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: November, 2018
Nov 26, 2018

Dr Carolyn Lam:                Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. We will be discussing accelerated diagnostic protocols for chest pain, a very, very important issue in Cardiology with very important new safety and effectiveness data on one such protocol provided in our feature paper this week. Coming right up after these summaries.

                                                Our first original paper this week identifies a new link between specific gut bacteria and atherosclerosis. Co-First authors, Dr Yoshida and Emoto, corresponding author, Dr Yamashita, from Kobe University Graduate School of Medicine, and colleagues recruited patients with coronary artery disease and controls without coronary artery disease but with coronary risk factors. They then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples. Subsequently, they used atherosclerosis prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Their analysis of gut microbial profile in patients with coronary artery disease showed a relative depletion of bacteroides vulgatus and bacteroides dorei compared to controls with coronary risk factors. Gavage with live bacteroides vulgatus and bacteroides dorei decreased fecal and plasma lipopolysaccharide levels and protected against atherosclerosis in apoE deficient mice. Fecal lipopolysaccharide levels in patients with coronary artery disease were significantly higher compared to controls. These findings suggest that bacteroides treatment may serve as a novel and effective therapeutic strategy for suppressing lipopolysaccharide-induced inflammatory response in coronary artery disease.

                                                The next paper identified a potential novel molecular target in the treatment of myocarditis. Co-First authors, Dr Chen and Zeng, Co-Corresponding authors, Dr Song from Fuwai Hospital in Beijing, and Dr Yang from Shenzhen University School of Medicine, and their colleagues aim to elucidate the role of BCL2 Like protein 12 in the pathogenesis of biased T Helper-2 response in myocarditis. Using a combination of mouse models of myocardial inflammation and human hearts from patients undergoing heart transplantation, the authors found that CD4 positive T-cells isolated from hearts in myocarditis at the end stage of heart failure expressed high levels of BCL2 Like protein 12, which was required for the development of aberrant T Helper 2 polarization in the heart. Thus, BCL2 Like protein 12 may be a novel target in the treatment of myocarditis, as well as other T Helper 2 biased inflammatory processes.

                                                Could vaccination against LDL be a way to prevent atherosclerosis? Well, the next paper brings us one step closer to this dream. First author, Dr Gisterå, corresponding author, Dr Hansson from Karolinska School University Hospital and colleagues developed T-cell receptor transgenic mice to study LDL autoimmunity in a humanized hypercholesterolemic mouse model of atherosclerosis. A strong T-cell dependent E-cell response was induced by ODL leading to production of anti-LDL IgG antibodies that enhanced LDL clearance and ameliorated atherosclerosis. Results show that anti-LDL immuno-reactivity evoked three atheroprotective mechanisms, namely 1) antibody-dependent LDL clearance, 2) increased cholesterol excretion, and 3) reduced vascular inflammation, thus targeting LDL-reactive T cells may enhance atheroprotective immunity, and vaccination against LDL components may be an attractive way to prevent atherosclerosis.

                                                MicroRNAs regulate nearly all biological pathways and dysregulation of MicroRNAs is known to lead to disease progression. However, are there cell type specific effects of MicroRNAs in the heart? Co-First authors, Drs Rogg and Abplanalp, corresponding author, Dr Dimmeler from Goethe University Frankfurt, and colleagues assessed MicroRNA target regulation using MicroRNA 92a3p as an example. Their data showed that MicroRNAs have cell type specific effects in vivo which would be overlooked in bulk RNA sequencing. Analysis of MicroRNA targets in cell subsets disclosed a novel function of MicroRNA 92a3p in endothelial cell autophagy and cardiomyocyte metabolism. These findings may have clinical applications for the fine tuning of autophagy and metabolism to mitigate tissue damage in patients with cardiac disease.

                                                The next paper establishes a mechanism by which cardiac inflammation may be initiated in response to hemodynamic stress, but in the absence of significant cardiomyocyte cell death. Co-First authors, Drs Suetomi and Willeford, Co-Corresponding authors, Drs Brown and Miyamoto from University of California San Diego, and their colleagues used conditional cardiomyocyte-specific calcium calmodulin-regulated kinase Delta all CaM kinase II Delta knockout mice to demonstrate that cardiomyocytes generate inflammatory chemokines and cytokines and are the initial site of NLRP3 inflammasome activation. They further identified a causal role for CaM-Kinase II Delta-mediated activation of NLRP3 inflammasome and inflammatory responses in macrophage recruitment, cardiac fibrosis, and development of heart failure induced by pressure overload. Their elegant mouse experiments revealed sites and mechanisms of proinflammatory gene and inflammasome activation within cardiomyocytes which could serve as targets for early intervention or disease prevention.

                                                Are there different metabolomic effects between PCSK9 inhibitors and statins? First author, Dr Sliz, Corresponding Author, Dr Würtz from Nightingale Health Limited in Helsinki, Finland, and their colleagues quantify 228 circulating metabolic measures by Nuclear Magnetic Resonance Spectroscopy for over 5300 individuals in the PROSPER Trial at six months post randomization. The corresponding metabolic measures were also analyzed in eight population cohorts, including more than 72,000 individuals using a specific PCSK9 inhibitor SNP as an unfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Scaled to an equivalent lowering of LDL cholesterol the effects of genetic inhibition of PCSK9 on these 228 metabolic markers were generally consistent with those of statin therapy. Alterations of lipoprotein lipid composition and fatty acid distributions were also similar. However, discrepancies were observed for very low-density lipoprotein or VLDL lipid measures where genetic inhibition of PCSK9 had weaker effects on lowering VLDL cholesterol compared with statin therapy. Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation, where a statin treatment weekly lowered this marker of inflammation. Thus, if VLDL lipids have an independent causal effect on cardiovascular disease risk, the observed discrepancy on VLDL lipid lowering could contribute to differences in cardiovascular risk reduction between statins and PCSK9 inhibitors for an equivalent reduction in LDL cholesterol. Moreover, these results exemplify the utility of large-scale metabolomic profiling with genetics and randomized trial data to uncover potential molecular differences between related therapeutics.

                                                The final original paper this week demonstrates a novel biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases. Co-First authors, Dr Mosley and Benson, co-corresponding authors, Dr Wang from Vanderbilt University Medical Center and Gerszten from Beth Israel Deaconess Medical Center, and their colleagues employed a virtual proteomic approach linking genetically-predicted protein levels to clinical diagnosis in more than 40,000 individuals. They used genome-wide association data from the Framingham Heart Study to construct genetic predictors for more than 1100 plasma protein levels. They validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in more than 41,000 genotyped individuals in the eMerge Cohort. They tested associations for each predicted protein with more than 1100 clinical phenotypes. These associations were validated using directly-measured protein levels and either LDL cholesterol or subclinical atherosclerosis in the Malmo Diet and Cancer study. Using this virtual biomarker strategy the authors identified CLC1B and PDGFR Beta as potential circulating biomarkers of atherosclerosis and validated them in an epidemiologic cohort. Thus, these results demonstrate that a virtual biomarker study may efficiently identify potential biomarker disease associations, and that wraps it up for our summaries. Now for our feature discussion.

                                                Accelerated diagnostic protocols for testing are used everywhere. They're designed to improve the quality and value of chest pain risk stratification. However, many of them lack sufficient prospective safety and effectiveness data. We're so pleased to have a paper today that provides such important data on one of these accelerated diagnostic protocols for chest pain, and it's the HEART Pathway. To discuss this, I've got the corresponding author of today's featured paper, Dr Simon Mahler from Wake Forest School of Medicine, as well as our Associate Editor, Dr Deb Diercks from UT Southwestern. Simon, could you start by just telling us, what is the HEART Pathway?

Dr Simon Mahler:             Sure. Yeah, it's an accelerated diagnostic protocol. It's based on an accelerated diagnostic protocol called the HEART Score. We use a modified version of the Heart Score. We actually use a HEAR score, and that stands for the history, EKG, Age, and risk factors. That is combined with two troponin measures at 0 and 3 hours. We also factor in whether or not the patient has had prior coronary artery disease or has an acute ischemic EKG. So, to be low-risk you have to have a HEAR score of 0-3. HEAR is an acronym. You get points for each of those categories. If you have less than 3 points that's a low score. You have to have a low score, a non-ischemic EKG, no history of prior coronary disease, and two troponins less than a 99th percentile at 0 and 3 hours to be considered low risk and recommended for early discharge. If you don't meet any of those criteria then you are considered non-low risk and appropriate for further in-hospital evaluation.

