Circulation on the Run

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

Now, the SGLT2 inhibitor, empagliflozin, has been shown to improve outcomes in the EMPA-REG OUTCOMES trial. But do these benefits also apply in the real world, and to other SGLT2 inhibitors as a class? Well, we may just have some answers this week in the CVD-REAL study. More soon right after these summaries.

The first original paper this week uncovers the mechanism of beneficial action of T-cells for proper healing after myocardial infarction. Now, the pro-inflammatory danger signal, adenosine triphosphate or ATP, is released from damaged cells, and degraded by the ectonucleotidase CD73 to the anti-inflammatory mediator, adenosine.

Using newly-generated CD4-CD73 null mice, first author, Dr. Borg, corresponding author, Dr. Schrader, and colleagues from Heinrich Heine University of Düsseldorf in Germany, showed that a lack of CD73 on T-cells enhanced tissue fibrosis and worsened myocardial function in the remodeling phase after myocardial infarction.

T-cells migrated into the injured heart and upregulated their enzymatic machinery to enhance the extracellular degradation of ATP to adenosine. T-cells lacking CD73 showed accelerated production of pro-inflammatory and profibrotic cytokines. Finally, the adenosine 2B receptor was upregulated on cardiac immune cells in the remodeling phase.

In summary, therefore, local adenosine formation by CD73 on T-cells appears to be the body's own defense mechanism to control inflammation induced by myocardial infarction. This is a mechanism that might be exploited to promote healing or remodeling by specifically targeting the adenosine 2B receptor in the infarcted heart.

The next paper provides insights on genetic determinants of susceptibility to peripheral artery disease, and specifically puts the spotlight on Bcl-2-associated athanogene-3, or Bag3, which is a cell chaperone protein previously identified in a genetic screen for determinants of tissue loss with hindlimb ischemia.

In the current study, Dr. McClung from East Carolina University, Brody School of Medicine in Greenville, North Carolina, and colleagues, used adeno-associated viruses to show that an isoleucine to methionine variant at position 81 in Bag3 was sufficient to confer susceptibility to ischemic tissue necrosis in BALB/c mice.

In a series of elegant experiments, they demonstrated that Bag3 was a modulator of ischemic muscle necrosis and blood flow. In summary, this study provides evidence that genetic variation in Bag3 plays an important role in the prevention of ischemic tissue necrosis, and highlights a pathway that preserves tissue survival and muscle function in the setting of ischemia.

The next study provides insights into inflammatory atherogenesis by studying psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction. First author, Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI, National Institutes of Health in Bethesda, United States, and colleagues, hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of non-calcified plaques with high-risk features.

To test this hypothesis, they compared total coronary plaque burden, non-calcified coronary plaque burden, and high-risk plaque prevalence between 105 psoriasis patients, 100 older hypolipidemic patients eligible for statin therapy, and 25 non-psoriasis healthy volunteers. All patients underwent CT coronary angiography, and a sample of the first 50 psoriasis patients were scanned again at one year following therapy.

The authors found that patients with psoriasis had greater non-coronary burden and increased high-risk plaque prevalence compared to healthy volunteers. Furthermore, compared to older hypolipidemic patients, patients with psoriasis had elevated non-calcified burden, and equivalent high-risk plaque prevalence. Finally, improvement in skin disease severity was associated with an improvement in non-calcified coronary burden at one year.

The clinical implications are that patients with psoriasis have similar coronary artery disease risk as hyperlipidemic patients one decade older, and these patients with psoriasis should be screened earlier for cardiovascular disease and educated about their elevated risks. Further investigations focus on the longitudinal impact of psoriasis treatment on high-risk plaque morphology, as well as on the extent of cardiovascular risk mitigation in randomized trials.

Well, those were your summaries. Now for our feature discussion. Now, we've heard of the EMPA-REG OUTCOME trial, that prospect...

This week's episode features highlights from Circulation's 2021 Cardiovascular Surgery Themed Issue. Join Executive Editor James de Lemos along with Associate Editors Marc Ruel and Michael Fischbein as they discuss all of the articles found in this special issue.

Dr. James de Lemos:

Hi, my name is James de Lemos. I'm a cardiologist at University of Texas Southwestern Medical Center in Dallas, and the executive editor for Circulation. And I'm standing in for Carolyn and Greg today to host our annual cardiovascular surgery-themed issue podcast. And I'm delighted to be joined by Marc Ruel, professor and chairman of the Division of Cardiothoracic Surgery at the Ottawa Heart Institute, and the director of cardiac surgery content for Circulation, as well as Michael Fischbein, associate professor of cardiothoracic surgery at Stanford and the director of the thoracic and aortic programs there. Marc, thanks for all that you do for Circulation with cardiovascular surgery content and let me turn it over to you to introduce the issue.

