an old question of whether bridging with LVAD confers at risk for post-transplant mortality. Because the field and pump technology has been rapidly changing. There has been a significant increase in utilization of devices nationwide to the extent that more than 50% of patients already have an LVAD in place by the time they receive a heart transplant. And patients also wait much longer on these pumps before they could get a heart.

                                                Currently, available devices provide continuous flow and patients essentially live without a pulse for many months to years waiting for a heart. And with this unique physiology, they also have unique complications such as RV failure and there has also been pre-survey reports including one from our center suggesting an increase in the primary graft failure rates after heart transplant. And mostly seen in patients who were bridge to transplant with an LVAD.

                                                To address some of these questions, we took advantage of the UNOS database, which is the largest prospective transplant data registry in the United States. We were able to identify more than 14,000 patients who are either medically or mechanically bridged to transplant. We then derived a cohort from patients who were LVAD baseline by propensity score and we looked at their outcomes.

                                                And what we found was that patients who were mechanically bridged to transplant with an LVAD, had 9.5% mortality at one year, compared to 7.2% in patients who were medically bridged. And this is more than 30% increase in relative risk of death for LVAD patients. When we looked at the specific cause of death at one year, LVAD patients had a higher number of cardiovascular death secondary to primary graft failure, confirming findings of the recent studies at a larger scale.

                                                Next, we looked at whether mortality risk factors were similar in the mechanical versus medical bridged patients. And this is a very important question clinically because the criteria for transplant listing do not distinguish between the two patient cohorts. For example, at my center age cutoff transplant listing is less than 72 years of age and that is whether or not patients are on VAD support. And same applies for example, GFR cutoff for renal function or PVR cutoff for pulmonary hypertension. And all the cutoffs that are utilized are essentially identical for transplant candidates irrespective of the bridging strategy.

                                                But what we found in this paper, however, what's quite different that if we apply the same thresholds for mechanical versus medical bridged patients, for some of these risk factors, you end up having outcomes that are remarkably different. For example, for patients with a normal renal function, the mortality risk is similar going into transplant with or without an LVAD, but for patients with borderline renal function observed mortality has more than doubled for those going into transplant with an LVAD, as opposed to medical therapy.

                                                And we also observed similar trends for recipient age, BMI and PVR, in which numerical increase in these factors would translate to high risk of mortality in LVAD patients going into heart transplant. Despite the limitations of this large registry analysis, I think these findings suggest that we may need to think of it differently when it comes to listing or transplanting patients who are on LVAD. And there seems to be a group of patients who are perhaps maybe better served by staying on an LVAD as opposed to moving on to heart transplant and we need to better identify who these patients are.

Dr Carolyn Lam:                Oh Wow. Veli, thank you. First, congratulations on a very important paper and also how you beautifully summarized. Mechanically bridging patients associated with a higher risk of early post-transplant mortality and even providing data on the cause and risk factors associated with that mortality. Mark, could I bring you in here? Not just as AE (associate editor), but as a doc[tor] who manages many of these patients. What were your perspectives?

Dr Mark Drazner:             As I step back and as Veli said, there's an increasing number of patients who are being bridged with a VAD, so the question clearly is important, and we don't really have any randomized data available to us in terms of how the bridging strategy may impact outcomes. When you look at the groups of patients who are supported with VADs or not, they're very different and so you need to do some statistical manipulation which here they did propensity matching, to try to come up with equal groups as you look at their outcomes. That was nicely done.

                                                And then theoretically I think you could argue there may be reasons why patients bridged with VADs may do better or they may do worse. They may do better because you may restore their functionality, you may improve renal function and, but they may do worse because they have coagulopathies, the VAD itself may lead to complications and so it's a question you can't really answer just logically. You really need some data which is I think the best study that's been brought forward so far as the one we're discussing today. Veli, let me ask you because the obvious question then is why do you think the outcomes are worse among the patients who are bridged?

Dr Veli Topkara:                I think they are doing worse for multiple different reasons. Having an LVAD is clearly an additional surgery which technically makes the second transplant surgery more complicated. But when we looked at the risk factors for primary graft failure at our institutions, the predictors of primary graft failure in LVAD patients were also very similar to factors we identified in this nationwide analysis which included renal failure, RV dysfunction, as well as trans-transplant and increased time on device support. I think it's clear that some subset of LVAD patients who have these risk factors are at higher risk for increased post-transplant mortality for some of the mechanistic reasons are unclear at this point.

Dr Mark Drazner:             Do you think their continuous flow exposure is part of it?

Dr Veli Topkara:                That's clearly one of the hypotheses that we have been talking about because as we discussed, these patients are exposed to continuous flow for a long time and one of the concerns is whether they lose their peripheral arterial venous-reactivity over time. And this could potentially also be the reason why patients who are on pump support for longer times are at higher risk for PGF. That's a possible underlying mechanism. But in this data set, we didn't have fair data with regards to pulse pressure and pulsatility, which could have helped answering this question.

Dr Mark Drazner:             And just for clarification for the listeners, this was pre-HeartMate 3 data, is that correct?

Dr Veli Topkara:                Yes. This analysis doesn't include any HeartMate 3 patients.

Dr Carolyn Lam:                And Mark, if you don't mind, could you also clarify for the listeners why you specifically pointed out HeartMate 3 in the setting of the pulsatility?

Dr Mark Drazner:             There is some degree of pulsatility reintroduced with the HeartMate 3, whether that has any physiological consequences is not yet known. Certainly, in terms of the impact of transplants. But as Veli said, the dataset available didn't yet include the HeartMate 3 so that's, remains an unanswered question for us currently, but certainly an important one.