Dr Carolyn Lam:                That's great. Could you just tell us what you did to give us some real-world safety and effectiveness data on this.

Dr Simon Mahler:             Yeah, so we had done a single-site randomized controlled trial. That was published in 2015 in Circulation: Quality and Outcomes, and really showed some promising results. We received some funding to do an implementation trial. So, this is the results of our implementation study. It's a before and after study. What we did was we sought to implement a HEART Pathway as a clinical decision support tool, integrated fully into our electronic medical record so that when providers see the patient with chest pain and order a troponin they interact with a HEART Pathway tool that guides them through the HEART Pathway risk assessment and then provides real-time decision support regarding their treatment and disposition decisions based on whether or not the patient has a low-risk assessment or a non-low-risk assessment. The design of the study was we collected data on all patients with chest pain and troponin order for one year while we worked on how we were gonna build this tool and embed it, and then we had three month watching period where we built the tool into the electronic health record across our three sites. Then, we had one year where we were post implementation where we collected data and looking at the difference in outcomes, particularly looking at both safety and utilization outcomes before and after use of the HEART Pathway.

Dr Carolyn Lam:                That's just such a clever design. Just give us a summary of the results before I ask Deb to chime in here.

Dr Simon Mahler:             There's a few really important things that we found. Probably the most important thing was the safety data that came out of this study. We had some good safety signals on prior studies. They didn't have enough sample size to really have a good precision around the safety point estimate, so in this study we had over 4000 patients in our post-implementation cohort, and about 31%, 30.7%, of those patients were classified as low-risk by the HEART Pathway. Among those patients that were classified by low-risk, the rate of death and MI, the composite outcome at 30 days, was 0.4%. Typically for these accelerated diagnostic protocols we want them to have an adverse cardiac event rate less than 1%, so a finding of 0.4% with a confidence in our role that doesn't extend beyond 1% that was a really important finding that really confirms the safety of this strategy.

                                                The other thing that we found which was interesting was that the use of the HEART Pathway was actually associated with detecting more myocardial infarctions during the index visit, which means that possibly the HEART Pathway use improved the recognition of those patients that were presenting with MIs. It's possible that without using the HEART Pathway some of those cases may have been missed. Finally, we were able to demonstrate that use of the HEART Pathway as a clinical decision support tool was able to decrease hospitalizations and some other utilization metrics such as stress testing and possible length of stay.

Dr Carolyn Lam:                Oh, that's awesome, Simon. I said it earlier. I'm gonna say it again. Thank you so much for publishing this wonderful work with Circulation. I really think that implementation, science, and decision support tools you've got that all in this paper, just beyond even the actual topic. Deb, take us behind the scenes a little bit with how we reacted as editors to this paper, please.

Dr Deb Diercks:                 Well, I think that overall, we were really excited about this paper. It really does add a real, real context to something we were really discussing and wondering about. I think one of the great things about the implementation, and Simon, please comment on this, is the diversity of the places that you actually used this in. I mean, most of us when we look at papers there's always a fear that it won't be able to be generalized to real-world practices. Correct me if I'm wrong, but you really applied it to just a wide variety of Emergency Departments that really support that this could be used anywhere.

Dr Simon Mahler:             Yeah, I think that's a really important point, that we did this across our system so that included a large academic busy Emergency Department that sees over 100,000 patients per year, all the way, basically to a smaller 12,000 per year, essentially almost a free-standing Emergency Department at the time that we started our study; it now has inpatient bed capacity, and then a suburban/rural hospital, as well, with about 30,000 patient visits per year. We extended beyond kind of the typical kind of comfort zone of large academic centers and into smaller community Emergency Departments as well.

Dr Deb Diercks:                 One of the things that this manuscript nicely articulated is that you kind of break it into the HEAR and then the troponin.

Dr Simon Mahler:             Right.

Dr Deb Diercks:                 Things change in the US with troponin. How do you think that's gonna impact how you guys apply this Pathway in the future?

Dr Simon Mahler:             It's a big topic of discussion right now, what to do with these Pathways. Are these Pathways still needed with the availability now of high-sensitivity troponins in the United States? I think that for many years as we've kind of followed data coming out of Europe we've been anxiously awaiting the arrival of these tests in the U.S., and there's a lot we can learn from the European data so far. Most of that data suggests that the high-density troponins are best used still in the context of a Pathway or an accelerated diagnostic protocol.

                                                I think that this particular study was conducted just using contemporary troponins, particularly given the time frame of the study in which we were accruing patients from 2013 through 2016, but I think it's still gonna be highly relevant, because I think that best practices are gonna still require us to use some sort of structured framework with high-sensitivity troponins. Now, it does remain to be seen a little bit what the best Pathway is gonna be to incorporate that. My take on this is that I believe that clinical decisions support tools or decision aids integrated with high-sensitivity troponins is going to be the best way to go. I'm a little bit skeptical about troponin-only approaches.

Dr Deb Diercks:                 That's a great summary. I don't think it's time to throw out all the value of that risk stratification tool, and I think your study showed that how it can easily be incorporated into what we do in a manner that doesn't really negatively impact the work flow, which I think is so important.

Dr Simon Mahler:             You know, we did a smaller study where we looked at the performance of the HEART Pathway with high-sensitivity assays. We studied it with both the Roche troponin high-sensitivity troponin T and the Abbott high-sensitivity I, and at the 99th percentile it actually made very little difference in terms of the performance of the HEART Pathway. What the potential advantages of incorporating high-sensitivity assays is that you probably no longer need a 0 and 3 hours, evaluation can be condensed. I think there's a lot of really interesting questions that availability of high-sensitivity troponins has created, and I think that there's gonna be a lot of emerging evidence over the next few years about new Pathways, and what are the best ways to fully take advantage of these higher-sensitive assays because, frankly, most of the decision aids that are currently in use they were developed using contemporary troponins, and they may not fully take advantage of high-sensitivity troponins. We may see modifications of our Pathway, and it will interesting to see kind of how things evolve as we study the impact of high-sensitivity troponin.

Dr Carolyn Lam:                Wow, exciting work ahead. Just one last question regarding the future. So, you followed up the patients in your study for 30 days. Am I wrong? Any plans to follow them up longer, and do you think such data are needed?

Dr Simon Mahler:             Yeah, we actually followed them for a year. Our primary analysis was through 30 days, and so we do have one-year data on all of our patients, and so we'll be doing a secondary analysis looking out to a year. Yeah, you can look forward to that coming up hopefully in the next six months or so.

Dr Carolyn Lam:                That is awesome. Thank you so much, Simon. Thank you so much, Deb. Thank you, listeners, for joining us today. 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 2018.

Nov 19, 2018

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

                                                Is there a unique lipoprotein profile for incident peripheral artery disease as opposed to coronary or cerebral vascular disease? Well, you're just gonna have to wait for our feature discussion to find out. That's coming right up after these summaries.

                                                Our first original paper this week tells us that gene variance known to be associated with idiopathic and peripartum cardiomyopathy are also associated with preeclampsia. First and corresponding author Dr Gammill from University of Washington and colleagues studied 181 participants with confirmed preeclampsia from the Preeclampsia Registry in BioBank. Saliva samples were collected for DNA isolation and whole exome sequencing was performed to detect rare variants in 43 genes known to be associated with cardiomyopathy.

                                                Results were compared with data from two controlled groups, unrelated women with a gynecological disorder, sequence using the same methods and instruments, as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium.

                                                The results showed that women who developed preeclampsia are more likely to carry protein altering mutations in genes associated with cardiomyopathy, particularly, the TTN gene which encodes the sarcomeric protein titin. Thus, detecting these gene variants may allow more specific diagnosis, classification, counseling and management of women at risk.