Dr. Marc Ruel:

Well, James, thank you very much. We're very delighted to introduce this 2021 cardiovascular surgery-themed issue. We already feel that this is going to put together some of the very best science at the interface between cardiac surgery or cardiovascular surgery, I should say, because there's some peripheral vascular topics as well, cardiology, and as well, mechanistic research. I think you're going to find that this is really a very jam-packed issue that has a lot of important messaging that will change the field going forward.

Dr. Marc Ruel:

Also, this year, I want to highlight a couple of changes in the preparation of the issue. I want to first thank the tremendous contributions over the years to Circulation and to the entire field of cardiac surgery of Tim Gardner. Really, Tim, is an absolute giant. I think he's the only person known to me who was both president of the American Heart Association and of the ATS in the field of cardiac surgery.

Dr. Marc Ruel:

Tim has really paved the way for us to develop and enhance this issue over the years, and I think 2021 is a testament to his legacy, because I would argue it's our strongest issue ever. And I also want to introduce Mike Fischbein, James and everybody, who's associate professor at Stanford. Mike is a thoracic-aortic surgery expert, also runs a translational lab, so has a very dedicated, basic science and translational surgical science expertise. So we're very, very happy to welcome Mike to the themed issue of Circulation.

Dr. James de Lemos:

Well, thanks Marc. We'll do is follow the order of the issue so that our readers and listeners can really get a sense of the content and its various types that we're publishing this year. And the issue starts with a provocative frame of reference piece from Verma and colleagues discussing the surgical left atrial appendage occlusion. Marc, what were your thoughts on that piece?

Dr. Marc Ruel:

It's obviously a game changer in cardiac surgery. I was privileged to serve as a part of the BSMB for this trial, and we can now say we toyed with the decision as to stop the trial at the appropriate time. And that's always a very difficult BSMB decision, which, frankly, you want to get it right, and you don't want to err on either side. Anyways, LAAOS III was recently published and we have a fantastic editorial in Circulation from Subodh Verma, Deepak Bhatt, and Elaine Tseng saying, which essentially highlights the importance of the trial for practice of cardiac surgery.

Dr. Marc Ruel:

It probably is that no patient who comes to cardiac surgery with a history of atrial fibrillation should, based on those findings, not have their atrial appendage ablated. There's already very little caveat, the trial has not shown what was feared prior with regards to an increased incidence of heart failure or symptoms. And really, the surgery has been effective. The ablation of the left atrial appendage is very effective in diminishing the primary outcome or of stroke, ischemic stroke or cerebral hemorrhage.

Dr. Marc Ruel:

And essentially, this was, in most cases, a surgical ablation, so cut and sew. So we don't have all the information about either endovascular devices or even ablative devices at the time of surgery. But it was a very large trial, it was a publicly funded trial. It is really the authoritative information in the field that's available so far.

Dr. Marc Ruel:

Mike, what are your thoughts around this? Do you now come to any one of your patients needing a cardiac surgical cooperation with a history of atrial fibrillation and thinking that I now need to address the left atrial appendage? Is that what you get out of this paper as well?

Dr. Michael Fischbein:

Yeah. Thanks, Marc. I think that...

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Joining on me in just a moment are two guests to discuss a very exciting new category of papers, known as the white paper. The topic for today is an evolution within the field of current day percutaneous coronary intervention that of the treatment of higher risk patients with an indication for revascularization. But first, here is your summary of this week's journal.

The first study is from first author doctor Jolis and corresponding author doctor Grainger, from the duke clinical research institute in Durham, North Carolina. These authors describe the American Heart Association Mission: Lifeline, STEMI Systems Accelerator. This exciting project represents the largest effort ever attempted in the United States to organize ST segment elevation myocardial infarction care across multiple regions, including 484 hospitals, 1,253 emergency medical services across sixteen regions and involving more than 23,800 patients.

Indeed, this project aims to organize coordinated regional reperfusion plans so as to increase the proportion of patients treated within guideline goals, that is a first medical contact to devise time of less than 90 minutes for STEMI patients directly presenting to PCI capable hospitals and less than 120 minutes for transferred patients.

The authors observed that during the study period of July 2012 to December 2013, there was a significant increase in the proportion of patients meeting these guideline goals, including an increase from 50% to 55% of STEMI patients directly presenting via emergency services and from 44% to 48% of those transfer patients. The authors concluded that these improvements, while modest, suggest the potential for reductions in total ischemic time and happily observe corresponding trends towards lower in-hospital mortality compared with the national data towards the end of the measurement period. Indeed, the tickle message is that the findings support continued efforts to implement regional STEMI networks.

