Circulation August 15, 2017 Issue

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our podcast today highlights an important perspective piece on charting a future together and turning discovery science into cardiovascular health. You don't want to miss this, coming up right after these summaries. The first original paper tells us about the importance of changes in exercise capacity following transcatheter aortic valve replacement or TAVR.

                                                First author, Dr. Altisent, corresponding author, Dr. Rodés-Cabau, and colleagues from Quebec Heart and Lung Institute in Canada studied a total of 305 patients undergoing TAVR with baseline and six month followup exercise capacity assessments by six minute walk tests. They found that close to one-third of patients undergoing TAVR failed to improve their exercise capacity despite an optimal hemodynamic result post-procedure.

                                                Factors associated with a lesser exercise capacity improvement included patient characteristics such as older age, female sex, non-cardiac comorbidities, such as chronic obstructive lung disease, peripheral artery disease and bleeding episodes resulting in reduced hemoglobin levels. Importantly, the absence of an improvement in physical performance at six months post-TAVR was an independent predictor of mortality and adverse cardiovascular outcomes during the ensuing four years and particularly among patients with a greater impairment of exercise capacity pre-TAVR.

                                                Thus, implementing exercise capacity assessment pre and post-TAVR may help to improve patient risk stratification and augment the accuracy of the prognostic information given to patients, helping to identify those requiring more intensive followup assessment. The next study provides mechanistic insights into the adverse health outcomes associated with particulate matter exposure in the air. First author, Dr. Lee, corresponding author, Dr. Kahn, from Fudan University in Shanghai, China and colleagues conducted a randomized double-blind crossover trial in 55 healthy college students in Shanghai. Real and sham air purifiers were placed in participant's dormitories in random orders for nine days with a 12 day washout period.

                                                Serum metabolites were quantified using gas chromatography mass spec and ultra-high performance liquid chromatography mass spec. They found that higher particulate matter exposure led to a significant increase in cortisol, cortisone, epinephrine and norepinephrine. Between treatment, differences were also observed for glucose, amino acids, fatty acids and lipids. They also found that higher blood pressure, hormones, insulin resistance and biomarkers of oxidative stress and inflammation were present among individuals with higher exposure to particulate matter.

                                                Thus, this study showed that activation of the hypothalamus-pituitary-adrenal and sympathetic-adrenal medullary axis may contribute to the adverse cardiovascular and metabolic effects of particulate matter exposure in the air. In China, indoor air purification may be a practical way to reduce personal exposure to particulate matter. The next study shows that N-acetylcysteine may be new effective thrombolytic treatment. First author, Dr. Lizarrondo, corresponding author, Dr. Gauberti and colleagues from Inserm, France hypothesized that N-acetylcysteine might cleave the von Willebrand factor multimers inside occlusive thrombi, thereby leading to their disillusion and arterial recanalization.

                                                To test this hypothesis, the authors used experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of Laser Doppler Flowmetry and magnetic resonance imaging. They showed that intravenous and acetylcysteine administration promoted lysis of arterial thrombi that were resistant to conventional approaches such as recombinant TPA, direct thrombin inhibitors and anti-platelet treatments. Furthermore, through in vitro and in vivo experiments, they provided evidence that the molecular target underlying the thrombolytic effects of N-acetylcysteine were principally the von Willebrand factor that crosslinked platelets in arterial thrombi.

                                                Co-administration of N-acetylcysteine and a non-peptidic GP2B3A inhibitor further improved its thrombolytic efficacy essentially by accelerating thrombus disillusion and preventing rethrombosis. In a new large vessel thromboembolic stroke model in mice, this co-treatment significantly improved ischemic lesion size and neurological outcomes. Importantly, N-acetylcysteine did not worsen hemorrhagic stroke outcome suggesting that exerted thrombolytic effects without significantly impairing normal hemostasis. Thus, in summary, N-acetylcysteine was shown to be an effective and safe alternative to currently available anti-thrombotic agents to restore vessel patency after arterial occlusion.