                                                Prior trials have shown that nonsteroidal anti-inflammatory drugs or NSAIDS confer cardiovascular risk. Now this has been postulated to be due to enhanced formation of methyl arginines in the kidney that would limit the action of nitric oxide throughout the vasculature. However, the next original paper in this week's journal suggests that this may not be correct. First author, Dr Ricciotti, corresponding author, Dr FitzGerald from University of Pennsylvania Perelman School of Medicine and colleagues, used multiple genetic and pharmacological approaches to disrupt the COX 2 pathway in mice and analyze plasma from patients taking NSAIDS.

                                                However, they did not observe an increase in methyl arginines. In contrast, they did observe an increase in plasma asymmetric dimethylarginine or EDMA in mice-rendered hypertensive by infusion of angiotensin II at a dose that also caused renal impairment. After a four week washout period following the infusion of angiotensin II, blood pressure, creatinine, and ADMA levels all fell back to normal levels.

                                                Celecoxib-treated mice also exhibited increased ADMA and plasma creatinine in response to infusion of angiotensin II and their levels also returned to normal thereafter. Thus, it seems likely that the previous reported elevations in ADMA reflected renal dysfunction rather than a direct consequence of COX 2 deletion or inhibition. The authors end by suggesting that the most plausible mechanism by which NSAIDS confer a cardiovascular risk, is by suppression of COX 2 derived cardioprotective prostaglandins such as Prostacyclin rather than by enhanced formation of methyl arginines.

                                                The next original paper identifies new targets with the potential to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia. Co-corresponding authors, Dr Ola and Eichmann from Yale University School of Medicine and colleagues looked at SMAD4, which is a downstream effector of transforming growth factor-beta/bone morphogenetic protein family ligands that signal via activin-like kinase receptors.

                                                The authors generated a tamoxifen inducible postnatal endo-fetal specific SMAD for a mutant mouse and showed that SMAD4 prevented flow-induced arterial venous malformations by inhibiting casein kinase II. The uncovered pathways provided novel targets for the treatment of vascular lesions in hereditary hemorrhagic telangiectasia related juvenile polyposis patients carrying SMAD4 mutations.

                                                The next original paper provides important data for the accurate diagnosis of long QT syndrome. Long QT syndrome can be a challenging diagnosis partly because the optimal method for QT assessment is not unequivocally established. QT experts advocate manual measurements with a tangent or threshold method.

                                                In today's paper, first and corresponding author, Dr Vink from Academic Medical Center University of Amsterdam and colleagues, aimed to assess similarities and differences between these two methods of QT interval analysis among 1,484 patients with a confirmed pathogenic variant in either KCNQ1, KCNH2 or SNC5A genes from 265 families. Both QT measurement methods yielded a high inter and intra reader validity and a high diagnostic accuracy.

                                                Using the same current guideline cutoff of QTC interval 480 milliseconds, both methods had similar specificity but yielded a different sensitivity. QTC interval cutoff values for the QT measured by the tangent method was lower compared to that measured by the threshold method. Plus, values were different depending on the correction for heart rate, age, and sex.

                                                The authors provided an adjusted cutoff values specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for long QT syndrome at has been made available as an aid in the interpretation of the QT interval.

                                                The next original paper demonstrates for the first time that thrombin mediated signaling may play a role in diet-induced atherogenesis. Co-first authors, Dr Raghavan and Singh, corresponding author Dr Rao from University of Tennessee Health Science Center and colleagues, used a mouse model of diet-induced atherosclerosis and molecular biological approaches and explored the role of thrombin and its G protein coupled receptor signaling in diet-induced atherosclerosis.

                                                They found that thrombin-induced CD36 expression and foam cell formation required protease activated receptor 1, G alpha 12, Pyk2, GAB 1, and protein kinase C theta dependent activating transcription factor 2 activation. Thus, inhibition of thrombin G protein coupled receptor signaling could be a promising target for the development of new drugs in reducing the risk of diet-induced atherogenesis.

                                                The next study provides insights into the long- term association of LDL cholesterol with coronary heart disease mortality in individuals at low tenure risks of atherosclerotic cardiovascular disease. First and corresponding author, Dr Abdullah, from VA North Texas Medical Center and UT Southwestern Medical Center and colleagues studied more than 36,000 subjects in the Cooper Clinic Longitudinal Study cohort who are at low tenure estimated risk of atherosclerotic cardiovascular disease. In other words, a low tenure risk of less than 7.5%. They've followed these patients for more than two decades.

                                                Results showed that LDL cholesterol and non-HDL cholesterol at or above 160 milligrams per deciliter were independently associated with a 50 to 80% increased relative risk of cardiovascular disease mortality. The associations between LDL cholesterol and cardiovascular disease mortality were more robust when follow up was extended beyond the traditional 10 year estimated risk period.

                                                The associations remain significant in those with an estimated tenure atherosclerotic cardiovascular disease risk of less than 5%. These data suggests that LDL cholesterol levels at or above 160 milligrams per deciliter in individuals deemed to be at low tenure atherosclerotic cardiovascular risk are associated with worse long term cardiovascular disease mortality. These findings, along with other observational data and data extrapolated from clinical trials, support further consideration of appropriate LDL cholesterol thresholds for lipid lowering interventions in individuals categorized as low short-term risk.

                                                The final paper this week uncovers a novel therapeutic target for the prevention and treatment of thoracic aortic aneurysms. First author, Dr Nogi, corresponding author Dr Shimokawa from Tohoku University Graduate School of Medicine and colleagues, used genetically modified mice to show a pathogenic role of the small GTP binding protein, GDP dissociation stimulator in the development of angiotensin 2 induced thoracic aortic aneurysms and dissection. Down regulation of this protein contributed to dysfunction of aortic smooth muscle cells and hence oxidative stress, and matrix metalloproteinase activities in the pathogenesis of thoracic aortic aneurysms and dissection.

                                                Local over expression of this small GTB binding protein GDP dissociation stimulator around the thoracic aorta inhibited aortic dilatation and rupture in deficient mice. And that wraps it up for this week's summaries. Now for our feature discussion.

                                                Atherosclerosis has been considered a systemic process, meaning that when we see a disease in one vascular bed, we assume that that's a risk marker for disease in other vascular territories, and that they share pathophysiology, they share risk factors. However, if we think about it, the prior studies have all been sort of focusing on coronary and cerebral vascular disease, but today's feature paper changes that a bit because it addresses a key knowledge gap in peripheral artery disease risk, and interestingly suggests that there may be a unique lipid profile that's related to peripheral artery disease.

                                                This is gonna be an exciting discussion and I have the first author, Dr Aaron Aday from Vanderbilt University Medical Center currently. We have our editorialist, Dr Parag Joshi from UT Southwestern, and our associate editor, Dr Anand Rohatgi from UT Southwestern. Welcome gentlemen and Aaron, could we start with you sharing about your study?

Dr Aaron Aday:                 So, as you mentioned, a lot of the previous epidemiologic data on atherosclerosis have been primarily in coronary artery disease and stroke, and when we looked at peripheral artery disease or PAD, there seemed to be some subtle differences. So for instance, total cholesterol on HTL cholesterol seemed to be the strongest risk factors for future peripheral artery disease and in terms of LDL cholesterol, the data are somewhat mixed. Some have found a weak association, some have actually found no association. And so building on that, we wanted to see if using nuclear magnetic resonance spectroscopy, we could elucidate more details about the litho protein pathways associated with peripheral artery disease.

                                                And we did this in the women's health study which is a prospective cohort study of women free of cardiovascular disease, the baseline, they were aged 45 and older. And what we've found in terms of the standards with their profiles, we again found that there was no association between LDL cholesterol and future peripheral artery disease, whereas certain standard lipid measures like HDL cholesterol were strongly associated with PAD, and then using the Endemol spectroscopy tool, we found that actually, small LDL particles and total LDL particles were concentrations of both of those markers, were strong risk factors for future PAD and other measures like total HDL particle concentration were even more strongly associated with future PAD than coronary artery disease.

                                                So essentially the signature associated with future peripheral artery disease, had some important differences than that for a composite of coronary artery disease and stroke.

Dr Carolyn Lam:                Aaron thanks for that. That's beautifully described and just so intriguing. Parag, could you tell us how should we be thinking about results like this?