The next study is by first author doctor Hidari and corresponding author doctor Kuang from the Brigham and Women's Hospital in Boston, Massachusetts. They describe the OMEGA-REMODEL randomized clinical trial. This is a multi-center, double-blinded, placebo control trial of 358 participants presenting within acute myocardial infarction who are randomized to six months of high dose omega-3 fatty acids at four grams daily versus placebo.

Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and following therapy with the primary study in point being a change in left ventricular systolic volume index. Indeed, the authors reported that compared to placebo, patients who received four grams daily omega-3 fatty acids experienced significant improvements in both left ventricular and systolic volume and surrogate measures of non-infarct myocardial fibrosis during the six months of treatment.

These remodeling benefits further followed a dose response relationship with the rise in the in vivo omega-3 fatty acid levels as quantified by your red blood cell index. They concluded that four grams daily of omega-3 fatty acid is a safe and effective treatment in improving cardiac remodeling in patients receiving current guideline based post-myocardial infarction therapies. Indeed, this does warrant perspective clinical studies.

The third study is by first author doctor Liu and corresponding author doctor Sia from University of Texas, Houston Medical School and Colleagues, who sought to understand the molecular basis underlying adaption to high altitude hypoxia. By conducting both human high altitude and most genetic studies, the authors identified a novel functional role of CD73-dependent elevations in extracellular adenosin signolin in response to high altitude hypoxia.

This led to sequential activation of a readthrough site AMP-activated protein kinase, which in turn resulted in increased 2,3-bisphosphoglyceric production and enhanced oxygen release capacity to peripheral tissues. Thus, reducing tissue hypoxia, inflammation and pulmonary injury. These findings have significantly added to our understanding of the molecular mechanisms underlying adaption to hypoxia. Thereby, opened novel therapeutic possibilities for the prevention and treatment of hypoxia related conditions.

The final study is from first author doctor Yen and corresponding author doctor Chen from the National Taiwan University and Colleagues, who aimed to determine the effect of betel nut chewing and paternal smoking on the risks of early metabolic syndrome in human offspring. The author studied more than 13,000 parent-child trios identified from more tha...

This week, please join author Roderick Tung, editorialist William Stevenson, and Associate Editor Sami Viskin as they discuss the article "First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial" and the editorial "Can Early Ablation of Ventricular Tachycardia Improve Survival?"

Dr. Greg Hundley:

Welcome listeners to this June 21st, 2022 issue of Circulation on the Run. And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Listeners, what a very interesting forum that we're going to have in this session today with Dr. Rod Tung, bringing us an article from first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy with concurrent defibrillator implantation. Some results from the Pause sudden cardiac death randomized clinical trial.

This article is really interesting because it is collecting data from multiple centers from multiple countries in Asia. But before we get to that article, why don't we grab a cup of coffee and go through some of the other articles in the issue? Well, the first is entitled cardiovascular magnetic resonance for rejection surveillance after cardiac transplantation. And it comes to us from Dr. Jim Pouliopoulos from the Victor Chang Cardiac Research Institute. In this study, CMR based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between cardiovascular magnetic resonance and endomyocardially based measures of cardiac rejection and determine the CMR cutoff values between various cardiac rejection grades.

Then after that, a prospective randomized noninferiority pilot study was undertaken in adult orthotopic heart transplant recipients who were randomized at four weeks post orthotopic heart transplant to either CMR or endomyocardially based rejection surveillance. And clinical endpoints were also assessed at 52 weeks. And so listeners, what did this investigative team find? Well, despite similarities in immunosuppression requirements, kidney function and mortality between the groups, the rates of hospitalization and the rates of infection were lower in the CMR group.

On 15 occasions, patients that were randomized to the CMR arm underwent endomyocardial biopsy for clarification or logistic reasons, representing a 94% reduction in the requirement for endomyocardially based surveillance. And so listeners, a noninvasive CMR based surveillance strategy for evidence of rejection in the first year after orthotopic heart transplantation is feasible. And interesting, listeners, these results really suggest the possibility for further studies to confirm whether CMR and perhaps in combination with other modalities could be used to survey orthotopic heart transplant patients for acute rejection without necessarily having to undergo endomycardial biopsy. There's an excellent editorial by Dr. Jim Fang from the University of Utah who also reviewed this paper.

Well, listeners, let's next turn to the world of preclinical science. And this paper comes to us from professor Simon Sedej from Medical University of Graz. It involves the insulin and insulin growth factor one or IGF-1 pathway. And that is known as a key regulator of cellular metabolism and aging. Now, although its inhibition promotes longevity across species, the effect of attenuated IGF-1 signaling on cardiac imaging really remains controversial. So what did the authors find? Well, they found that cardiomyocyte IGF-1R over expression in mice resulted in physiological hypertrophy and superior cardiac function in early life, but led to accelerated cardiac aging, heart failure and reduced lifespan in late life. Mechanistically, increased cardiomyocyte IGF-1R signaling accentuated cardiac dysfunction by reducing autophagy and mitochondrial oxidative capacity at old age, and therefore clinically pharmacologic inhibition of cardiac IGF-1R signaling in late life could suppress the age related deterioration of cardiac performance and perhaps increase lifespan. And therefore age should be considered as a major outcome determinant in future clinical trials, testing IGF-1R P13K inhibitors for cardiac benefits.

