POPULARITY
5 episodes with cpvt
3 episodes with cpvt
2 episodes with cpvt
2 episodes with cpvt
2 episodes with cpvt
This week we review a recent large scale study on catecholaminergic polymorphic ventricular tachycardia (CPVT) in children which is based on two large international registries. How do outcomes differ between those symptomatic CPVT patients treated with or without an ICD? Who amongst symptomatic CPVT pediatric patients likely warrant an ICD? What sort of ICD might be optimal - subcutaneous or transvenous? Are there ways to program ICD's in CPVT patients that may reduce inappropriate shocks? Why should the ICD be rarely employed in the CPVT pediatric patient? These are amongst the questions reviewed this week on the podcast. We speak with the work's senior author, Dr. Shubhayan Sanatani who is the chief of pediatric cardiology at BC Children's Hospital in Vancouver, British Columbia, Canada. doi: 10.1016/j.hrthm.2024.04.006. Epub 2024 Apr 7.
Dr. Amit Goyal, along with episode chair Dr. Dinu Balanescu (Mayo Clinic, Rochester), and FIT leads Dr. Sonu Abraham (University of Kentucky) and Dr. Natasha Vedage (MGH), dive into the fascinating topic of channelopathies with Dr. Michael Ackerman, a genetic cardiologist and professor of medicine, pediatrics, and pharmacology at Mayo Clinic, Rochester, Minnesota. Using a case-based approach, they review the nuances of diagnosis and treatment of channelopathies, including Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and long QT syndrome. Dr. Sonu Abraham drafted show notes. Audio engineering for this episode was expertly handled by CardioNerds intern, Christiana Dangas. The CardioNerds Beyond the Boards Series was inspired by the Mayo Clinic Cardiovascular Board Review Course and designed in collaboration with the course directors Dr. Amy Pollak, Dr. Jeffrey Geske, and Dr. Michael Cullen. CardioNerds Beyond the Boards SeriesCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Channelopathies One cannot equate the presence of type 1 Brugada ECG pattern to the diagnosis of Brugada syndrome. Clinical history, family history, and/or genetic testing results are required to make a definitive diagnosis. The loss-of-function variants in the SCN5A gene, which encodes for the α-subunit of the NaV1.5 sodium channel, is the only Brugada susceptibility gene with sufficient evidence supporting pathogenicity. Exertional syncope is an “alarm” symptom that demands a comprehensive evaluation with 4 diagnostic tests: ECG, echocardiography, exercise treadmill test, and Holter monitor. Think of catecholaminergic polymorphic ventricular tachycardia (CPVT) in a patient with exertional syncope and normal EKG! ICD therapy is never prescribed as monotherapy in patients with CPVT. Medical therapy with a combination of nadolol plus flecainide is the current standard of care. Long QT syndrome is one of the few clinical scenarios where genetic testing clearly guides management, particularly with respect to variability in beta-blocker responsiveness. Notes - Channelopathies 1. What are the diagnostic criteria for Brugada syndrome (BrS)? Three repolarization patterns are associated with Brugada syndrome in the right precordial leads (V1-V2): Type 1: Prominent coved ST-segment elevation displaying J-point amplitude or ST-segment elevation ≥2 mm, followed by a negative T wave. Type 2/3: Saddleback ST-segment configuration with variable levels of ST-segment elevation. It is important to note that only a type 1 pattern is diagnostic for Brugada syndrome, whereas patients with type 2/3 patterns may benefit from further testing. The Shanghai score acknowledges that relying solely on induced type 1 ECG changes has limitations. Therefore, one cannot equate the presence of a type 1 Brugada ECG pattern alone to the diagnosis of Brugada syndrome. The score suggests incorporating additional information—such as clinical history, family history, and/or genetic testing results—to achieve a definitive diagnosis. 2. What is the significance of genetic testing in Brugada syndrome? There are 23 alleged Brugada syndrome susceptibility genes published with varying levels of evidence. However, only one gene mutation, the loss-of-function variants in the SCN5A gene encoding for the α-subunit of the NaV1.5 sodium channel, is considered to have sufficient evidence. The overall yield of BrS genetic testing is 20%. The presence of PR prolongation (>200 ms) along with type I EKG pattern increases the yield to 40%. On the contrary, in the presence of a normal PR interval, the likelihood of SCN5A positivity drops to
This week we enter the world of cardiogenetics and electrophysiology when we review the topic of catecholaminergic polymorphic ventricular tachycardia (CPVT). Is there a 'best' beta blocker for the treatment of this condition? Why is one better than others? How should one manage the patient who is intolerant of beta blockade but needs it for prevention of arrhythmia? What is the role of flecainide, sympathectomy or even ICD's for these patients? PhD candidate and physician Dr. Puck Peltenburg and CPVT world authority, Dr. Christian van der Werf (both of University of Amsterdam) share their deep insights this week. doi: 10.1161/CIRCULATIONAHA.121.056018. Epub 2021 Dec 7