Dr Parag Joshi:                   It's a great paper and it really highlights a new and unique approach in that we ... Peripheral artery disease as an isolated incident event is fairly understudied I guess we could say and so, this is a really nice paper to start choosing out some of the risk factors for that. I think overall, when we think of peripheral arterial disease in general, I think historically, we've thought of it as similar pathophysiology, you know LDL particles and perhaps other particles depositing in the arterial space. But this does highlight some important differences that might exist and I think one of those seems to be that maybe this is more a signature of elevated remnant lipoproteins or triglyceride rich remnant lipoproteins, small dent LDL particles, low HDL, that sort of metabolic syndrome type patterns that we look at as a high risk factor that may be more contributory to peripheral artery disease than coronary disease, or at least more specific to peripheral artery disease.

                                                I guess one of my main questions about that from your work Aaron is, how can we be sure this isn't just a pre-clinical marker of diabetic patients which we know have this type of pattern?

Dr Aaron Aday:                 Sure, it's certainly a possibility. I think what's notable in the cohort, at least a time enrollment. And there was a very little diabetes and actually there was a much greater prevalent of metabolic syndrome. So in my mind, it may be more of a metabolic syndrome specific marker rather than necessarily down the diabetes pathway, but it's certainly something that needs to be explored further.

Dr Parag Joshi:                   I wonder whether women's health studies such a healthy cohort that I wonder if this is picking up some signal before the answer to diabetes or as you said, metabolic syndrome, you know which certainly suggests an insulin resistance pattern and we know the association of diabetes with peripheral artery disease is stronger and so I wonder if this may be a sort of earlier way of picking that up.

Dr Aaron Aday:                 It may be. I think one thing to notice is the outcome of peripheral artery disease that we're using. So it is symptomatic disease. So, we're not picking up a lot of ulcers that are developing in the future, it's more the claudication and then people who've undergone revascularization. Certainly diabetics have both of those as well but I think that may suggest it's not fully unexplained by developing diabetes than peripheral artery disease further down the line.

Dr Parag Joshi:                   Yeah that's a great point.

Dr Carolyn Lam:                Yeah great questions, great thoughts. Anand, what about you? Did you have questions too?

Dr Anand Rohatgi:            I think from my perspective and thinking about it for circulation and its readership, we found this really interesting for several reasons. Number one, I think is, as you all have discussed, peripheral arterial disease just is not as well characterized and you can see that here in over 25,000 people, add about a 100 a bed, so I think in younger folk, it takes a lot of people to study, to be able to really understand kind of the pathophysiology of peripheral arterial disease.

                                                The other thing that they think they really shed some light on is how this is happening in women in particular and in women, of course as we know have been understudied in all cardiovascular diseases, but in particular, diseases like this which are less common. It's really insightful to see that these lipid abnormalities in women are contributing to peripheral arterial disease more so than your typical LDL cholesterol management and interestingly enough, most of the women who had PAD events in this study, did not have other cardiovascular events.

                                                They really just had PAD events exclusively and I thought that was really intriguing, and the use of this advanced lipoprotein testing, this NMR modality has been very useful in terms of biology and research, and I think that's the case here where we really go under the hood Carolyn, as you said, and get kind of deep dive, the lipid metalobles on abnormalities. And I think Parag and Aaron hit the nail in the head that this is really capturing an insulin resistance of phenotype and what I really liked about this is, instead of studying people who are 70, 80 years old and a lot of things are sort of clustering, a lot of diseases are clustering and they're manifesting all at the same time, it's very hard to tease apart the effective age.

                                                Here, we captured women in their 50s and middle aged, just as they have kind of gone through menopause and this adverse metabolite's phenotype starts to rise in women. And then we could follow them over time and see what the natural history of that is, and the women who have this phenotype go on to have this devastating consequence, this peripheral arterial disease. One of the questions I had then, Aaron for you is, what do you think the implications are from these findings? Does it mean that in terms of diagnostics, we should be doing more advanced testings looking at LDL and HDL type particles with NMR or some other mortality? Does it change therapies with new therapies beings studies right now? What do you think the implications are from your work?

Dr Aaron Aday:                 That's important right. I think you mentioned this and I see the inter marked tool in this study, is really a way to try to dig further into the biology of peripheral artery disease as a form of atherosclerosis. I think that we already know patients who are extremely high risk or PAD, those are patients with diabetes, smoking history, metabolic syndrome et cetera., and as you can see in a patient population in 28,000 middle aged women who are pretty healthy, we only had just over a 100 PAD events.

                                                So, I think even if you were to scale this up in terms of cost, I'm not sure that that would necessarily be a viable option for patients, but I think it does suggest that truly focusing on LDL in a very high-risk patient population, meaning patients with PAD, or we may not be fully addressing their risk. And so I think this is a need to highlight that important gap, think about other therapeutic options and we'll soon have ongoing trials, triglyceride low in therapy that may be particularly beneficial in this patient population and so that's how I see this being used.

Dr Anand Rohatgi:            That makes a lot of sense and particular because in middle aged women like this, your standard risk score algorithms will not really capture that they're at increased risk, even if they smoke, just because they're women and they're younger and so, I think this really is a call to arms to more refined risk assessment in these women.

Dr Parag Joshi:                   Aaron, do you think there's actually a difference in the biology in the peripheral arteries compared to the coronary and cerebral vascular beds, or is there data to kind of look at that or maybe histopathological data to look at that?

Dr Aaron Aday:                 We know there's a lot of overlaps, so I don't wanna suggest that PAD is not a former atherosclerosis. I think one limitation is that the primary animal model for PAD is the hyperCKemia model. That doesn't fully recapitulate what's happening in a limb with PAD and so I think that has been one limitation in understanding the biology. But I think what we're starting to see in some clinical trials that have come out in the last couple of years or starting to see a somewhat different signal for therapies in patients with PAD so for instance, in 48, we actually saw that there was a greater benefit to LDL lower [inaudible 00:21:00] inhibitors than for coronary disease. We now have the compass trial results, again, more events, higher risk among these patients but for their benefit, add on River Oxodine therapy, we've seen lymph events or lymph signals in the SGLP2 inhibitor trials. So, I think we're starting to get a sense that there may be something else on top of the traditional ascariasis biology that may be a potential target on down the road.

Dr Parag Joshi:                   I think it's really a fascinating biological question of how these different territories might actually differ in their pathophysiology. I think it's a really a nice time to look at this. Also I think, Anand and Aaron both mentioned ongoing trials. The omega 3 fatty acid trials I think reduce it, will be soon to be presented and hopefully published in the next month or so. It would be nice to see if they evaluate peripheral events in that group, I'm sure they will.

Dr Carolyn Lam:                Indeed, these have been just such great thoughts and discussion. Nothing really much to add there. I suppose I could say something cheeky like for the first time, and I never thought I'd say it on the podcast, I feel kind of bad that there are no men included in this trial but anyway, I just learnt so much from this. I just wanna thank you gentlemen for a great discussion.

                                                Thank you, listeners, for joining us today and don't forget to tune in again next week to Circulation on the Run.

Nov 12, 2018

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

                                                This week's feature discussion focuses on first and man pilot study results of pericardiotomy and its influence on left ventricular diastolic reserve with volume loading. Very fascinating implications for heart failure with reserved ejection fraction, coming right up after these summaries.

                                                Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. But what are the underlying mechanisms and potential therapeutic approaches to this? Well, in today's paper from co-first authors Drs Sun and Yao, corresponding author Dr Chang, and colleagues from UT Southwestern Medical Center, the authors examine the status of cardiac autophagy and its role during sepsis pathogenesis using a rodent lipopolysaccharide-induced sepsis model. They've found that forced overexpression of Beclin-1 in the heart promoted autophagy and mitophagy, protected mitochondria, improved cardiac function, and alleviated inflammation and fibrosis after a lipopolysaccharide challenge. Whereas, haplosufficiency for Beclin-1 resulted in the opposite effects. For the more injection of a cell permeable Tat-Beclin-1 peptide improved outcomes in lipopolysaccharide-challenged animals. Thus promoting Beclin-1-dependent signaling may be a novel and effective intervention to alleviate organ dysfunction caused by maladaptive autophagy during severe sepsis.

