Podcasts about sekar kathiresan

Gene editing's therapeutic application has transitioned from hypothetical to reality, marked by the recent approval of a CRISPR-based therapy for sickle cell and beta thalassemia. In the wake of these developments, new biotech companies are springing up spurred by advancements that redefine what conditions might soon become treatable.   One contender in this rapidly changing landscape is Verve Therapeutics. This week on "The Top Line," Fierce Biotech's Max Bayer sits down with the company's CEO Sekar Kathiresan, M.D., to discuss how Verve intends to distinguish itself. They also chat about what drove Dr. Kathiresan to biotech after more than 20 years as a cardiologist and geneticist.   To learn more about the topics in this episode:  Verve Therapeutics unveils its lead program—a one-and-done treatment for genetic high cholesterol Lilly beams up Verve gene therapy programs for $600M from deal-hungry Beam Verve shows base editing works in humans in first clinical data—and is punished by investors Verve's base editing hold lifted, starting a thaw on a regulatory blockade that sent peers ex-US  See omnystudio.com/listener for privacy information.

Synopsis: Sekar Kathiresan is the Co-Founder, CEO and Board Member of Verve Therapeutics, a clinical-stage biotechnology company developing gene editing medicines to treat patients with cardiovascular disease. Sekar discusses Verve's work developing single-course, in vivo liver-directed gene editing medicines for patients with and at risk of cardiovascular disease and what the company pipeline looks like. He talks about the evolution of his pitch after years of experience with fundraising, how he approaches team building, and his perspective on why people are leaving academia for biotech. He also discusses what he's learned about being a board member and what a good board for a pre-revenue biotech looks like. Biography: Dr. Sekar Kathiresan is co-founder and CEO of Verve Therapeutics, a biotechnology company pioneering a new approach to the care of cardiovascular disease, transforming treatment from chronic management to single-course gene editing medicines. Dr. Kathiresan is a cardiologist and scientist who has focused his career on understanding the inherited basis for heart attack and leveraging those insights to improve the care of cardiovascular disease. Based on his groundbreaking discoveries in human genetic mutations that confer resistance to cardiovascular disease, Dr. Kathiresan co-founded Verve Therapeutics with a vision to create a pipeline of single-course, gene editing therapies focused on addressing the root causes of this highly prevalent and life-threatening disease. Today, Verve is advancing two initial programs that target PCSK9 and ANGPTL3, respectively – genes that have been extensively validated by Dr. Kathiresan and others as targets for lowering blood lipids, such as low-density lipoprotein cholesterol, which is a major driver of cardiovascular disease. Prior to joining Verve, Dr. Kathiresan's roles included director of the Massachusetts General Hospital (MGH) Center for Genomic Medicine, director of the Cardiovascular Disease Initiative at the Broad Institute and professor of medicine at Harvard Medical School. There, Dr. Kathiresan's research laboratory focused on understanding the inherited basis for blood lipids and myocardial infarction. For his research contributions, he has been recognized by the American Heart Association with its highest scientific honor – a Distinguished Scientist Award and by the American Society of Human Genetics with the 2018 Curt Stern Award. Dr. Kathiresan graduated summa cum laude with a B.A. in history from the University of Pennsylvania and received his M.D. from Harvard Medical School. He completed his clinical training in internal medicine and cardiology at MGH and his postdoctoral research training in human genetics at the Framingham Heart Study and the Broad Institute.

In this conversation, Daniel Belkin and Mitch Belkin speak with Sekar Kathiresan, MD, about using gene editing medications to treat cardiovascular disease. We discuss Dr. Kathiresan's company Verve Therapeutics, which has pioneered a lipid nanoparticle delivery system of a CRISPR-based gene editing technology. We delve into the pathophysiology of cardiovascular disease, the role played by LDL and the LDL receptor in atherosclerosis, the genetics underlying monogenic and polygenic risk for myocardial infarction, CRISPR and the future of gene editing technologies, and Verve's ongoing phase I trial of a PCSK9 gene editing medication (VERVE-101) in humans. Who is Sekar Kathiresan?Dr. Sekar Kathiresan, a cardiologist, geneticist, and the CEO and co-founder of Verve Therapeutics. Verve Therapeutics is a company pioneering a new approach to the treatment of cardiovascular disease with single-dose gene editing medications. Prior to co-founding Verve, he served as the director of the Massachusetts General Hospital Center for Genomic Medicine and was a Professor of Medicine at Harvard Medical School. References:Sekar Kathiresan's TwitterVerve Therapeutics websiteTirzepatide for the treatment of obesity (NEJM, 2022)____________________________________ Follow us @ExMedPod and subscribe to our Youtube channel.Daniel Belkin, MD, and Mitch Belkin, MD, are brothers and resident physicians. The External Medicine Podcast is a podcast exploring nontraditional medical ideas and innovation.   

Sekar Kathiresan, co-founder and CEO of Verve Therapeutics, on a gene edited single shot for cardiovascular disease.

Sekar Kathiresan, MD, sits down with Chadi to discuss his unique career path from esteemed cardiologist and physician-geneticist at Massachusetts General Hospital to co-founder and CEO of Verve Therapeutics.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             I'm Greg Hundley, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia. Dr Carolyn Lam:                A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal. Dr Greg Hundley:             Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.                                                 In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.                                                 During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.                                                 They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished. Dr Carolyn Lam:                Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings? Dr Greg Hundley:             It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.                                                 They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy. Dr Carolyn Lam:                Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"                                                 The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.                                                 What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction. Dr Greg Hundley:             Interesting. How do we apply this clinically, Carolyn? Dr Carolyn Lam:                These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.                                                 However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter. Dr Greg Hundley:             Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.                                                 But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.                                                 So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.                                                 So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury. Dr Carolyn Lam:                Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.                                                 Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.                                                 And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.                                                 And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.                                                 However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively. Dr Greg Hundley:             That's a lot of data, Carolyn. Help me synthesize all that. Dr Carolyn Lam:                This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.                                                 That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked. Dr Greg Hundley:             Very good. That was a very nice summary, Carolyn. Dr Carolyn Lam:                Thanks. Let's move on now to our feature discussion, shall we? Dr Greg Hundley:             Very good. Dr Carolyn Lam:                Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.                                                 The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.                                                 Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.                                                 And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed. Dr Shreyansh Shah:         I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.                                                 As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.                                                 What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.                                                 What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.                                                 While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.                                                 There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy. Dr Carolyn Lam:                Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts? Dr James Grotta:              It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.                                                 I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.                                                 There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.                                                 I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.                                                 And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.                                                 I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.                                                 I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.  Dr Shreyansh Shah:        To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.                                                 And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.                                                 And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.                                                 It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving. Dr Carolyn Lam:                Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there? Dr James Grotta:              Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.                                                 It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.                                                 So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.                                                 We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.                                                 We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.                                                 Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.                                                 So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.  Dr Shreyansh Shah:        At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome. Dr Carolyn Lam:                Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under. Dr Graeme Hankey:        Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.                                                 And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.                                                 So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.                                                 This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.                                                 And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer. Dr Carolyn Lam:                Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.  