This month on Episode 41 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the September 30 and October 14 issues of Circulation Research. This episode also features an interview with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, to discuss their study, Transcriptional and Immune Landscape of Cardiac Sarcoidosis. Article highlights: Tian, et al. EV-Mediated Heart Brain Communication in CHF Wleklinski, et al. Impaired Dynamic SR Ca Buffering Causes AD-CPVT2 Masson, et al. Orai1 Inhibition as a Treatment for PAH Li, et al. F. Prausnitzii Ameliorates Chronic Kidney Disease Cindy St. Hilaire: Hi, and welcome to Discover Circ Res, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to highlight articles from our September 30th and October 14th issues of Circulation Research. I'm also going to have a chat with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to discuss their study Transcriptional and Immune Landscape of Cardiac Sarcoidosis. But before I get to the interview, I'm going to highlight a few articles. Cindy St. Hilaire: The first article I'm going to share is Extracellular Vesicles Regulate Sympathoexcitation by Nrf2 in Heart Failure. The first author of this study is Changhai Tian, and the corresponding author is Irving Zucker, and they are at University of Nebraska. After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling, and ultimately, heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI, likely due to upregulation of Nrf2-targeting microRNAs. These microRNAs can also be packaged into vesicles and released from stressed heart cells. Now, this group has shown that rats and humans with chronic heart failure have an abundance of these microRNA-containing EVs in their blood. In the rats with chronic heart failure, these extracellular vesicles were found to be taken up by neurons of the rostral ventrolateral medulla, RVLM, wherein the microRNA suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system, and in the presence of EVs, it is ramped up by sympathetic excitation. Because such elevated sympathetic activity can induce the fight or flight response, including increased heart rate and blood pressure, this would likely worsen heart failure progression. The team, however, found that inhibiting microRNAs in the extracellular vesicles prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically. Cindy St. Hilaire: The next article I want to highlight is titled, Impaired Dynamic Sarcoplasmic Reticulum Calcium Buffering in Autosomal Dominant CPVT2. The first author of this study is Matthew Wleklinski, and the corresponding author is Bjӧrn Knollmann, and they are at Vanderbilt University. Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure, and other features of the fight or flight response. For people with catecholaminergic polymorphic ventricular tachycardia, or CPVT, physical activity or stress can cause potentially lethal arrhythmias. Mutations of calsequestrin-2, or CASQ2, which is a sarcoplasmic reticulum calcium-binding protein, is a major cause of CPVT, and can be recessive or dominant in nature. For many recessive mutations, disease occurs due to loss of CASQ2 protein. This group investigated a dominant lysine to arginine mutation in this protein, and found by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so, too, was the protein's subcellular localization. The mutation instead interfered with CASQ2's calcium binding or buffering capability within the sarcoplasmic reticulum. The result was that upon catecholamine injection or exercise, the unbound calcium released prematurely from the sarcoplasmic reticulum, triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations. Cindy St. Hilaire: The next article I want to highlight is from our October 14th issue of Circulation Research, and the title of the article is ORAI1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. The first author is Bastien Masson, and the corresponding author is Fabrice Antigny, and they're from Inserm in France. In pulmonary arterial hypertension, the arteries of the lungs become progressively obstructed, making it harder for the heart to pump blood through them, ultimately leading to right ventricular hypertrophy and heart failure. A contributing factor in the molecular pathology of pulmonary arterial hypertension is abnormal calcium handling within the pulmonary artery smooth muscle cells. Indeed, excess calcium signaling causes these cells to proliferate, migrate, and become resistant to apoptotic death, thus leading to narrowing of the vessel. This group now identified the calcium channel ORAI1 as a major culprit behind this excess signaling. Samples of lung tissue from pulmonary arterial hypertension patients and a pulmonary arterial hypertension rat model had significantly upregulated expression of this channel compared with controls. And in patient pulmonary arterial smooth muscle cells, the high ORAI1 levels resulted in heightened calcium influx, heightened proliferation, heightened migration and reduced apoptosis. Inhibition of ORAI1 reversed these effects. Furthermore, in pulmonary hypertension model rats, ORAI1 inhibition reduced right ventricle systolic