                                                The clinical implications of the study are wide reaching considering the very wide availability, low cost and apparent safety of N-acetylcysteine. This is discussed in an accompanying editorial by Dr. Lillicrap from Queens University, Kingston, Canada. The final study identifies a novel mechanism for regulation of cardiac fibrosis that revolves around plasminogen activator inhibitor type 1 or PAI-1. First, author, Dr. Flevaris, corresponding author, Dr. Vaughan and colleagues of Northwestern University, Feinberg School of Medicine in Chicago, Illinois showed that cardiac fibrosis was detected by late gadolinium enhancement cardiac MRI in two otherwise healthy humans with complete PAI-1 deficiency due to a homozygous frameshift mutation in serpene 1.

                                                They further performed a series of mouse experiments to show that treatment of young PAI-1 deficient mice with angiotensin 2 induced extensive hypertrophy and fibrotic cardiomyopathy. Ventricular myocytes were found to be the important source of cardiac transforming growth factor beta or TGF beta and PAI-1 regulated TGF beta synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. PAI-1 deficiency significantly enhanced multiple TGF beta signaling elements and transcriptional targets. Thus, in summary, this study show that PAI-1 is an essential repressor or cardiac fibrosis and access a molecular switch that controls the cardiac TGF beta access and its early transcriptional effects that lead to myocardial fibrosis.

                                                Modulation of the cardiomyocytes TGF beta access represents a unique therapeutic strategy that may abrogate fibrotic signaling and cardiac fibrosis. Well, that wraps it up for your summaries. Now for our featured discussion. We are incredibly privileged today to have the director of the National Heart, Lung and Blood Institute, Dr. Gary Gibbonss with us on the podcast, as he talks about his perspective piece entitled "Charting Our Future Together: Turning Discovery Science into Cardiovascular Health." Also, joining me today is our editor in chief, Dr. Joseph Hill from UT Southwestern. Joe, I know you share my incredible excitement and enthusiasm at having Dr. Gibbonss on this podcast with us.

                                                Maybe could I invite you to say a few words to frame just how important this perspective piece is for Circulation?

Dr. Joseph Hill:                   We all know that cardiovascular medicine and science are evolving at an unprecedented pace. The challenges we face are evolving and yet the opportunities and the tools and the resources at our disposal are unprecedented in their scope and vision. We're very pleased that Gary has provided strong leadership at NHLBI now for several years and has laid out in this perspective piece here where he thinks the next steps are specifically around this strategic vision that focuses on precision medicine and data science. I would love to hear Gary provide additional perspective on that vision.

Dr. Gary Gibbons:            Well, thank you, Joe. As the director of NHLBI, clearly we're public servants and we're accountable stewards of the nation's investment in heart, lung and blood and sleep disorders. This piece gave us an opportunity to outline some of the opportunities that lay ahead in a strategic visioning process. First, I should note that a key part of the legacy of the NHLBI is to make strategic investment with enduring principles in mind to really support investigator initiated discovery science as really the core foundational element of our research portfolio, as well as to maintain a balance portfolio to really expands to spectrum of basic translation clinical population and implementation science.

                                                In this piece, we particularly want to highlight our strategic visioning process in which we encourage the broad input of the NHLBI community that actually included over 4,000 participants in this process from every state in the country. Indeed, 42 countries around the world to provide the most compelling questions and critical challenges that the field faces around strategic goals of understanding normal human biology, reducing disease, accelerating translation and preparing a biomedical workforce and resources for the discovery science of the 21st century.

                                                Out of that strategic vision, we focus in on two elements that emerged that relate it to precision medicine and data science for this piece and really that was the central core of what we wanted to share with the Circulation readership about how these two areas we think are going to be transformative in the years ahead.

Dr. Carolyn Lam:               Dr. Gibbons, you know, when the term precision medicine is used, sometimes it's a bit fuzzy I think in the minds of a lot of people. Could you maybe give a few examples or perhaps a specific idea that comes to mind?

Dr. Gary Gibbons:            You're right. There's often a lot said about it than probably a bit of hype about it. In some ways you could see this as a legacy of cardiovascular medicine and science. It could be argued that the definition of cardiovascular risk factors that came out of the Framingham Heart Study many years ago was the first sort of forerunner of precision medicine. It helped us indeed define those individuals who are at the greatest risk of having a heart attack and that to this day has played a role in directing targeted preventive treatments of the highest risk individuals in order to prevent heart attacks. That has continued to evolve.