Jane:                                     Hi, everyone. Welcome to Episode 18 of Getting Personal: Omics of the Heart. I'm Jane Ferguson, and this podcast is brought to you by the Circulation: Genomic and Precision Medicine Journal and the American Heart Association Counsel on Genomic and Precision Medicine. It is July 2018, which means that the best possible place to be listening to this episode is at the beach, but failing that I can also recommend listening on planes, during your commute, while exercising or while drinking a nice cup of tea.                                                 So before I get into the papers we published this month, I want to ask for your help. If you're listening to this right now, hi, that means you, we're a year and a half into podcasting and I would love to know what content you like and where we could improve things. We have a poll up on Twitter this week, and I would really appreciate your input. If you're listening to this a little bit later and miss the active voting part of the poll, you can still leave suggestions.                                                 Okay, so what I would like you to do right now is to go to Twitter. You can find us as Circ_Gen and locate the poll. If you don't already follow us on Twitter, go do that now too. We want you to let us know what content we should focus on and what is most useful to you, so go ahead and pick your favorites from the options and also please reply or tweet at us with other thoughts and suggestions.                                                 Options include giving summaries of the recent articles like I'm about to do later this episode, conducting interviews with authors of recently published papers, interviews with people working in cardiovascular genomics, broader topics. For example, to get their insight on career paths and lessons learned along the way.                                                 And something we have not done yet on the podcast but are considering, would be to record podcasts that focus on particular topics in genomics and precision medicine. These could give some background on an emerging field or technology and we could talk to experts who are leading particular innovations in the field. So, if that sounds good to you, let me know! If you're not on Twitter, I don't want to exclude you, so you can email me at jane.f.ferguson@vanderbilt.edu and give me your thoughts that way. I'm looking forward to hearing from you.                                                 Okay, so on to the July 2018 issue of Circ.: Genomic and Precision Medicine. First up is a PhWAS from Abrahim Rao, Eric Ingelsson, and colleagues from Stanford. The discovery of the PCSK9 gene as a regulator of cholesterol levels has led to a new avenue of LDL lowering therapies through PCSK9 inhibition. However, some studies suggest that long term use of PCSK9 inhibitors could have adverse consequences. Because of the long follow-up time required, it will take many more years to address this question through clinical studies. However, genetic approaches offer a fast and convenient alternative to address the issue.                                                 In this paper, entitled: "Large Scale  Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke," the authors use genetic and phenotype data from over 300,000 individuals in the UK BioBank to address whether genetic loss of function variants in PCSK9 are associated with phenotypes including coronary heart disease, stroke, type II diabetes, cataracts, heart failure, atrial fibrillation, epilepsy, and cognitive function.                                                 The missense variant RS11591147 was associated with protection against coronary heart disease and ischemic stroke. This SNP also associated with type II diabetes after adjustment for lipid medication status. Overall, this study recapitulated the associations between PCSK9 and coronary disease, and revealed an association with stroke.                                                 Previous studies suggested use of LDL lowering therapies may increase risk of cataracts, epilepsy, and cognitive dysfunction, but there was no evidence of association in this study. Overall, this study provides some reassurance that the primary effect of PCSK9 is on lipids and lipid related diseases, and that any effects on other phenotypes appear to be modest at best. While a PhWAS can't recapitulate a clinical trial, what this study indicates is that PCSK9 inhibition is an effective strategy for CVD prevention, which may confer protection against ischemic stroke and does not appear to convey increased risk for cognitive side effects.                                                 Next up we have a manuscript form Jason Cowan, Ray Hershberger, and colleagues from Ohio State University College of Medicine. Their paper, "Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Non-segregating LMNA Pedigrees," explored pedigrees of apparent LMNA related cardiomyopathy identifying family members who manifested disease, despite not carrying the purported causal LMNA variant. Of 19 pedigrees studies, six of them had family members with dilated cardiomyopathy who did not carry the family's LMNA mutation. In five of those six pedigrees, the authors identified at least one additional rare variant in a known DCM gene that was a plausible candidate for disease causation.                                                 Presence of additional variants was associated with more severe disease phenotype in those individuals. Overall, what this study tells us is that in DCM, there is evidence for multi-gene causality and bilineal inheritance may be more common than previously suspected. Future larger studies should consider multi-genic causes and will be required to fully understand the genetic architecture of DCM.                                                 Yukiko Nakano, Yasuki Kihara, and colleagues from Hiroshima University published a manuscript detailing how HCN4 gene polymorphisms are associated with tachycardia inducted cardiomyopathy in patients with atrial fibrillation. Tachycardia induced cardiomyopathy is common in subjects with atrial fibrillation, but the pathophysiology is poorly understood. Recent studies have implicated the cardiac hyperpolarization activated cyclic nucleotide gated channel gene, or HCN4, in atrial fibrillation and ventricular function.                                                 In this paper, the authors enrolled almost 3,000 Japanese subjects with atrial fibrillation, both with and without tachycardia-induced cardiomyopathy, as well as non-AF controls. They compared frequency of variants in HCN4 in AF subjects with or without tachycardia-induced cardiomyopathy, and found a SNP, RS7164883, that may be a novel marker of tachycardia-induced cardiomyopathy in atrial fibrillation.                                                 Xinyu Yang, Fuli Yu, and coauthors from Tianjin University were interested in finding causal genes for intracranial aneurysms, and report their results in a manuscript entitled, "Rho Guanine Nucleotide Exchange Factor ARHGEF17 Is a Risk Gene for Intracranial Aneurysms." They sequenced the genomes of 20 Chinese intracranial aneurysm patients to search for potentially deleterious, rare, and low frequency variants. They found a coding variant in the ARHGEF17 gene which was associated with associated with increased risk in the discovery sample, and which they replicated in a sample of Japanese IA and in a larger Chinese sample.                                                 They expanded this to other published studies, including individuals of European-American and French-Canadian origin and found a significantly increased mutation burden in ARHGEF17 in IA patients across all samples. They were interested in further functional characterization of this gene and found that Zebra fish ARHGEF17 was highly expressed in blood vessels in the brain. They used morpholinos to knock down ARHGEF17 in Zebra fish, and found that ARHGEF17 deficient Zebra fish developed endothelial lesions on cerebral blood vessels, and showed evidence of bleeding consistent with defects in the vessel. This study implicates ARHGEF17 as a cerebro-vascular disease gene which may impact disease risk through effects on endothelial function and blood vessel stability.                                                 Sumeet Khetarpal, Paul Babb, Dan Rader, Ben Voight, and colleagues from the University of Pennsylvania used targeted resequencing to look at determinants of extreme HDL cholesterol in their aptly titled manuscript, "Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of HDL Cholesterol in Humans." Stay tuned because we're gonna hear more about this paper from the first author Dr. Sumeet Khetarpal later this episode.                                                 Rounding out this issue we have a Perspective article from Chris Haggerty, Cynthia James, and coauthors from Geisinger and Johns Hopkins Medical Center entitled, "Managing Secondary Genomic Findings Associated With Arrhythmogenic Right Ventricular Cardiomyopathy: Case Studies and Proposal for Clinical Surveillance." In this paper the authors discuss the challenges for returning findings from clinical sequencing for arrhythmogenic right ventricular cardiomyopathy, presenting case studies exemplifying these challenges. They also propose a management approach for returning clinical genomic findings, and discuss new innovations in the light of precision medicine.                                                 We also published a review article by Pradeep Natarajan, Siddhartha Jaiswal, and Sekar Kathiresan from MGH on "Clonal Hematopoiesis Somatic Mutations in Blood Cells and Atherosclerosis", which discusses recent advances in our knowledge on the role of somatic mutations in cardiovascular disease risk.                                                 Finally, we have an update on some pharmacogenomics research into CYP2C19 Genotype-Guided Antiplatelet Therapy by Craig Lee and colleagues which we published a few months ago. Dr. Lee was also featured on Podcast episode 15 in April of this year.                                                 Jernice Aw and colleagues from Khoo Teck Puat Hospital, Singapore shared from complimentary data from their sample of 247 Asian subjects which found the risk for major adverse cardiovascular events was over 30-fold greater for poor metabolizers, as defined by CYP2C19 genotype on clopidogrel, as compared to those with no loss of function allele.                                                 You can read that letter and the response from Dr. Lee and colleagues online now. And, as usual, all of the original research articles come with an editorial to help give some more background and perspective to each paper. Go to circgenetics.ahajournals.org to find all the papers and to access video summaries and more.                                                 