                                                The next paper presents important experimental data that causes us to consider the potential cardiovascular hazards of anti B-cell activating factor immunotherapy, which is currently approved for the treatment of autoimmune systemic lupus erythematosus. You see, genomic data has shown that B-cell activating factor receptor pathway is specifically essential for the survival of conventional B lymphocytes, which is a key driver of coronary heart disease. However, in today's paper from co-first authors, Drs Tsiantoulas and Sage, corresponding author Dr Binder and colleagues from Medical University of Vienna, the authors reported an unexpected finding that B-cell activating factor neutralization increased atherosclerotic plaque size and complexity despite efficient depletion of mature, conventional B lymphocytes. Furthermore, the authors provided evidence suggesting a novel B-cell independent anti-inflammatory property of B-cell activating factor. They showed that the expression of the alternative B-cell activating factor binding receptor, transmembrane activator and CAML interactor in myeloid cells limited atherosclerosis thus showing novel atheroprotective pathways. Thus, these results introduce a new perspective with respect to the potential cardiovascular hazards that may be associated with the long term blockade of B-cell activating factor in chronic inflammatory settings. There is a need for more refine therapeutic approaches targeting the B-cell activating factor pathway.

                                                Vascular smooth muscle cells are known to possess remarkable plasticity undergoing fundamental phenotypic switches from a differentiated to a dedifferentiated state in response to vascular injury or remodeling. However, what are the underlying cellular processes by which vascular smooth muscle cells maintain their cell identity? Well, in today's paper from co-first authors Dr Yao, Yu and Li, corresponding Dr Wang from Fu Wai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking University Medical College. The authors applied single cell RNA sequencing to analyze disease human arteries and identified histone variant H2A.Z as a key histone signature that maintains vascular smooth muscle cell identity. H2A.Z occupied genomic regions near vascular smooth muscle cell marker genes and it's occupancy was decreased in vascular smooth muscle cells undergoing dedifferention. H2A.Z expression was dramatically reduced at both messenger RNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescued injury-induced loss of vascular smooth muscle cells identity and new intima formation. Together, these data introduced dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions and implied that H2A.Z may be a potential intervention known for vascular diseases.

                                                What is the causal role of body mass index and cardiovascular health in young adults? In the next paper from first and corresponding author Dr Wade from University of Bristol in United Kingdom and her colleagues. The authors used a combination of conventional multivariable regression analyses, Mendelian randomization and subsample recall by genotype methodologies. Recall by genotype is a novel approach that exploits the random assortment of alleles through meiotic cell division at conception to inform genetically base recall and enables the collection of precise phenotypic measures in smaller studies while maintaining statistical power and ability for causal inference. The authors use these methods to estimate the causal effect of body mass index on gross level and detail cardiovascular health in healthy participants from the Avon longitudinal study of parents and children at age 17 years as well as in an independent sample from the same cohort study at age 21 years.

                                                Their results showed that higher body mass index was likely to cause worse cardiovascular health specifically higher blood pressure and higher left ventricular mass index even in youth. Higher body mass index also resulted in increased cardiac output in the recall by genotype study which appeared to be solely driven by stroke volume, as neither the Mendelian randomization nor the recall by genotype analyses suggested a causal effect of body mass index on heart rate. These consistent results support efforts to reduce body mass index from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using a recall by genotype methodology.

                                                Older adults undergoing aortic valve replacement are at risk for malnutrition, however, what is the association between pre-procedural nutritional status at midterm mortality? First author, Dr Goldfarb, corresponding author Dr Afilalo from McGill University in Montreal, Quebec, reported results of the FRAILTY-AVR prospective multicenter international cohort study conducted between 2012 and 2017 in 14 centers in three countries. This study included patients 70 years and older who underwent transcatheter aortic valve replacement or surgical aortic valve replacement. The mini nutritional assessment short form was assessed by trained observers pre procedure with scores seven or less out of 14 being considered to be malnourished. The short performance physical battery was simultaneously assessed to measure physical frailty. The authors found that malnutrition was associated with higher one-year mortality and 30-day adverse events following aortic valve replacement via a transcatheter or surgical approach. While malnutrition and frailty were interrelated, the integration of nutritional assessment resulted in improved predictive value for frail patients. Clinical trials are needed to determine whether pre and post procedural nutritional interventions can improve clinical outcomes in these vulnerable patients.

                                                Do newer generation ultra-thin strut drug-eluding stents improve clinical outcomes over contemporary thicker strut stents? First and corresponding author, Dr Bangalore from New York University's School of Medicine and colleagues search PubMed, Embase and Central and identified 10 trials that randomized more than 11,650 patients and evaluated three newer generation ultra-thin strut drug-eluding stents, that is defined as a strut thickness less than 70 microns, versus thicker strut second generation drug eluding stents and reported clinical outcomes. They found that newer generation ultra-thin strut drug-eluding stents were associated with a 16% reduction in target lesion failure, which was a composite of cardiovascular death, target vessel myocardial infarction or ischemia-driven target lesion revascularization evaluated at one year follow-up. Ultra-thin strut drug-eluding stents reduced the risk of target-lesion failure driven by a reduction in myocardial infarction and also a qualitatively lower rate of stent thrombosis compared to contemporary thicker strut second generation drug-eluding stents.

                                                Ambient air pollutants are known to be associated with increased cardiovascular morbidity and mortality, however, what is the association between air pollution and cardiac structure and function? First and corresponding author Dr Aung from Queen Mary University of London and colleagues performed a cross-sectional analysis of a large population free of preexisting cardiovascular disease in the UK Biobank population study. They found that higher past exposure to fine particulate matter and nitrogen dioxide were associated with larger cardiac biventricular volumes. Proximity to major roads, a surrogate for chronic air pollution exposure, was additionally associated with higher left ventricular mass. These associations between ambient air pollution and at first cardiac phenotypic changes, in individuals without prevalent cardiovascular disease, suggest that air pollution should be recognized as a major modifiable risk factor which needs to be targeted by a public health measures.

                                                The final original paper this week is the first study to demonstrate a causal link between atrial fibrillation and the NLRP3 inflammasome, which is an innate inflammation signaling complex. Co-first authors, Drs Yao and Veleva, corresponding author Dr Li from Baylor College of Medicine and colleagues assessed MLRP3 inflammasome activation by immunoblot in atrial whole tissue lysates and cardiomyocytes from patients with paroxysmal or long-standing persistent atrial fibrillation. They found that NLRP3 inflammasome activity was increased in these patients. To determine whether cardiomyocytes specific activation of NRLP3 was sufficient to promote atrial fibrillation, they established a cardiomyocyte specific knock in mouse model which expressed constitutively active NLRP3. These mice developed spontaneous premature atrial contractions, an inducible atrial fibrillation, which was attenuated by a specific NLRP3 inflammasome inhibitor. Cardiomyocyte-specific knockdown of NRLP3 suppressed atrial fibrillation development in these mice. Thus, these results establish a novel pathophysiological role for cardiomyocyte NLRP3 inflammasome signaling with a mechanistic link to the pathogenesis of atrial fibrillation, and suggests that inhibition of NLRP3 may be a potential novel atrial fibrillation therapy approach.

                                                And that brings us to the end of our summaries.

                                                Now for our feature discussion.

                                                Is pericardiotomy going to be our next treatment for heart failure with preserved ejection fraction or HFpEF? I have the first and corresponding author of a very intriguing research letter. Dr Barry Borlaug from Mayo Clinic in Rochester, Minnesota, joining me today to tell today about his great paper. Barry, welcome back to the show. You are amazing. Congratulations on yet another wonderful publication. So, could you set us up. Those of us who don't think about this every day. The hemodynamics of what pericardiotomy does. Tell us what was the rationale of doing this study?

Dr Barry Borlaug:              You know, it's interesting. We think about intracavitary pressures on the left side ventricle and the left atrium causing congestion and pulmonary hypertension. We think that this is all related to left ventricular issues, but about 30 or 40% of the pressure is actually related to external restraint on the heart as mediated by the right ventricle across the septum and the pericardium and external pericardial contact restraints. In animals, we've known since back in the late 1970s, that with the chest open, if you open up the pericardium, which we know in HFpEF, on average, is shifted up and to the left. It's stiffer. This effect really comes into play more at higher heart volumes. It doesn't have as much of an affect at lower heart volumes like might be absorbed with rest. It's even been rumored that in some species like greyhounds, illicit dog racers, would actually cut away the pericardium so these dogs could race better. It's actually been shown that they can experimentally, in a paper in the 1980s, that they can exercise the higher peak VO2. They have a higher cardiac output response, because the heart is better able to utilize the Frank-Starling relationships to augment ventricular filling and ejection at fuller pressures.