pressure and attenuated right ventricle hypertrophy when compared with untreated controls. This study indicates that ORAI1 inhibitors could be a new potential target for treating this incurable condition. Cindy St. Hilaire: The last article I want to share is titled Faecalibacterium Prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis. The first author of this study is Hong-Bao Li, and the corresponding author is Tao Yang, and they are from the University of Toledo. Progressive renal inflammation and fibrosis accompanied by hypertension are hallmarks of chronic kidney disease, which is an incurable condition affecting a significant chunk of the world's population. Studies indicate that chronic kidney disease is linked to gut dysbiosis. Specifically, depletion of lactobacillus bifidobacterium and faecalibacterium, prompting investigations into the use of probiotics. While supplements including lactobacillus and bifidobacterium have shown little effectiveness in chronic kidney disease, supplementations with F. prausnitzii have not been investigated. Now, this group has shown in a mouse model of chronic kidney disease that oral administration of F. prausnitzii has beneficial effects on renal function, reducing renal fibrosis and inflammation. This bacterial supplementation also produced the short chain fatty acid butyrate, which was found to be at unusually low levels in the blood samples from the CKD model mice and from chronic kidney disease patients. Oral supplementation with this bacterium boosted butyrate levels in the mice, and in fact, oral administration of butyrate itself mimicked the effects of the bacteria. These findings suggest that supplementation with F. prausnitzii or, indeed, butyrate could be worth investigating as a treatment for chronic kidney disease. Cindy St. Hilaire: Today I have with me Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to talk about their paper, Transcriptional and Immune Landscape of Cardiac Sarcoidosis. This is in our September 30th issue of Circulation Research. Welcome, and thank you for taking the time to speak with me today. Chieh-Yu Lin: Thank you for inviting us. It's a great honor to be here today. Kory Lavine: Thank you. Cindy St. Hilaire: Really great paper, ton of data, and hopefully, we can pick some of it apart. But before we get into it, I actually want to just talk about sarcoidosis generally. I know it's a systemic inflammatory disease that has this kind of aggregation of immune cells as its culprit, and it can happen in a bunch of different organs. It's mostly in the lung, but it's also, like you're studying, in the heart. Can you just give us a little bit of background? What is sarcoidosis, and how common is cardiac sarcoidosis? Chieh-Yu Lin: Well, this is actually a great question, and I'll try to answer it. You actually capture one of the most important kind of features for sarcoidosis. It happens in all kind of organ system, mostly commonly in lung, in lymph nodes, but also in heart, spleen, even in brain, or even orbit, like eyes. It's really a truly multisystemic disease that has been characterized by this aggregate of macrophages, or myeloid cells, with scattered multinucleated giant cells, as the name implies, have multiple nuclear big, chunky, cells that form an aggregate. That's kind of like a pathognomonic feature for sarcoidosis, whether it's happening in lung, in the heart. When any organ system, a lot of studies has been done, but as of now, a very clear pathogenesis or mechanism has been, I would say, still pretty elusive, or still remain quite unclear, despite all the great effort has been made in this field. The other thing is that a lot of the studies actually focusing on pulmonary sarcoidosis for good reasons. Actually, that's one of the most common manifestations. For cardiac sarcoidosis, although it's only effect in probably, I would say depends on the data, 20% to 30% of the outpatient that with sarcoidosis, with or without lung involvement. It's actually carry a very significant clinical implications as of matter that the presentation of cardiac sarcoidosis can be devastating and sometimes actually fatal. Some of the study actually show that cardiac sarcoidosis actually higher, up to 80%, just because the first presentation's actually, unfortunately, sudden cardiac death. That's why Kory and I, we teamed up. I'm a cardiothoracic pathologist, so in my clinical practice I see specimens and samples from human body, from patient suffer from sarcoidosis, both in lung, lymph node, and heart. Kory is an outstanding heart failure, heart transplant cardiologist, see the other end, which is the patient care. This disease, specifically in heart, its presentation and its pathogens in heart, really attracts our attention. Cindy St. Hilaire: Do we know any or some of the potential causes? Why it would start, maybe in a different patient population, but also in the heart versus the lung? Do we know anything about that process? Kory Lavine: We know nothing about it. Sarcoid has no known etiology. There's been thoughts in the past that it may be driven by infection, the typical pathogens or autoimmune ideologies, but really, there's little data out there to support those