Our interview is with Dr. Sumeet Khetarpal who recently completed his MD-PhD training at the University of Pennsylvania, and is currently a resident in Internal Medicine at Massachusets General Hospital. Sumeet kindly took some time out from his busy residency schedule to talk to me about his recently published paper, and to explain how molecular inversion probe target capture actually works.                                                 So I am here with Dr. Sumeet Khetarpal who is co-first author on a manuscript entitled, "Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of High-Density Lipoprotein Cholesterol in Humans."                                                 Welcome Sumeet, thanks for taking the time to talk to me. Dr. Khetarpal:                    Thank you so much Dr. Ferguson, it's really a pleasure to talk to you today. Jane:                                     Before we get started, maybe you could give a brief introduction on yourself and then how you started working on this paper. Dr. Khetarpal:                    Sure, so this work actually was a collaboration that came out at the University of Pennsylvania that I was involved with through my PhD thesis lab, my mentor was Dan Rader, and also a lab that is a somewhat newer lab at Penn, Benjamin Voight's lab which is a strong sort of computational genomic lab.                                                 This work actually highlights the fun of collaborating within your institution. We had, for some time, been interested in developing a way to sequence candidate genes. Both known genes and also new genes that have come out of genome-wide association studies that underlie the extremes of HDL cholesterol, namely very high cholesterol versus low HDL cholesterol. We've been looking for a cost-effective and scalable way to do this.                                                 Independently, Ben, who is very interested in capturing the non-coding genome, was interested in developing a method to better understand the non-coding variation, both common and rare variation that may be present at all of these new loci that have come out for complex traits such as HDL.                                                 We, at some Penn event several years ago, were talking about our common interest and Ben had actually identified this work that had come out of J. Shendure's lab at the University of Washington. A paper by the first author, Brian O'Rouke, in Science in 2012 in which they had developed an approach that involved molecular inversion probes, or MIPs, to capture regions of the genome related to target the gene that they were interested in studying for autism-spectrum disorders.                                                 They had applied this largely to coding regions of, I think, almost 50 genes and almost 2,500 patients with the feedback to do deep, targeted sequencing. So our thought was, well, we could try to apply this approach and adapt it to capture non-coding regions, and also see if we can expand the utility of this approach to study the phenotypic extremes of a complex trait such as HDL cholesterol. Jane:                                     Yeah, that's really cool. I love how you saw this method in a totally different application and then realized that there was expertise at Penn that you could bring together to apply this in a different way.                                                 I'd love to hear more about this MIP, the molecular inversion probe. How does it work? How difficult is it to actually do? Is it very different from normal library preparation for sequencing or is it something that's actually relatively easy to apply? Dr. Khetarpal:                    These MIP probes are oligonucleotide probes that capture your region of interest by flanking them and capturing by gap filling. There's a method to capture parts of the genome in a library-free way. They do ultimately involve barcoding the way traditional library-based target capture does and then deep sequencing.                                                 But the most impressive feature about them is just that they're very scalable. I think in the original paper by O'Rouke and colleagues they were able to sequence their set of genes and their set of samples at about a sample preparation cost of $1 per sample, and we were actually able to do about the same for our study.                                                 The main utility of the approach is just the economic scalability, and the ability to customize your panel to capture several regions of the genome that are adjacent to each other. Jane:                                     Right, so how many genes or regions can you multiplex at the same time? Is it just one prep, like you just design all of your oligos, you put them all together in one reaction, or are you doing separate reactions for each region? Dr. Khetarpal:                    We're actually doing all of our oligos together. In our case, I think it ended up being around the order of almost 600 oligos together to capture our ultimately 50kB of genomic territory that we wanted to capture. Really, our study was kind of a pilot experiment where we picked a few genes or regions of high interest to us, both known genes that effect HDL and also those that have been implicated in genome-wide association studies that were of high interest to our labs.                                                 I think that this approach could actually be expanded to capture much more genomic territory in a single capture reaction. We sort of touched the surface probably of what we could do. Jane:                                     Wow, that's cool! And then for sequencing it, I guess it's really just a function of how many samples you wanna multiplex and how much you want to sequence from each region. So I suppose the way you did it, you had about 50kB and then you had over 1,500 participants and you were able to do those on a single HiSeq run, right? Dr. Khetarpal:                    Right. Jane:                                     So I suppose if you'd done more genetic regions, you would've had fewer people and vice versa so you can balance that out depending on if you're having more samples or more genomic regions to sequence. Dr. Khetarpal:                    Exactly, in certain ways the design of our experiment we had a limited sample size that did afford us some luxury in terms of knowing that we would have deep coverage of the region that we were targeting. I think that's always a critical question in sort of targeted or just sequencing in general. The balance between the number of regions that you want to sequence and the number of samples you want to sequence is going to dictate what your sequencing depth with be. Jane:                                     Right, okay so I guess if we go on to what you actually found, how'd you pick this? You picked seven regions which encompasses eight candidate genes for HDL, so how did you select those? Dr. Khetarpal:                    The population that we were studying, the samples we were looking to sequence were largely individuals which fall into two bins if you will. One was extremely high HDL cholesterol which we're defining as the greater than the 95th percentile, but really there was a range within that population that spanned individuals with probably greater than the 99th percentile of HDL.                                                 We were hoping as a proof of principle effort to identify variation in genes that were known causes of high HDL cholesterol in prior studies of Mendelian genes for HDL. So genes such as LIP gene which encodes endothelial lipase or CETP or SCARB1, these 3 genes are, at this point, well-known genes that loss of function mutations are associated with extremely high HDL. We thought that capturing some of those genes would potentially both provide a level of validation for the approach, hypothesizing that individuals with high HDL would be enriched with these genes, but also may allow us to find new variants in these genes or also non-coding variants which has not previously been studied before.                                                 Some of the genes came out from that line of thinking, then some of the other genes happened to be genes that in the Rader laboratory we had a vested interest in understanding the genetic variation that might link the genes to HDL, which may not have necessarily come out before.                                                 For example, the gene GALNT2 is one of the first g-loss implicated novel genes for HDL, novel as in the earliest g-loss study for plasma lipids had identified that gene as associated with HDL but it never had come out before as being so. Our laboratory was very interested in better understanding the genetic relationship between genes such as GALNT2 and several of the others such as CCDC92 and ZNF664 with HDL.                                                 It ended up being a hodge-podge or a sampling of genes that had at some level been implicated with HDL, but really it's just a proof of principle that this method could work for both identifying variation in known genes and also less studied ones. Jane:                                     You validated the MIP genotyping by exome genotyping, and then saw concordance of over 90%, is that lower than you were expecting? Was it about what you were expecting based on these two different methods of genotyping? Dr. Khetarpal:                    Yes, I think we were expecting somewhere on the order of 90 plus percent. It's hard to know why we just hit that, we likely would've benefited from being able to genotype all of the individuals by the exome chip that we had sequenced as well, where we were able to validate in about two-thirds of those individuals.                                                 It's hard to know exactly what the cause of the about 10% discordance rate might be, whether it's just in certain samples the genotyping quality was perhaps on the border of being valid or the sequencing quality. Jane:                                     Right, I'm wondering sort of with the MIP, what's the gold standard? Is the XM chip genotyping still the gold standard and the MIP maybe is more error-prone, or perhaps the other way around? Or is it you can't tell at this point which is the true genotype and which is an error potentially for those discordant ones? Dr. Khetarpal:                    Certainly whenever there's a new sequencing methodology that is proposed I think it's critical to have some sort of validation. We happened to cover regions that would span the genome enough that we had XM chip genotyping in a large subset, that that might be the best approach. But if you had a limited number of regions or variance that you were interested in one could imagine also doing Sanger sequencing as the tried and tested validation approach. Of course it becomes not so scalable at a certain point.                                                 