Dr Carolyn Lam:                Oh my goodness. I didn't know that latter fact about the racing dogs. Could I ask you something? We've talked about this before back in the day. When you say the left side the filling pressures go up when there's pericardial restraint, remember we used to talk about a parallel shift upwards versus true intrinsic stiffening ... diastolic stiffening. You still do mean that parallel shift upwards, right?

Dr Barry Borlaug:              That's right. If it was purely an increase in stiffness, we would expect it to sort of rotate, pivot from the bottom left up, but what we see, and in human data, we published a number of years ago, most of the increase in LV end-diastolic pressure is a parallel shift upward in the diastolic pressure volume relationship. That really suggests that there's an increase in restraints on the heart. That's why we think that that's an important target and it's possibly more remediable to treatment since we're having such tough luck changing the viscoelastic properties of the left ventricle, not that we shouldn't be doing that, but this might be something different that we could do that might give us a little bit more of a benefit in terms of filling pressure reduction.

Dr Carolyn Lam:                True. True. But the way you describe it too, it does mean that we may be talking about, I hate to say this but, specific subsets or types of HFpEF, where that may play a bigger role and I'd just like to bring the audience to your incredible paper that I think that I've cited a gazillion times already on the obese HFpEF phenotype. Do you want to remind everyone about that because I think there you really [inaudible 00:16:30], didn't you that ventricular interdependence played a big role.

Dr Barry Borlaug:              So, in people with obese HFpEF, which is now becoming by far one of the most dominant. Oh God. We did a study that compared them to non-obese and we see that the obese patients have a bit more plasma volume expansion, a bit more cardiac remodeling, right heart enlargements, increase of LV mass and an increase in epicardial fat. What all this does is increases the total heart volume in the pericardial space. Because the pericardium doesn't appear to grow as much as the heart volume, this increases the coupling between the right and left heart. Some people, perhaps like the obese phenotype of HFpEF, might be more poised to derive benefit from approaches to therapeutically remove this excess pericardial restraint.

Dr Carolyn Lam:                Okay, now you just have to get down to telling us what you did. This was a first in man pilot study. Drum roll everybody. You gotta listen up. This was so cool.

Dr Barry Borlaug:              This physiology just got us thinking that maybe we could do this to help our patients with HFpEF. First we tested this in dogs, then with pigs with features of HFpEF and it seemed to work there so the next step was to show that it might work in people. We took people that were already going to get their pericardium open, so people that were referred for cardiac surgery. We wanted to choose people that had risk factors for HFpEF and diastolic dysfunction but maybe not necessarily diagnosed HFpEF.

Dr Barry Borlaug:              We took people who were referred for aortic valve replacement for AS, coronary artery bypass grafting or both and consented them ahead of time, put catheters into them to measure hemodynamics and then we measured resting hemodynamics with the chest open, but pericardium intact, because the changes that we see occur predominantly when there's an increase in volume load to the heart, we then had to stress the system. Now we can't have them exercise cause they're under general anesthesia with an open chest. You achieve that by elevating their legs and giving them a little saline bolus, so we had a pressure at rest, pressure with saline load.

                                                Then we asked our surgeons to open the pericardium, which they do obviously to gain access to the heart for cardiac surgery and we repeated the same assessments and intervention. What we saw was that the resting filling pressures, again these people did have diastolic dysfunction, the resting pulmonary wedge pressure was about 16. With the volume load maneuver, it increased to 25 when the pericardium was intact. After we had opened the pericardium, the increase in wedge pressure, which was our primary endpoint, was reduced from an increase in nine millimeters of mercury down to an increase of only three millimeters of mercury. So that verified our hypothesis that the pericardium contributed and that we could prove total cardiac diastolic reserve, if you will, just by removing that pericardial restraints.

Dr Carolyn Lam:                Wow. I love the figures, by the way, that you've drawn as always they illustrate that so beautifully. And listeners, this is a research letter, so there's that one central figure that you must get your hands on right away. Now Barry, I think the first question is this wasn't really HFpEF patients right? Let's be very clear with the audience who these were though and then you did a subset analyses though, a further analysis that showed this may apply more to people with higher wedge at rest. Could you elaborate?

Dr Barry Borlaug:              Absolutely. While these people, and Carolyn, I think you know as well, I think a lot of people probably have HFpEF that they have a sort of occult HFpEF, that's not been diagnosed maybe because unfortunately, not everybody else thinks about this diagnosis. When you look at the charts very carefully, and found out about 13 of the 19 patients complained of significant dyspnea based on chart review. Of those 13, 10 had other indicators that according to current criteria would give them the diagnosis. When we looked at this at this very post hoc, sort of exploratory subset, we actually saw that these patients, even though they didn't necessarily have a clinic diagnosis of HFpEF, that these patients actually responded even more favorably to the effects of pericardiotomy in their greater reduction in the increase in wedge pressure. When we plotted in the figure that you mentioned, we plotted the change in the increase in wedge pressure, it was really the patients that had the greatest increase with volume loading initially that derived the most benefit. That makes sense because those were the people where the pericardium and the restraint is the becoming most operative, when the heart is most distended and congested.

Dr Carolyn Lam                 Maybe one quick last question. What next Dr Borlaug? Gosh, you just keep coming up with one thing after another with the animals. I noticed that it was a non-invasive pericardiotomy. I'm reading between the lines here. What are you going to do next? Do you think this is ready for prime time?

Dr Barry Borlaug:              As usual, you're reading correctly between the lines. We have filed a patent awhile back for this and we have a device that can achieve a pericardial modification or an anterior pericardiotomy without the need for open heart surgery, so that you don't crack the sternum. It's done from a subxiphoid approach and we've actually just received some funding to start doing this under an IDE, which we will need to work with the FDA. We hope to do and start testing this in patients that have HFpEF and then look at the acute hemodynamically affects. Then we'll also begin to explore the safety and potential efficacy using other indices like imaging, exercise capacity and things like that.

Dr Carolyn Lam:                That is just so cool. I think that one of the immediate take home messages for me now though is when we see patients who we think have HFpEF, have a low threshold to look for evidence of constriction. I would say that we may miss the diagnosis of people who legitimately have constrictive pericarditis and may need to benefit from this. I think it's one of those hidden diagnosis, so that's one thing. And then the next thing, if I could just ask you, are there any patient populations that you say should not undergo this? And I say this because I remember back in the day again, when we were experimenting with dog models, this is just gestalt okay, but I thought that the dogs who had right-sided heart failure, severe right-sided heart failure, needed that pericardium to lean on, and if you released it, the dilatation on the right side would just be inexorable because there is no pericardium to rein them in. Do you get what I mean? I don't know. I'm just curious if you have any patient population right now that you're already thinking I'm not going to include in my trial.

Dr Barry Borlaug:              Yeah. That's a very important point, Carolyn. We would not want to apply or test initially certainly this therapy where eccentric cardiac remodeling is a problem because we know that there is a little bit of eccentric dilatation even in people after a regular cardiac surgery with pericardiotomy. Marty Molenter showed that, in a paper back in the 1980s, you have a patient who already has some dysfunction, we would hypothesize that they may get a bit worse, so we would not want to test this in people with the right ventricular dysfunction, right ventricular enlargement phenotype of HFpEF. We would not want to give this to people with HFrEF. Remember with HFrEF, we wanted to do just the opposite. We tested this years ago with the ACORN trial or older studies wrapping the latissimus dorsi around the heart to cause reverse remodeling so this is really something that would maybe work more for people with smaller stiff hearts, HFpEF, where that concern that they're going to dilate and get low EF heart failure either on the left or on the right side. We would want to focus more on the small hearts and away from those people with dilation.

Dr Carolyn Lam:                That is so great. Thanks so much Barry for letting us under the hood. Congratulations once again. These are just great papers. Keep them coming. Well listeners. I'm sure you enjoyed that as much as I did. Don't forget to tune in again next week.