                                                I think what's new now is that we have, as Dr. Hill mentioned, new modalities of both imaging and analytics of computational science, as well as novel biomarkers and genetic markers that can help us be even more precise in that risk assessment. That's really I think the greater opportunity to further subcategorize patient populations to get the right drug to the right patient at the right time with a more strategic treatment approach.

Dr. Joseph Hill:                   Gary, that's very exciting. I think your vision is absolutely compelling. I like how you categorize the NHLBI as a catalyst for the future. I'd like to think that the Biomedical Journals, the AHA Portfolio of Journals and Circulation are also catalysts that will partner with NHLBI and other entities to chart the course for the future. That again the challenges that we face now are different than they were back in the era when Framingham first got started after World War II. The tools that we have are also evolving rapidly and certainly our perspective from Circulation is that we are stewards of helping chart that course, helping identify and bring forth the best science around the world. In many ways we look to you as a partner.

Dr. Gary Gibbons:            Oh, absolutely. The NHLBI really can't fulfill our mission of turning discovery science into the health of the nation and indeed around the world without a circle of partners and that certainly includes the platforms of disseminating new knowledge like Circulation, as well as partner organizations such as American Heart Association. We definitely appreciate the value that your organ brings to really enhancing our efforts to not only take discovery science, but make that knowledge available to practitioners and researchers and patients.

                                                I think a key part of the 21st century is how we not only can discover and generate new knowledge, but how we can facilitate that movement of data to knowledge and from knowledge to action that actually enhances the lives of patients in the real world context. Again I believe your journal plays an important role in helping to do that.

Dr. Carolyn Lam:               You both mentioned critical challenges that we're facing and will face. The Chinese for these challenges or crisis, the word is actually wéijī. Okay? Wéi is actually meaning danger, whereas jī is for jīhuey which is opportunity. In every challenge, there's always this new opportunity and I just really would like to ask what are the greatest challenge and perhaps the greatest opportunity?

Dr. Gary Gibbons:            I think the challenge that we probably face is the emerging epidemic of non-communicable diseases typically cardiovascular disease throughout the world. Not only in the most industrialized nations, but indeed mainly the developing nations. This will quickly surpass communicable infectious diseases as the major burden and causes of mortality worldwide. We're dealing with a global challenge. Increasingly, we recognize that scientific discovery and analysis is often siloed in various packets. Our vision for the future is really to promote the creation of a global reach of what we're calling a Data Commons. That is that a disease has no borders. Science should not be limited to national states.

                                                It is part of the commonwealth if you will of information and knowledge that really should transcend national borders. We say this is a global community of data and information and knowledge exchange and collaboration. As part of this global community, it's that we think this diverse and inclusive approach will be critical to the best minds and best practitioners of the world learning from each other and contributing to this commonwealth of knowledge. We're excited because the opportunity on the other side of that challenge is that it's an unprecedented capability of power to communicate now. We I think are communicating with you from Singapore and we're in a digital age in which this notion of communication and knowledge exchange should be more fast than it's ever been before.

                                                Indeed, we can create computer platforms that are similar to what exist for a Facebook or a Google that are global in scope. The vision is really to say what would happen if we could turn that toward biomedicine and make biomedicine part of this data science such that we have global contributions to our understanding, knowledge exchange and really create that sort of global sandbox if you will of knowledge exchange and discovery. That's part of this notion of creating a Data Commons and really advancing data science as an element of a strategic vision.

As we move forward with precision medicine and data science, our most sacrosanct stewardship is for the next generations. A critical element is to ensure that we're providing them with the tools and training to really lead the charge of advancing these exciting areas of science and that indeed will be a global enterprise.

Dr. Joseph Hill:                   That's very exciting, Gary. I take my hat off to you for the leadership that you have maintained at the NHLBI during these times that are once very challenging and at the same time exhilarating. I look forward to working with you through our journal and partnering with you to bring to fruition much of what you had laid out in your vision.

Dr. Gary Gibbons:            Thank you, Joe. We look forward to our ongoing partnership.

Dr. Carolyn Lam:               Thank you, listeners, for joining us today. Do join us again next week.