Certainly we would say that the MIPs, while the method has been developed and expanded by the Shendure lab, our hope is that through our studies maybe it will be applied further. It's still very much a new approach and so validation is key. Jane:                                     Very important. What do you think was the most exciting finding that came out of this, after you analyzed the data, what were you most excited about seeing? Dr. Khetarpal:                    The critical finding for us, which I think implies the utility of the approach, was just the validation of four of the loci that we had studied. Validation in our cohort of known genome-wide significant associations for HDL that had been published previously in almost 200,000 individuals in terms of sample size, in our experiment involving just about 1,500 people we were able to find consistent associations of those same variants that segregated with low versus high HDL. Directionally consistent with the large genome-wide association studies.                                                 I think the value of this finding is really just to emphasize the utility of the case control design in these phenotypic extremes, in addition to the overarching goal of our study, which was in a way that perhaps provides the most validation of the approach in terms of concordance with prior known studies. Jane:                                     So if somebody was listening to this and was trying to decide should they use MIP for a study they have in mind, should they use another technique? Based on your experience, what would you recommend? Dr. Khetarpal:                    I think in our current stage it's a very exciting time because we're just seeing whole genome sequencing really take off and being used at scale to ask critical questions about non-coding variation as it relates to both disease and complex traits. I don't think we're quite there yet with being able to apply that approach in a cost effective manner. The ability to annotate and analyze that data is still at it's infancy. The utility of the MIPs is that it provides a very cheap alternative.                                                 I can say from my experiences actually doing the capture and preparation from sample to sequencer stage that it's a very easy to use methodology that is very fast and cheap. That if one is really interested in a handful, or more than a handful, of candidate genes and their non-coding regions as it relates to a trait or disease of interest, it may not be the era for going full on with whole genome sequencing, especially at the current cost. That's where I think the MIPs really come in to be very useful. Jane:                                     It sounds great, is there anything else that you'd like to mention? Dr. Khetarpal:                    Just to say that we recognize it's a relatively small study as our pioneer approach with this method but that the Rader lab and Voight labs are actively pursuing larger applications of this to study, not only HDL, but other complex traits, such as diabetes, in much larger populations. I can't overemphasize how easy of a method it is to apply, but also that I think a bigger take home of this study for me as a very recent graduate student working in a very collaborative institution the ability of two laboratories to come together with different sets of expertise to try to tackle a problem that I think goes beyond the individual science. For any human geneticist how to find the variation you're interested in and not break the bank is kind of at the core of what we do, and so I think it was very fun to be part of this collaboration and our hope is that the outcome of it is a method that can be useful for many people, both in our field and beyond. Jane:                                     I think it's great and I'm hoping this will inspire a lot of other people to try this method and see if it can work for them. So, congratulations on the study, it's really nice work. Dr. Khetarpal:    Thank you so much!                                                                                                                                       Jane:                                     That's all I have for you for July, thanks for listening. Send me your thoughts on the podcast via Twitter or email, or leave us a review in Itunes. I look forward to talking to you next month.  

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 paper takes a deep dive into nitric oxide signaling, that extremely important pathway in cardiovascular health and disease. This time, taking a novel look at genetic predisposition, phenotypic consequences, and therapeutic implications. All that coming right up after these summaries.                                                 The first original paper describes the derivation and validation of a novel model to stratify the risk of death due to circulatory etiology in patients resuscitated from cardiac arrest without an ST elevation MI.                                                 First author, Dr. Bascom, corresponding author Dr. Setter from Maine Medical Center in Portland and their colleagues use the International Cardiac Arrest Registry to derive a novel model termed the CREST Model, which describes an incrementally high risk of circulatory etiology death with an increasing score.                                                 Now, CREST is a simple score with components of C for prior coronary artery disease. R for non-shockable rhythm. E for ejection fraction less than 30% on admission. S for shock at the time of admission. T for ischemic time more than 25 minutes. The authors showed that this CREST tool may allow for estimation of circulatory risk and improve triage of cardiac arrest survivors without STEMI at the point of care.                                                 The next study reports associations between usual sodium, potassium and blood pressure using gold standard 24-hour urinary data collected for the first time among a nationally representative sample of adults in the United States.                                                 First and corresponding author Dr. Jackson from Centers for Disease Control and Prevention used cross-sectional data from 766 participants aged 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 national health and nutrition examination survey.                                                 They found that there was a strong direct relationship between higher sodium excretion and higher blood pressure and hypertension. In addition, there was an inverse relationship between potassium excretion and blood pressure and hypertension. When added to the evidence based from longitudinal and interventional studies, these results support clinicians dietary advise to lower sodium intake and increase consumption of potassium containing foods.                                                 The next two studies in this week's journal examine the utility of circulating biomarkers to aid in the diagnosis of acute aortic dissection. As a reminder, the AHA/ACC guidelines published in 2010, proposed using the aortic dissection detection risk score or ADD risk score as a primary screening tool based on scoring the presence of three categorical risks.                                                 Number one, high risk conditions such as Marfan Syndrome, a family history of aortic disease, known aortic valve disease, known thoracic aortic aneurysm or previous aortic manipulation. Number two, The pain features such as chest, back or abdominal pain described as being of abrupt onset severe intensity or ripping, tearing. Number three, the examination features such as evidence of profusion deficit, systolic blood pressure difference, spoken neurological deficit or aortic diastolic murmur and hypertension or shock.                                                 The presence of one or more markers within each of these categorical features is given an ADD score of one with a maximum cumulative score of three if all three categorical features are present. In the first of these two papers in this week's journal, first author Dr. Nazareen, corresponding author Dr. Morello and colleagues from Molinette Hospital in Italy performed the advised International Multi Centers Study, which prospectively assessed the diagnostic performance of standardized strategies integrating pre-test probability assessment and D-dimer in 1,850 patients from the emergency department.                                                 They found that in patients with an ADD risk score above one and D-dimer less than 500 nanograms per milliliter, the rate of acute aortic syndromes was significant at one in 22 cases. Rule out strategies for acute aortic syndromes integrating an ADD risk score of zero or one with D-dimer less than 500 were found to miss only around 1 in 300 cases of acute aortic syndrome.                                                 Integrating the ADD risk score with D-dimer could help to standardize diagnostic decisions on advanced imaging for suspected acute aortic syndrome balancing the risks of misdiagnosis and over testing. The authors concluded that patients at high probability of acute aortic syndrome such as with an ADD risk score above one should proceed to computer tomography and geography or other conclusive imaging irrespective of D-dimer levels.  However, in those with an ADD risk score of zero or one, with a D-dimer of less than 500 were possible rule out diagnostic strategies for acute aortic syndrome.                                                 The second manuscript in the present issue suggests that soluble ST2 might be an even better biomarker than D-dimer to rule out aortic dissection. In this paper by first author, Dr. Wang, co-corresponding authors, Dr. Du and Guo from Beijing Anzhen Hospital and Peking University respectively, the authors measured plasma concentrations of soluble ST2 using the R&D Systems assay in 1,360 patients including 1,027 participants in the retrospective discovery set and 330 patients with an initial suspicion of acute aortic dissection and ruled in a prospective validation cohort.                                                 The proportion of acute aortic dissection, this acute chest pain cohort was high at more than 40%. The authors found that soluble ST2 measured using this research grade assay showed higher levels in acute aortic dissection than in acute myocardial infarction or in acute pulmonary embolism. The result suggested that soluble ST2 levels could be useful as a rule out marker possibly even to an extent moderately superior to D-dimer.                                                 A cut-off level of around 35 nanograms per milliliters using the research grade soluble ST2 assay appeared to reliably rule out acute aortic dissection if used within 24 hours after symptom onset with a negative likelihood ratio of 0.01 and a negative predictive value of more than 99%. These intriguing findings are discussed in an accompanying editorial by Dr. Toru Suzuki from University of Leicester and Dr. Kim Eagle from University of Michigan. Well, that wraps it up for our summaries. Now, for our future discussion.                                                 Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. In fact, the pharmacologic stimulation of nitric oxide pathway is emerging as a therapeutic strategy in cardiovascular medicine in many areas including in heart failure preserved dejection fraction.                                                 Today's paper is therefore all the more intriguing because it seeks to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on the risk for cardiovascular disease as a way of informing of the potential utility of pharmacologic stimulation of the nitric oxide pathway.                                                 Intrigued? Well, I certainly and I'm so glad to have with us the corresponding author, Dr. Sekar Kathiresan from Massachusetts General Hospital as well as a familiar voice, Dr. Peipei Ping, associate editor from UCLA here to discuss this paper.                                                 Sekar, could I ask you as an introduction to tell us a little bit more of the general approach of looking at genetic predisposition as a way of perhaps forecasting potential utility of pharmacologic stimulation? Could you tell us a little bit more about that? Dr. Sekar Kathiresan:      Yes. I'm delighted to speak a little bit more about this idea of using naturally occurring genetic variation to understand if a medicine developed against a target is going to work in terms of efficacy and also potentially lead to on target side effect.                                                 As you know, there are lots of variants for mutations in genes that eventually become targets for medicines. Over the last 10, 15 years, there's been an explosion in our understanding of human genetic variation, specifically in genes targeted by medicines.                                                 The idea here is that if there's a naturally occurring mutation in that target gene, you can simply ask what are the phenotypic consequences of carrying that mutation. Also use that information to predict, as I said, the efficacy of pharmacologic manipulation and potentially on-target side effects. This approach has become a very powerful approach.                                                 A famous recent example of gene, PCSK9, where mutation in this gene occur naturally. A lower function of PCSK9 and individuals who carry this mutations have lower LDL levels and lower risk of heart attack. This information has led to the development of medicine that mimic those mutations and those medicines have been proven now to lower LDL as well as lower risk of heart attack, a phenomenon anticipated by the genetics. Dr. Carolyn Lam:               If I understand it right then, with regards to today's paper, the idea is that if a genetic predisposition to enhanced nitric oxide signaling associates with reduced risk of cardiovascular disease, then that would support the hypothesis that pharmacologic stimulation of the nitric oxide pathway would prevent or treat the cardiovascular disease, right? Could you further expand? Because you also did a meditation analysis. How would we understand that? Dr. Sekar Kathiresan:      Let me walk you through the basics of this paper. Our hypothesis initially was a genetic predisposition to enhance nitric oxide signaling would actually affect a range of cardiovascular diseases. Nitric oxide is a well-known molecule, a regulator of a number of important processes; vascular tone, blood pressure, platelet aggregation.                                                 A couple of important genes in the nitric oxide pathway are, one, nitric oxide synthase, the key enzyme that generates NO. Second is a soluble guanylyl cyclase that is a regulatory molecule involved in NO biology. One of the genes that is part of that pathway is called GUCY183, which is basically a subunit of the soluble guanylyl cyclase.                                                 What we did was we looked at those two genes and asked, "Are there naturally occurring variations in those two genes that actually give us a sense that they gain function that they actually activate nitric oxide signaling. It turned out there are two polymorphisms. One in nitric oxide synthase and the other is in the soluble guanylyl cyclase subunit that are essentially gain of function. They're common polymorphisms.                                                 We know their gain of function because the carriers of these DNA variants have lower blood pressure. An indicator that there's enhanced NO signaling. We use these two polymorphisms as an instrument to understand the phenotypic consequences of having lifelong enhanced nitric oxide signaling.                                                 What we looked at was the relationship of individuals who carried both of the gene variants or gained a function and asked whether these individuals what the relationship of carrying the variant was to a range of cardiovascular diseases as well as a range of quantitative traits like blood pressure or kidney function.                                                 We looked at this in extremely large human population samples where genotype and phenotype had been collated. Most important of these samples is a recent study of a population-based cohort study called the UK Biobank, which has involved about a half million people where genotype and have phenotype have been assembled.                                                 What we found was that genetic predisposition to enhance nitric oxide signaling was associated with reduced risk of several important cardiovascular diseases. First, coronary heart disease. Second, peripheral arterial disease, and third, ischemic stroke.                                                 That provide a very compelling evidence that atherosclerotic cardiovascular disease would be lower based on enhanced nitric oxide signaling. What was surprising to us is we also found a couple of other diseases where it seemed to benefit from enhanced nitric oxide signaling namely kidney function and pulmonary function. These were a little surprising to us, but I think it really suggest that NO plays an important role in a range of diseases.                                                 In terms of your question about what aspect of NO biology is leading to be relationship to these diseases, is it simply the blood pressure effect for example or could you actually infer a mechanisms beyond the blood pressure? We looked at that specifically in the context of cardiovascular disease and we're able to show that the protection afforded by the enhanced nitric oxide signaling gene variants, that protection exceeded the amount predicted by the blood pressure change. In fact, by quite a bit suggesting that there are probably non-blood pressure mechanisms that are at play in terms of the protection afforded by enhanced nitric oxide signaling gene variants. Dr. Carolyn Lam:               Peipei, I have to invite your thoughts now. This is such an amazing paper. We had great discussions as an editor team. Tell us your thoughts. Dr. Peipei Ping:                 The editorial team as well as the reviewers have been very impressed with the quality of the datasets and the value and detail, the metadata analysis together with the appropriate analytical approach. The study is done in our view in a very careful manner and the analysis was performed through the highest standards.                                                 What we also recognized is the potential impact that this particular study may have on multiple areas of studies, in particularly with their findings, the spectrum of individuals, how they carry nitric oxide signaling trends. You could appreciate that the individual score or genetic score paired with the analysis of the genetic variance that they have done, they see from the mental idea that examine both genetic as well as phenotype of each individual is critically important for medicine to be prescribed in the next step of therapies. Dr. Carolyn Lam:               Building on that thought, Sekar, could I ask you? You found some rare inactivating variance. Are these the patients then you think should be targeted for NO enhancing therapies? What's the clinical implications of your findings? Dr. Sekar Kathiresan:      I think there are two ways to think about the implications of these findings. One is there's just a simple biologic insight, the pharmacologic activation of NO signaling maybe protective beyond pulmonary hypertension. As you know, there are actually compounds in the clinic right now that are pharmacologic activators of soluble guanylate cyclase. Those medicines work in the rare condition of pulmonary hypertension.                                                 our work suggest that those medicines are likely to work in a broader range of indications including atherosclerotic cardiovascular disease, kidney disease and pulmonary function. At a simple level, those experiments, I think, should be looked at. Those indications should be looked at.                                                 Whether we've identified a subset of a population that particularly will respond versus it will be a general phenomenon across a range of different individuals that have impaired nitric oxide signaling, I think time will tell. Certainly, one group to think about would be those who are indigenously deficient in nitric oxide signaling and we did find that there are small subset of patients who have inactivating mutations in these two genes and they have higher blood pressure and increased risk for cardiovascular disease.                                                 It was a pretty rare phenomenon, so very small number of individuals would be relevant there. I'm not sure actually that you necessarily want to limit the potential benefit of NO signaling, enhanced NO signaling to just that subgroup. In fact, my prediction would be that the medicine would be relevant for a very large percentage of the population. That you do not need to limit the potential application of this therapy to just those who carry the inactivating mutations. Dr. Peipei Ping:                 I agree largely of what Sekar has discussed. I would add that in situations where genetic information are available with the patients, what the study has offered is fairly clear in the patients where rare variance that inactivate the NOS3 or the guanylyl cyclase off the genes. Maybe a failure it is with a higher systolic blood pressure risk. I'm entirely supportive with the general conclusion that we have come to a time point where NOS outside signaling activation is a critical new element of therapy in cardiovascular health and disease. Dr. Sekar Kathiresan:      Thank you Peipei. Thank you Sekar for taking the time to share your thoughts with us. We are so proud to be publishing paper in circulation. So proud and happy to be chatting about this on this podcast. You've been listening to Circulation on the Run. Thank you for joining us and please tune in again next week.