Nov 5, 2018

James de Lemos:              Welcome everyone to Circulation on the Run my name is James de Lemos, I am the executive editor for Circulation based at UT Southwestern in Dallas and I will be filling in for Carolyn today as we discuss this year's surgery themed issue. I would like to welcome Dr Marc Ruel, the chairman of cardiac surgery at the University of Ottawa and a long-time editor of the Circulation of surgery themed issue, as well as Dr Tim Gardner, professor of cardiac surgery at The University of Pennsylvania and our leader at Circulation on the editor team for issues related to cardiac and vascular surgery. Marc and Tim, welcome and thanks for all your tremendous work in this issue.

Dr Marc Ruel:                    Thanks James for having us.

Dr Tim Gardner:               Thank you. Glad to be here.

James de Lemos:              Why don't we start Marc with your thoughts on how this issue comes together, how it came to be, you picked the papers and how we ended up with this terrific issue.

Dr Marc Ruel:                    It’s been a really important year for surgery and for this issue, as some of you may know the supplement which used to be the old designation of this issue has been changed to the surgery themed issue in about 2014 or so where the new Circulation leadership and what we tried to do every year is to bring the very best, not only of cardiovascular surgical science but also of clinical care and pearls around clinical and surgical care. So, I think this year we have had probably more than 60 submissions sent to us. Tim and I have looked at those very closely and you as well, James, we really wanted to get the feedback and the approach from not only cardiac surgeons but also from cardiologists and cardio vascular care specialist around those. We've tried to select the best of science and also some papers that we feel would be very useful with regards to providing new clinical pearls for surgeons and anyone in the circle of care around cardiovascular surgery.

Dr Tim Gardner:               If I could just add, James, of course we have other papers that have been submitted by surgeons that are published or that deal with cardiac surgical or vascular surgical topics during the year, this particular issue is very much focused on cardiac surgery but throughout the year we have plenty of submissions of manuscripts by surgeons about surgery about surgically related topics and so on. So, I am actually kept quite busy reviewing and commenting and consulting on manuscript submissions of Circulation. There are plenty of papers over the course of the year that relate to surgical topics.

James de Lemos:              Wonderful, I think you will see, as we talk about these papers, really that what Marc and Tim are talking about in terms of papers that are broadly relevant to cardiac surgeons and cardio vascular providers really rings true. Let’s walk through the issue, its set up like most of our issues begins with a couple of opinion pieces, a brief frame of reference, articles about important topics. Marc, do you want to talk about the Domanski paper, talk about revascularization for ischemic cardiomyopathy?

Dr Marc Ruel:                    Absolutely, we've asked experts, namely Mike Farkouh and Micheal Domanski, to provide us where their thoughts regarding the optimal treatment on patients with LV dysfunction and severe coronary disease. What many of us would call an ischemic cardiomyopathy, which may be construed as a misnomer or as an accurate term, I will not debate on this today, but certainly it remains a very vexing clinical problem. I think we could all agree that the last niche where we still see very high in terms of treatment for coronary disease this is probably mortality and kind of an inability to provide for a tangible result.

                                                Once LV dysfunction has set in and the present of CAD the outcomes are poor, and it took years and literally almost ten years for the STICHES trials to show a benefit for surgical treatment. This is relatively all study now and it has to be put in context and I then that Mike and Mike are doing this extremely well in terms of providing the caveat, for instance, STICHES at its inception added had a 5% mortality rate around CABG, so we know that the modern outcome are probably better than that. It’s very difficult to actually decipher what sound be the mainstay of treatment for each challenging patient and I think the frame of reference provided by Dr Farkouh and Domanski is extremely useful in helping with that.

James de Lemos:              Tim we have another frame of reference that is also provocative. Trying to make a case that we think about in patients with hypertrophic cardiomyopathy with obstruction early surgical procedures to relieve the obstruction. Do you want to tell the readers a little bit about this opinion piece and what your thoughts on it are?

Dr Tim Gardner:               Sure James, this is a really nice frame of reference article from both doctors Martin and Barry Maron and then their European contributor Paolo Spirito and the point of their opinion paper is that the surgical art for managing this very difficult obstructive cardiomyopathy syndrome has reached the point where we really shouldn't wait until patients are in extremist or in class 3 or 4 status in term of syndromic problems and can consider earlier surgery for these patients. They make the very important point which I think we have to except is that for patients to do well with this operation they need to be in a center where there is experienced surgery and experienced surgeons, but the point is now that the state of the art for managing obstructive cardiomyopathy is as such that good result are obtained and patients should be offered this surgery when appropriate, but earlier, in order to avoid the challenges of end stage cardiomyopathy and difficulty relieving the obstruction, so this is a really important opinion piece. It’s great to see our cardiology colleagues who are experts in this field make this point based on well published data from centers like the Mayo Clinic.

James de Lemos:              Moving now to the original articles, we've got 5 original articles, maybe Marc we can start with your thoughts on 2 articles related to revascularization, one in coronary disease and one identifying a really novel approach for treating type A aortic dissection with malperfusion.

Dr Marc Ruel:                    I think that's well said James, the first of these original papers will be likely somewhat controversial. The first author is Dr Bo Yang and essentially it is a series from Michigan where they look at just shy of 600 patients with acute Type A Aortic Dissection, of whom 135 were identified to have malperfusion syndrome. Essentially defined by the authors as something slightly different than malperfusion per say but really malperfusion accompanied with evidence of necrosis in one of the organs.

Their approach has been new and somewhat controversial in that they have brought these patients first to the interventional radiology suite in order to fenestrate in many cases or at least open the culprit artery or the culprit perfusion territory that leads to malperfusion syndrome and then depending on how the patient is doing they would then proceed to open repair as soon as 24 hours afterwards or they may wait longer in someone where there is no sign of improvement yet prior to moving to the ER, so they have found this has not only improved the results with regards to in hospital mortality after operative repair type A aortic dissection, but also to allow them to better discern or differentiate should I say between patients in whom malperfusion may lead to a futile situation and who then may be avoided from undergoing a very complex and difficult OR so would argue this is probably the first such large organized, well documented series of such an approach and I think it will lead to some head scratching, this being said it must be remembered that the goal standard for Type A aortic dissection is dealing with the intrapericardial aorta first and hoping that the perfusion gets better from this and everyone knows that the results of this approach are not fantastic.

We know that even in the best centers, including the latest data from Germany such an approach has about a 20% mortality rate so clearly there are ways that we can improve with Type A aortic dissection and this paper may be a strike in the right direction.

James de Lemos:              The other revascularization paper addresses that, I would say also a quite controversial topic which is how many atrial grafts are optimal in patients that are undergoing surgical revascularization?

Dr Marc Ruel:                    This is a paper from Toronto where the Ontario ICES database was used and several papers actually dozens and dozens of papers have come out previously from this well established and well allocated database. Steve Fremes who is the senior author and one of his trainees, Dr Rocha and the team of authors got together and decided to look at the impact of 3 versus 2 arterial grafts in patients undergoing cabbage with regards to survival. They have very nice, very compelling follow up information and they basically carry out 2 exercises.

First, they wanted to see if the 3,000 patients or so had 3 or more arterial grafts had a better outcome than the 8,000 patients or so who had 2 arterial grafts and frankly they found there was no significant difference with regards to survival at 8 years and freedom from MACCE at 8 years. However, when they compare those 9 or 8,000 patients or so who had 2 arterial grafts to the rest of 40,000 or so patients who had 1 arterial graft and completions with veins they found that again there was a survival benefit. This last finding is not new and its obviously subject to indication biases as well as expertise bias as we've seen in many of the observational perspectives studies around multiple arterial grafting. But I think the concept of comparing 2 versus 3 arterial grafts is very novel in surely in this paper is being addresses with very high scientific related from the numbers and the quality of the follow up that's been brought to the exercise.

James de Lemos:              I've really been struggling, I love your thoughts and Tim, your thoughts on how to reconcile the data in space. I really am having a hard time getting my head around what seems to be conflicting data about the number of arterial grafts in what an optimal CABG looks like in 2018 with the evidence that we have. What are your thoughts on that question?

Dr Tim Gardner:               I think that this supports the concept that 2 arterial grafts whenever possible for some patients, younger patients perhaps 3 but I think the important point is, multiple arterial grafting should be attempted and carried out whenever possible. I leave the is 3 better than 2 to some future study or future review that can be more precise about that.