Well listeners, what is our next study? And this study is somewhat related to our feature discussion, which we'll get to in a few minutes. It's from Dr. Paolo Della Bella from San Rafael Hospital, and it is a two phase prospective multicenter randomized clinical trial that was performed to evaluate the benefit of ablation after first implantable cardiovert defibrillator, or ICD shock. And patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock. And that was phase A of the study. Then afterwards, they...

Speaker 1: 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. Joining me in just a moment are Dr. James Gammie and Dr. Timothy Gardner to discuss our feature paper this week describing the first-in-human clinical experience with a novel transapical beating heart mitral valve repair.

First, here are the highlights of this week's journal. The first paper is from co-primary authors doctors Yoon, [Tsue 00:00:49], and [Cha 00:00:50] as well as corresponding authors Dr. [Che 00:00:55] and Dr. Kim from the Seoul National University College of Medicine. These authors examine mechanisms underlying diabetes-induced microvasculopathy, testing the hypothesis that Notch signaling in endothelial cells may play an important role in this condition.

The authors tested this hypothesis by inducing diabetes in eight-week-old adult mice using intravenous streptozotocin. They then modulated endothelial Notch signaling using chemical inhibitors in both wild type and transgenic mice. Results showed that the Notch ligand called Jagged-1 was markedly increased in endothelial cells of diabetic mice. Using endothelial specific Jagged-1 knocked down mice, they found that blocking Jagged-1 prevented diabetic microvaculopathy. Furthermore, using the induceable endothelium-specific Jagged-1 knocked down mice, blocking Jagged-1 even at four weeks after the establishment of diabetic microvaculopathy could reverse the condition.

In summary, these findings show that diabetes induces Jagged-1 over expression and suppresses Notch signalling in endothelial cells leading to diabetic microvaculopathy in adult mice. The clinical implications are that dysregulated intercellular Notch signalling may therefore represent a novel molecular target in the treatment of diabetic retinopathy.

The next study by Dr. Smith and colleagues at the Leiden University Medical Center in the Netherlands evaluated the association between LDL cholesterol variability and four cognitive domains at 30 months in the 4428 participants of the prosper study.

Results showed that a higher LDL cholesterol variability was associated with lower cognitive test performance for intermediate and delayed memory-related tasks, selective attention, and processing speed. Higher LDL cholesterol variability was also associated with lower cerebral blood flow and greater white matter hyperintensity load in an MRI substudy of 535 patients.

In addition to being independent of the mean LDL cholesterol levels and of clinically overt cardiovascular diseases, these associations were present both in the placebo and pravastatin treatment [inaudible 00:03:43] of the prosper trial suggesting that the findings did not mearly reflect pleiotropic effects of statins or of nonadherence.

The study importantly provides the first observational evidence that lipid variability, not just absolute or mean values, but the variability, maybe of importance to neurocognitive function and thus contributes while understanding potential pathways of neurocogniticve decline.

The next study is by first author, Dr. [Huh 00:04:19], and corresponding author, Dr. Ralph, from the Menzies School of Health Research Charles Darwin University in Australia. These authors aimed to investigate the long term outcomes from acute rheumatic fever and rheumatic heart disease.

They achieved this aim by using linked data between the rheumatic heart disease register, hospital data, and death register for residents of the northern territory of Australia, and examined 1248 patients with rheumatic heart disease as well as 572 patients with acute rheumatic fever in the period 1997 to 2013.

The main findings were that in the first year after an acute rheumatic fever episode, the incidents of progression to rheumatic heart disease was 10 times higher than acute rheumatic fever recurrence; 10% of rheumatic heart disease patients had severe disease at diagnosis. The presence of comorbidities was associated with higher incidence of rheumatic heart disease complications and mortality. In particular, comorbid renal failure and hazardous alcohol use accounted for 28% of the access indigenous mortality.

These findings have global relevance for settings with high acute rheumatic fever, rheumatic heart disease rates and really emphasized the need for integrated chronic disease management strategies for these patients.

The final paper is by first author Dr Bettencourt, corresponding author Dr. Blankstein, and colleagues from Brigman and Women's Hospital in Boston, Massachusetts. These authors sought to answer the question what is the most appropriate score for evaluating the pretest probability of obstructive coronary artery disease?

To answer the question, the authors compared t...