Jane Ferguson:                Hello, I'm Jane Ferguson and you are listening to Getting Personal: Omics of the Heart, the podcast from Circulation: Cardiovascular genetics, and the functional genomics and translational biology council of the AHA. This is episode ten, from November 2017.                                            November is always a big month for AHA and the annual Scientific Sessions were held in Anaheim, California, November 11th through 15th. For those of you who were able to attend, hopefully you came away feeling refreshed and invigorated and with your desired level of Disney merchandise. For those of you who could not attend, or who didn't make it to all of the genomic sessions, this month's episode should catch you up.                                            For the past several years, the FGTB Council has been organizing boot camps at AHA sessions to give people a chance for hands on learning in a flipped classroom model. This year was no exception and in addition to a clinical genomics boot camp focused on patient centric genomics including single gene testing, whole genome sequencing and pharmacogenomics there was also a new boot camp focused on tackling big data network systems analysis for high input data interpretation.                                            These boot camps are always very well attended and popular, so if you're interested in attending one next year, make sure to get in early and sign up during registration. There was also a hands on session in collaboration with the AHA's Precision Medicine Institute to teach people how to use the precision medicine platform to further their research.                                            In addition to this, there was a full day of programming related to precision medicine in the precision medicine summit, which is held on the Tuesday of Sessions. That covered topics ranging from big data, electronic health records, collaborations and the All of Us initiative to rapid fire reports from ongoing consortium, large scale analysis to disease specific approaches in cardiomyopathy.                                            We were planning to have an in depth focus on the Institute for Precision Cardiovascular Medicine in a future podcast episode, so stay tuned for more on that coming soon. There were a number of individuals who were recognized for their contributions to science and we would like to congratulate all of these outstanding individuals.                                            The FGTB medal of honor was awarded to Stuart Cook from the Duke National University of Singapore. The FGTB mentoring award was awarded to Robert Gerszten from Beth Israel Deaconess Medical Center. The FGTB distinguished achievement award went to Sekar Kathiresan from the Broad Institute. And the functional genomics and epidemiology mid-career research award went to Kiran Musunuru from the University of Pennsylvania. Congratulations to all of these.                                             One of the highlights for the FGTB council at sessions is the FGTB young investigator award. This award celebrates early career investigators and recognizes outstanding research in basic science, populations science, genetic epidemiology, clinical genetics and translational biology. Four finalists presented their research on the Sunday afternoon sessions and I had the chance to chat with all four of them before and after their presentations. So listen on for a behind the scenes over view of the finalists research and the announcement of the winner.                                            Mark Benson is a cardiology fellow at Brigham and Women's Hospital and is working on post-doctoral research at the Beth Israel Deaconess Medical Center in Boston with Dr. Robert Gerszten. His talk was entitled "The Genetic Architecture of the Cardiovascular Risk Proteum." Mark Benson:                  My name's Mark Benson. I'm just finishing up a cardiology fellowship at Brigham and Women's Hospital and am in the middle of post doc in Robert Gerszten’s lab at Beth Israel. Jane Ferguson:                Great, and congratulations on being chosen as a finalist for the FGTB Young Investigator Award. We would love to hear a little bit more about what you’re working on and what you're gonna be telling us. Mark Benson:                  Yeah, absolutely. So the goal of the project was really to integrate proteomic data with genomic data, with the idea that we may be able to use the overlap between those data sets to identify potentially novel biological pathways that underlie very early cardiovascular disease risk.                                            And the thinking behind that was that the lab had just finished up applying DNA-aptamer-based proteomic platform to profile over 110 proteins and the Framingham-Offspring Cohort and from that work, we had identified a very specific signature of 156 proteins in plasma that were each very strongly associated with cardio-metabolic risk.                                            The idea was while those associations were very strong, it was unclear if we were capturing cart or horse or how these associations were fitting together. We wanted to incorporate the genomic data to try to get a better handle on that, to try to connect those pathways to see how these proteins might actually associate with the end phenotype of risk. Jane Ferguson:                It's a sort of Mendelian randomization-esque. Mark Benson:                  Exactly, yeah. So what we were able to find in doing this, we were able to use peripheral blood samples from participants at the Framingham-Offspring study. With a validation in participants of the Swedish Malmo Cancer and Diet Study. Then we did protein profiling using commercial DNA aptamer platform, soma scan. What we were able to find is we were able to detect very strong associations between these circulating cardio metabolic risk-proteins and genetic variance.                                            What was fascinating was we were able to see many things. We were able to start mapping where are these associations, where are these genetic variance in relation to, for example, the gene that's coding the protein that we're measuring. That had some interesting implications because for about half of the protein that had significant associations, we could track those genetic variance back to the gene. It was coding the protein that we were measuring, which was interesting because it's validating the specificity of the proteomic platform that we're using. Jane Ferguson:                Right that's nice, because so often you found a gene that's nothing related to what you think it's going to be so it's nice actually the gene you expect. Mark Benson:                  Yeah, it's very reassuring too when you're looking at rows and rows and rows of data. When the top association of the p value of 10 in the minus 300 is the actual gene you thought would be coding the protein that you're measuring. So that was very reassuring, but we also found dozens and dozens and dozens of associations that were totally unexpected and that may point to completely unexplored biological pathways in cardiovascular disease. So that was obviously very exciting.                                            That actually led us to do two things. One was to make all these data available publicly on dbGaP because as a resource for cardiovascular research there is just way too much data for one group or a handful of groups to digest. The other thing that was fun about the project, is we were able to take one association that was particularly interesting for a number of reasons and experimentally validate it in a tissue-culture model. Jane Ferguson:                So how did that work? Mark Benson:                  So this was an interesting challenge where we all of a sudden got all of these hits back, which was probably to be expected, but to try to figure out which of these dozens and dozens and dozens of new, unexpected hits, what do you do? There was one hit, one association, that was particularly strong and it was between several variance around this gene. That's a phosphatase called PPM1G. It's a transcription factor.                                            These variants, which was interesting, were associated with several different circulating cardio metabolic risk proteins. So our idea was, isn't that interesting? Is it possible that this is mapping to some central regulator? And so it fit that that would be ... that the nearest gene to these variants was a transcription factor and could be a central regulator.                                            What made it more interesting to us was that several variants in the GLGC had recently been described that were highly associated with circulating levels of total cholesterol and triglycerides and they were located around this PPM1G locus as well. The association between those variants and circulating cholesterol didn't have a clear biological connection.                                            So what our work had shown is that those same variants were associated with circulating levels of apolipoprotein E. So wouldn't that be interesting if these variants mapped to PPM1G, the transcription factor, this PBM1G in turn regulated circulating apolipoprotein E and that would provide some insight into the biology behind the GLGC findings.                                            