Dr Marc Ruel:                    This being said I think we don't view efficiently coronary surgery as being an area of expertise and many centers including very strong academic centers may not necessarily marry the concept that coronary surgery has to be something with the dedicated expertise. I think when we look at those observational perspectives series we see the effect of it may be the expertise bias, but it may be more than just 2 or 3 arterial grafts, they may be the whole wrapping of care that comes with it including optimizing beta blockers and managing diabetes etc. So, I think it may be more than purely conduits but definitely, as Tim said, 2 arterial grafts are probably better than just 1 and the jury is still out on whether 3 is better than 2.

James de Lemos:              Excellent. Switching gears now Tim, an area that obviously you have tremendous experience and expertise we've got 2 innovative papers addressing surgery for individuals who have congenital heart disease. Can you update us on what we are publishing here?

Dr Tim Gardner:               Sure, the one study focuses on the risks of pulmonary valve surgery in adult patients who underwent a correction of tetralogy of Fallot earlier in life. This is a growing population actually we refer to as young adult with congenital heart disease and in many centers they are more numerous in terms of the patients groups than infants because this group has been successfully treated early in life, but this particular group of patients, patients who have had tetralogy of Fallot repaired and end up with what the author calls right ventricular outflow disfunction generally regurgitation through the outflow tract pulmonary valve sometimes obstruction, these patients then face significant clinical challenges in death from heart failure, right ventricular failure or arrhythmias in their late 20's and 30's. We have been focusing now on the timing and the type of pulmonary valve replacement.

Dr Tim Gardner:               Now there is catheter replacement options available, but when to do this and how to minimize risk is really the focus of this one paper that describes a four multi-center study looking at predictors of risk for these patients. Sort of a hypothesis generating paper, but it is an important study none the less, focusing on how to identify patients with right ventricular out flow tract dysfunction and who should have pulmonary valve replacement and when that should optimally be done. It a very good study. The other important study that we have is that the other age spectrum of neonates and this is a study that is based on a review of data from the pediatrics heart health information systems database, led by the group at the Children's Hospital Philadelphia.

Looking at variations in pre-operative care and management of neonates with transposition of the great arteries. This was a little controversial actually when we reviewed it among the editors because the suggestion is that earlier surgery this would be in the first week of life and more perhaps aggressive use of atrial balloon septostomy seems to improve outcomes. This is a generally low risk population, the point of the paper is that these pretty good results can be improved by paying more attention to the timing of surgery and the appropriate use of balloon septostomy. It’s sort of a quality improvement perspective based on a large database and I think it’s a very nice study and undoubtedly creates additional attention to this particular area.

James de Lemos:              Marc, our last original paper is a really novel issue engineering approach to creating vascular conduits, can you tell the readers briefly what happens to her in this paper?

Dr Marc Ruel:                    Indeed. It’s a paper from Stanford, from Joe Woo’s lab and the first author is Daniel von Bornstädt. Essentially, as you say it’s a very innovative novel approach to try to recreate a bioengineered blood vessel. We surely know there's quite a need for such off the shelf conduits, not only in cardiac surgery but also in vascular and vascular surgery and even for things such as AV fistulas and others. It’s really interesting to see that this is what I would call transitional science at its best and surgeons have had an important role over, as you know, centuries in helping develop this and many discoveries have come from surgical labs, especially a few decades ago.

In any case, what Joe and his team have performed is to try to use clinically applicable methods to derive and create a bioengineered blood vessel and they started first with human aortic smooth muscles cells and skin fibroblasts which are literally easy to get and they used those to constructs bi-level cell sheets, they then used a 22 gauge angiocath needle so that the sheets would be wrapped around this in order to lead to a tubular vessel construct. Then the next problem has been traditionally that those bioengineered vessels would burst out with atrial pressure. What Joe's team came up with is to use a commercially available adhesive, so a glue essentially, which is dermabond which typically we use after any form of surgery to keep the incision together and they put dermabond on the surface of this sheet wrapped around an angiocath needle to act as a temporary external scaffold. They then led this into a bioreactor and implanted it in series of 20 rats as a femoral artery interposition graft. The results were excellent. Essentially, patency was perfect and there was a full vascular maturity with all 3 layers of blood vessel that you would expect including an intima that had been formed as a result of the experiment.

I think this is all very promising because none of the methods here are involving something that would have non-autologous issues, or you could easily see this being used with a patient’s own cells in order to achieve an autologous. I think this is obviously small vessels, there are 22-gauge needle is not a big conduit, you’re not going to bypass an LED with this, but I think it’s a start and it’s all done using transitional or clinically applicable methods. I guess the next step would be moving to a large animal model and certainly I think we should stay tuned to see where this leads us.

James de Lemos:              I think that's exactly my thinking as well about that discussion and really leads us into some of the issues that come up in the review paper that you are a co-author on new strategies for surgical revascularization. I think this basic in translational science piece is designed to address some of the limitations of current revascularization and you all did a really beautiful job covering some new more clinically ready strategies in your papers. Can you just tell us very briefly what you all covered in that review paper?

Dr Marc Ruel:                    Indeed, this is a paper that was kind of aiming at being a state of the art around CABG and rapidly the focus was reshaped towards kind of new strategies around surgical myocardial revascularization. Initially we have a section on OPCAB on this and that and minimizing the inflammatory effects of the pump and quickly it became apparent that the desire of Circulation and this themed issue was to focus it more on really what are the up and coming improvements around surgical coronary revascularization. This paper focuses on essentially 4 main areas. One is hybrid coronary revascularization, the second one is less invasive coronary surgery, the third one is the use of multiple arterial grafts to which we eluded a little earlier during this podcast and fourth is the use of an aortic coronary surgery, essentially meaning bypass surgery performed without any manipulation of the aorta.

James de Lemos:              As we think about innovation in terms of conduits, the procedure itself, the other aspect that's covered in our last paper is can we make the procedure safer perhaps by modifying our use of anti-platelet therapies based on meshment of the platelet phenotype and Tim do you want to bring us home by just telling us a little bit about what we learned from Paul Gurbel and his group of platelet experts?

Dr Tim Gardner:               Well we learnt a lot about platelet science and appropriately so Dr Gurbel is a well-recognized expert in platelet physiology or platelet management and this is a really quite a challenging area because many of our patents come to surgery especially for coronary surgery already on platelet inhibitor agents and what Dr Gurbel and his co-authors showed in this paper is that although there is somewhat limited data there can be and should be platelet function testing and with an appropriate understanding of platelet inhibition drugs that we may be able to limit the time between removal of these or discontinuation of these platelet inhibitor drugs and the necessary surgery which will improve outcomes and reduce bleeding in patients requiring urgent CABG surgery. It’s a very useful update and it is a good example of a paper that isn't written by surgeons, but really applies very much to the cardiac surgical treatment of coronary artery disease

James de Lemos:              I really like the very practical tables and figures that lay out the potential tests that surgeons or anesthesiologists may consider for assessing this and even how one might implement. I would like to bring us to conclusion now, first I want to acknowledge, Sara O'Brien at the Circulation office for her amazing work together with Marc and Tim pulling this issue together, making sure that we have a consistent high quality issue with wonderful figures and tables and it really came together beautifully and thank you both for joining me today and the podcast I think it’s obvious that we've got an issue that all of you listen to this podcast need to actually pull out the issue or download it because we have a co-host of wonderful papers to look at and cardiac surgery thriving at Circulation. As we've talked about this is the tip of the iceberg, this themed issue, we've got great content coming, issue after issue. We are already open for business next year’s issue, so please send us your best cardiac surgery research. Please pay attention to these important papers and apply them in your practice because I think many of them are already directly applicable.

Marc given your leadership role in the issue do you want to bring us home and make any concluding remarks?

Dr Marc Ruel:                    I think your points are very well taken James and I want to reintegrate that if I speak on behalf of the cardiovascular surgical community, we are very thankful to the leadership with Circulation. James, Joe, Tim and many others and obviously the support from the staff in clearly establishing that cardiovascular surgery is a very important therapeutic mentality and the overall scope in the broad scope of cardiovascular therapeutics.

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