Dr Veli Topkara:                We would probably be able to do this analysis now that we have accumulated more patients with HeartMate 3. At the time of the study we didn't have any HeartMate 3 patients in the registry. In terms of primary graft failure, we have implanted over 160 patients with HeartMate 3 at my center, but we still see primary graft failure in HeartMate 3 patients going into heart transplant, but that would clearly be an interesting follow up project.

Dr Mark Drazner:             Yeah, for sure. Another point that people, as they looked at your paper and asked me, is in terms of the impact of the VAD complications, whether the patients who are doing worse or those who, because they are patients who had VAD who have had complications and then went on a transplant and the impact of that, in terms of your findings. I know you did some analyses on that. Could you just clarify that for our listeners as well?

Dr Veli Topkara:                Sure, so we wanted to look at for the LVAD patients, if there were any VAD related factors that would impact the posttransplant mortality and one of the things that we looked at was, their specific complications on LVAD support and were able to pull that data by looking at their reason for 1A upgrade status which clarifies the complication pipe. And when we looked at, based on complication type, we didn't see any impact of complication on the post LVAD mortality. In other words, the other patients who are transplanted with an infection or they were transplanted because of device thrombosis, they did not have any difference in terms of their posttransplant mortality.

                                                We also compared patients who were supported by axial flow devices versus centrifugal flow devices and again, there was no significant difference in terms of posttransplant mortality. One factor that we found that was significant was the duration of the LVAD support and patients who stayed on the LVAD for longer times clearly had increased higher risk of posttransplant mortality. And this is also something that we had found in our institutional data.

Dr Mark Drazner:             And Veli that would potentially speak to the impact of the continuous flow if duration of VAD is a risk factor.

Dr Veli Topkara:                That's our hypothesis Mark. And I think we all tend to think that continuous flow is not natural, and we have pulse style flow for a reason. Now it's possible that if our bodies and end organs and vessels are exposed to continuous flow for a long time, that may be potentially a reason for, increased risk of PGF or raise of PGF after heart transplant. But I don't think we have enough data yet.

Dr Mark Drazner:             Veli, one of the other interesting findings was the lack of impact on long-term outcomes. I'd be interested in your thoughts about that, why there was an impact on the first year but not long term.

Dr Veli Topkara:                Absolutely. And that was a critical part of the findings and when we looked at our survival, when we visually looked at the curve, it seemed like the curves really separated early on and they sort of remain parallel to each other after one year. And for that reason, we did a conditional survival analysis starting from one year and then we compared starting for one year. There was actually no difference between the LVAD versus medical group. Again, confirming that the adverse impact of survival was really early, within the first year after transplant and I think that really has to do with primary graft failure as well as vasoplegia which are, typically seen early posttransplant. And I think the reason the VAD support is increasing mortality is most likely through increasing risk of PGF as well as vasoplegia. Now that's my read on the early risk rather than the late impact.

Dr Mark Drazner:             Do you think that speaks to maybe not as big an impact on the immunological milieu of VADs as one might anticipate?

Dr Veli Topkara:                Certainly, I mean the immunology, one thing we know is that LVAD patients have higher HLA sensitization going into transplant. However, primary graft failure is typically very early after transplant. And in general, we don't find, obviously we don't see any rejection in these patients. The mechanism is not related to HLA mediated rejection.

Dr Mark Drazner:             That's interesting.

Dr Carolyn Lam:                Well Mark and Veli, thanks so much. This is such an important and interesting discussion. Could I wrap it up now by asking each of you, you've already covered possibly the important areas for future research including the pulsatile devices, but what should clinicians take home right now? Veli, if I could start with you, because you had already said earlier that perhaps these patients need to be more carefully considered. What do you mean by that? What's the take home for now?

Dr Veli Topkara:                I think the question is whether we should be listing or transplanting LVAD patients who are high-risk, and I think the research should focus on developing tools to better identify LVAD patients who are too high-risk for transplant. In this project, we only worked with a limited number of variables that were available in the UNOS registry, but there may be more specific clinical risk factors or even biomarkers predicting outcome in this unique cohort of LVAD patients potentially transitioning into transplant. I think that's an important question to figure out.

                                                And another important question is whether we should be using identical cutoffs for listing patients with or without LVAD and if not, what would be the ideal cutoff for each one of these risk factors? Because what I read from this paper is that, a creatinine level of 1.8 may signal a different risk in an LVAD patient versus another patient on a minor trump. That's another important question.

                                                And also, since October of last year, the new heart allocation policy has been in place, which now defines LVAD patients to appear status three or four based on their complication profile. And it will be interesting to see how the new allocation system would impact patients are on LVAD support waiting for an organ. And it's possible that these patients may end up waiting longer compared to patients who are with cardiogenic shock and are assigned to higher tier status. And if LVAD patients wait longer as we see from this data, they will have worse posttransplant outcomes. It's going to be very interesting to see how the new allocation policy impacts.

                                                Another point I want to make is that with the recent MOMENTUM-3 trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality risk at one year and this is actually lower than 17.6% mortality at one year in high risk LVAD patients in our study. Again, questioning transitioning from LVAD to transplant in high risk patients.

Dr Mark Drazner:             I might take a step back even further. It's an important, it touches on a critical question in my mind, which is if you have a patient who needs to go into transplant and they're not crashing and burning. I'm assuming if they're crashing and burning, you need to go onto an LVAD, the following comments won't apply to that group. If you're a patient who's relatively stable, is it a better strategy to try and get them to transplant directly? Or is it better to go through and VAD and then transplant them? And ultimately that strategy question I think would require randomization to really answer that. But the data that we have discussed today, I think are opening that question and touch upon that in terms of the strategy of the impact of bridging people with VADs itself, which is why I think this is such an important question.

Dr Carolyn Lam:                Thanks again, Mark and Veli. That was an amazing discussion.

                                                Thank you, audience, for joining us. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.