So sure enough we were able to knock down PPM1G using SRNA and hepatocytes and then see that that led to a significant down regulation of the transcription of Apo-B and extra-cellular presumably secreted Apo-B in this model, which is kind of a nice proof of principal that this idea of integrating proteomics and genomics may lead to some novel biological pathways. Jane Ferguson:                Yeah, it's really interesting. So what's next. There are probably a lot more associations that you're going to have to go after? Mark Benson:                  Yeah, I think that what this showed us is that this seems like a powerful tool. Joining these orthogonal data sets to find new pathways and so we're continuing to pursue that with an increasing number of proteins for example, so we're doing genome-wide association studies and x-gamma rays. We've gone from 156 to 1100 to 1300 and are now going beyond that and so as those numbers get higher, you start to see these central nodes come together and more interesting targets and potential pathways. It's also interesting to use these data to find new associations or new tools that you would never think to look for as ways to modulate protein levels.                                            So you can imagine, for example, one thing that we've been exploring for the last few months is can we identify, for example, SNP associated with an interesting circulating protein. That SNP maps to an enzyme or some other druggable mechanism and very preliminary studies, it seems like the answer is probably yes, but there is still a lot of work to be done. Jane Ferguson:                Well that's cool. That sounds really interesting. Mark Benson:                  Yeah, I think the key thing is that all these data will soon be out there and so it's a very rich data set and I think there are many ways that we could use the data. Jane Ferguson:                So is that the genomic data and all the proteomic data or it's the summary of the those associations? Mark Benson:                  All the genomic data, all the proteomic data and the associations as well. You can do the associations yourself if you'd like to. Jane Ferguson:                We can find that  dbGaP. Awesome, well thank you for talking to us. Mark Benson:                  Thank you. It's been fantastic. Jane Ferguson:                Congratulations again. Mark Benson:                  Thanks so much. ... Jane Ferguson:                Jenny Lin is an instructor at the University of Pennsylvania, working with Dr. Kiran Musunuru. Her presentation was entitled, "RNA binding protein A1CF Modulates Plasma Triglyceride Levels through Transcriptomic Regulation of Stress-Induced BLDL Secretion".                                            Jenny, can you take a moment to introduce yourself? Jenny Lin:                          Yes, hi. Thank you for this opportunity to participate. I'm Jenny Lin. I'm an instructor of medicine at the University of Pennsylvania, a nephrologist by clinical training, but training in cardiovascular research in Kiran Musunuru's lab. Jane Ferguson:                So congratulations for getting selected as a finalist for the Young Investigator Award. We'd love to hear a little bit more about what you've been presenting and what you've been working on. Jenny Lin:                          Thank you. So basically, what I've been working on over the past year is functional follow-up of this A1CF locus, which is a novel locus for triglycerides. So say Sek Kathiresan's group recently published in Nature Genetics and x and y association study on plasma lipids involving more than 300,000 individuals.                                            One of the key findings from that study is this strong association between a lo-frequency coding variant and elevated plasma triglycerides. So we wanted to delve more deeply into the biology for why we have that genotype/phenotype connection. One of the key things that we wanted to do was ... A1CF is not a stranger to lipo-protein metabolism, but we wanted to see what else it may be doing outside of its canonical role of facilitating the editing of Apo-B messenger RNA.                                            It really took us on a little bit of a wild journey using different unbiased approaches to try to figure out some of the mechanisms that could be behind it. Jane Ferguson:                So you had to do a lot of different types of experiments to really get at this question. Jenny Lin:                          Yeah. So again, one thing we wanted to see was: if you lose A1CF function, whether or not you would have differences in Apo-B 100-B48. We actually found that A1CF isn't even needed for that editing reaction and that our mice that we were able to create with crispr cas9 genome editing, so knocking in the mutation and knocking out the gene, actually have the phenotype even though they don't have changes in editing.                                            But what surprised us was that we know that A1CF as an RNA binding protein binds Apo-B transcript, yet it somehow does not alter transcriptional abundance of the Apo-B messenger RNA. And it has nothing to do with Apo-B synthesis so we basically had to think, what is A1CF doing outside of Apo-B biology?                                            We found that you have A1CF loss of function, you have increased triglycerides secretion. There is more Apo-B secretion, but that seems to be a downstream effect of other processes going on in the cell and to really try to figure out what those processes are, we had to take an unbiased approach using enhanced clipseek to figure out binding targets and also doing some transcriptional profiling with RNA sequencing and found that it's not necessarily regulating that transcriptum on a differential expression level, but there are some key alternative splicing events as well as messenger RNA binding to affect translational efficiency of some key targets that could be driving the biology. Jane Ferguson:                That's really interesting and you wouldn't have been able to find that by just looking at levels of protein or levels of mRNA, you really had to do these additional clipseek and some experiments to really get at this splicing. Jenny Lin:                          Yeah, so it's been interesting. Clipseek is not as commonly performed method, so we had to collaborate with some brilliant people over at UCSD, to help us facilitate this. But again, finding that A1CF binds many more transcripts than Apo-B itself is a novel finding and the fact that it can regulate alternative splicing is also a very novel finding as well. Jane Ferguson:                So what was the most challenging part of this whole project? Jenny Lin:                          I think the challenging part was that when we saw there wasn't necessarily a direct effect on Apo-B abundance and having to then cast this wide net and then figure out from all of the different unbiased data we have and integrating it find different pathways that may be relevant. In this case, it may all be relevant to ER stress, which is a field that is a little bit controversial in VLDL secretion in terms of directionality, but certainly is important in the biology. Jane Ferguson:                So is that something that you're going to have to start doing in the future? Are you going to start looking at ER stress or what kind of other experiments do you think you're going to keep doing to move this project forward? Jenny Lin:                          Yeah, so actually, I think focusing in on A1CF as an RNA-binding protein and pursuing some of these additional targets will also be relevant, so I think in terms of ER stress, we could be looking at different targets, but there other processes going on in the cell that's mediated by A1CF, that could contribute maybe doing some isoform specific studies just to really prove that these alternative-splicing changes are driving some of the biology.                                            There's a lot of work to do as I would joke to anyone on study section listening to this, perhaps four to five years of work for an RO1. Jane Ferguson:                Sounds very appropriate. Jenny Lin:                          Yeah, there's a lot of exciting work to do. A1CF is actually also a locus for other cardio-metabolic relevant traits such as uric acid, gout and kidney function so there could be something very interesting going on. There could be cross talk among cellular processes that could lead to these different phenotypes. Jane Ferguson:                Really interesting project and a lot of really great work. Congratulations again on being selected as finalist and on this really interesting paper. Jenny Lin:                          Thank you. Jane Ferguson:                Thanks.                                            Sarah Parker is based in Cedar Sinai Medical Center in LA and her mentor is Dr. Jenny Van Eyk. The title of her presentation was "Identification of Putative Fibrous Plaque Marker Proteins by Unsupervised Deconvolution of Heterogeneous Vascular Proteomes ". And I apologize in advance for the quality of this recording. The background noise wasn't that noticeable at the time, but that recording really gives you that full immersive audio experience of a busy hotel lobby.                                            Hey Sarah. Thank you for joining us. Could you just take a few moments to introduce yourself to the audience? Sarah Parker:                   So I'm Sarah Parker. I'm a project scientist at Cedar Sinai Medical Center where I'm doing work to study the basic mechanisms of vascular biology of various indolent conditions. Jane Ferguson:                So congratulations on being selected as a finalist for the Young Investigator Award. It's a great achievement. I'd love to hear a bit more about your project, how that started and what you found. Sarah Parker:                   The work that I did was under the overarching umbrella of a project called the Genomic and Proteomic Architecture of Atherosclerosis. So with this project, we're using tissues that we're able to obtain from individuals who are young and have passed away from traumatic and violent and so non-cardiovascular causes of death. Because of the presence of atherosclerosis in the population, we get this range of lesion, both fatty streak and fibrous-plaque lesions in these asymptomatic or non-diseased individuals and this gives us this opportunity to do some molecular profiling to really try to find protein-signatures of early stage plaque formation, that could ultimately and hopefully be used for biomarker development. Jane Ferguson:                That's really cool and that's such a valuable sample resource. Sarah Parker:                   Yeah so we've essentially, in this project I was able to set up a pipeline that enabled us to do these proteomics on such a large scale, because that's actually really difficult in label free quantitative proteomics and to use other forms becomes very expensive and cost-limiting.                                            So we were able to find a panel of proteins that we think are a putative early set of fibrous plaque markers and with this panel, we took them to see if any of these tissue derived markers would then be detectable and informative in plasma, because that's the next really big translational leap with these discovery-type data sets. Of our 58 initial candidates, we were able to detect 39 of them and about a handful 10-13 are showing informative behavior in the plasma of initial cohort of women with known coronary-artery disease. Jane Ferguson:                So out of the 58 that you first found, how many of them were potentially known to be involved in disease and how many were novel? Sarah Parker:                   I would say, going through the list, it was probably about 50/50 in terms of background data that shows role as a biomarker, so there are a lot of apolipoproteins, which have all been characterized as potential biomarkers. There were a lot that could feasibly be linked through the literature to atherosclerosis. Most of them made a lot of sense, but having been proposed as potential biomarkers, some of them were more rare. Jane Ferguson:                Were there any of them that were sort of in different directions, let's say were elevated in tissue, but then were lower in plasma? Sarah Parker:                   Funny you should ask. That actually has us scratching our heads a little bit right now. There were a couple of apolipoproteins that are more associated with HDL biology that we saw as being elevated in the tissue but then lower in the plasma [inaudible 00:23:34] so that's a really interesting observation so something about the role of these proteins to scavenge cholesterol and then once they're in the blood, they're cleared really quickly relative to normal, or something. So we're really trying to figure out what that biology means. Jane Ferguson:                Maybe if they're building up in the tissue, that's bad. But while in circulation, they're fine. Sarah Parker:                   Yeah, maybe they're trapped in the circulation. We have a lot of exciting hypotheses to test along that front. Jane Ferguson:                So what's next? Are you following up some of these proteins? Sarah Parker:                   Yep, so we have a huge discovery arm to the project where we're looking for more molecular mechanisms like why do we have these things in the tissue versus plasma and then we are working to really validate and optimize these multi-plexes in much more generalized large-scale populations to determine whether this strategy of instead of one or two biomarkers, more of a signature-style panel can be informative, especially as we try to press towards a precision medicine approach where different substratum might be informed by different protein signatures. Jane Ferguson:                Right, so you might have to have a specific panel based on sex or age or race or some other demographic. Sarah Parker:                   Yes and to find those signatures, it's going to be very big numbers, with very accurate, careful quantitation. Jane Ferguson:                So you have a lot of work to do. Sarah Parker:                   Yes. Jane Ferguson:                Alright, well thank you for talking to us and congratulations again.                                            Louie Wang, a cardiologist and PhD student came all the way from the Victor Chang Cardiac Research Institute in Syndey, Australia. His mentor is Dr. Diane Fatkin. The title of his talk is "A novel zebrafish model of human A-band truncated titan exhibits alternated ventricular diastolic compliance in vivo and reveals enhanced susceptibility to the effects of volume overload in mutation carriers.                                            So thank you for joining me. Could you take a few minutes to introduce yourself? Louie Wang:                     So I'm Louie Wang. I'm a cardiologist based in Australia. I work and live in Sydney. I'm a PhD student at the Victor Chang Cardiac Research Institute and I'm an NHMRC (National Health and Medical Research Council and National Heart Foundation of Australia post-graduate scholar). I have previously been based at St. Vincent's Hospital. Jane Ferguson:                Great. So we'd love to hear a little bit in advance of what you're working on and what you're planning to present. Louie Wang:                     So basically what I'm presenting is what I think is a different form of functional of genomics. What we're actually looking at is the impact of genetic changes, specific genetic change on function of the heart at an organ level. So there is a problem out there that is very common in cardiology and it's a big problem in cardiology and that is there are mutations in the sarcomere protein titan, truncating variants which actually are associated with dilated cardiomyopathy.                                              Now they're pretty common in idiopathic dilated cardiomyopathy, present in about 15-20% of the cases depending on which cohort study you look at. But they're also widely prevalent in the general population. Somewhere between 0.3 to 1% of the general population carries this truncating variants or various forms of this truncating variant.                                            So it's not sure whether these are disease-causing in their own right or if it's just a genetic susceptibility factor for heart failure and so what our work involves is that we actually, by chance, at St. Vincent's Hospital and at Victor Chang Cardiac Institute, two families who had the identical genetic truncation in the A-band region of his human titan gene where the individuals in the family, typically who carried the gene, typically developed systolic heart failure, which is a mild phenotype and occurred at middle age, but in two individuals, they developed severe onset accelerated disease trajectory in a very severe phenotype when exposed to conditions associated with chronic volume overload.                                            We suspect and this was a hypothesis, not only was this genetic-truncation disease-causing, but at volume overload was disease-modifying and given that volume overload is a very common condition present in birth, a lot physiological processes like lung endurance, exercise, pregnancy as well as a lot of pathological disease states in cardiovascular disease, this was actually a very important modifiable factor.                                            So what we did, was we created a novel zebrafish model of this human A-band truncated variant. We then studied the animals when they became adults to look at their heart structure and function and we used zebrafish echocardiography. So reversed translated all the techniques you can do in human echocardiography so they can be used in the zebrafish.                                            What we found was, yes, this animal, or heterozygotes developed dilated cardiomyopathy but also the volume overload exacerbated this condition. So this is a phenomenon that has conserved this by four hundred million years of vertebrate evolution so this is a pretty important mechanism. Jane Ferguson:                So what kind of next steps do you see for this project? Louie Wang:                     So one thing is that we obviously have shown that there is an association with volume overload in precipitous disease. The corollary of our work is that perhaps interventions that could reduce volume load in these genetic susceptible individuals or alternatively in people who can't avoid volume overload. Because a lot of volume overload conditions can be modifiable and perhaps this could be protective and that would have wide-ranging population benefits. Jane Ferguson:                Thank you for sharing that soundbite of your work and good luck. Congratulations again on becoming a finalist. Louie Wang:                     Thank you. ... Jane Ferguson:                Each of these four finalists gave compelling presentations of their research and the judges were highly impressed of the quality of the research and level of accomplishments of these early career investigators.                                            Just getting selected as a finalist for this award is a huge accomplishment. But there did have to be one winner. I'm delighted to announce that Jenny Lin was selected as the 2017 FGTB Young investor award winner. Congratulations, Jenny, and thanks to all four finalists for agreeing to appear on this podcast.                                            And that's all for this month. We'll be back at the end of December with a new episode. Subscribe to the podcast through iTunes or your favorite podcast app. to get new episodes delivered automatically and thank you for listening.

Eric Topol speaks with Sekar Kathiresan about cardiovascular genomics, why 'DNA isn't destiny,' and why we still have heart attacks in spite of statins.

Dr. Sekar Kathiresan. Genetic Mapping for Blood Lipids and Risk for Myocardial Infarction: What Have We Learned? Recorded 2011-03-07.