possibilities. Right now, the field's wide open. The other challenge is we don't really have a good way to treat this disease, so a lot of the therapies available are things like steroids, which can have some effect on the disease but carry a lot of risk of complications. The other agents that we sometimes use to lower the doses of steroids, things like methotrexate and azathioprine, are only modestly effective. These are really the motivation for Chieh-Yu and myself to pursue this. We don't really know what causes the disease, and we don't really have very good treatments. We really wanted to take the first step, that's to study the real disease, and understand what are the pathologic cell types that are present within the granuloma, which is these aggregation of immune cells that Chieh-Yu was speaking about. Cindy St. Hilaire: What is actually happening at the beginning of this disease? These granulomas form, and then what is the pathological progression in the heart? What goes on there? Chieh-Yu Lin: This is actually another great question that I will say there's not much that has been discovered because, especially in human tissue, every time we have a sample, it's actually a kind of time point. We cannot do a longitudinal study. But in general speaking, very little is known about how it's initiated because it will need to accumulate to a certain disease burden for this to have a clinical symptom sign and be manifested, and then being clinically studied. We do know that in both heart and lung after treatment of progressions, it's usually in, a general speaking, going through a phase from a more proliferative means that it's creating more granulomas, more inflammatory cell aggregate, to a more fibrotic phase. Means that sometimes you actually see the granuloma start to disappear or dissipate, and then showing this kind of dense collagen and fibrosis. That has been commonly documented in both lung and heart sarcoidosis. The other things is that very difficult to study this disease that we do not have a great animal model, so we cannot use animal model to try to approximate or really study the disease pathogenesis. There are several animal models they try to use microbacteria or infectious agents, and these infectious agents can create morphologically similar granuloma, per se, but just like in human body. For instance, patients suffer from TB in their lung, biopsy will show this. But clinically, these are two very distinct disease entities, even though they look alike. Even in the heart, one of the conditions that we study in our paper is giant cell myocarditis, as the name implying having multinucleated giant cells granuloma. It looks really alike under microscopy for pathologists like me, but their clinical course in response to treatment is drastically different. This type of barriers and in the current limitations of our study tool makes, as Kory just said, this is really a wide open. We just know so little despite all the effort. Cindy St. Hilaire: Yeah. I'm guessing based on this granuloma information, to start with, the obvious question you went after is going after the immune cell populations that possibly contribute to sarcoidosis. To do this, because you have the human tissue, you went for single cell transcriptional profiling, which is a great use of the technology. But what biological sources did you use, and how did you go about choosing patient? Because the great thing about single cell is you can do just that, you can look at however many thousands of cells in one patient. But how do you make sure or check that that is broadly seen versus just a co-founding observation in that patient? Kory Lavine: We use explanted hearts and heart tissue from patients that underwent either heart transplantation or implementation of LVADs. It's a pretty big hunk of myocardium, and we're lucky to work with outstanding pathologists both at WashU, JU, as well as our collaborators at Duke. Between the two institutions, we're able to pull together a collection of tissues where we knew there were granulomas within that piece of tissue we analyzed. You bring up an important challenge. You need to make sure the disease and cause of the disease is present in the tissue that you're analyzing, otherwise you'll not come up with the data that really is informative. Chieh-Yu Lin: Kory beautifully answered the question, but I just wanted to add one little thing, and that's also why we use various different modalities. Some of them is more inside you, like the NanoString Technologies' spatial transcriptomic. You can visualize and confirm that we are studying the phenomenon that has been described for sarcoidosis, and then using multichannel immunofluorescence to validate our sequencing data, to complement such limitations of certain technology. Cindy St. Hilaire: Especially, I feel like with this diseased tissue that it's such a large tissue, there's so much information, it's really hard to dig in and figure out where the signal is. This was a wonderful paper for kind of highlighting, integrating all these new technologies with also just classical staining. Makes for great pictures as well. How does this cellular landscape of cardiac sarcoidosis compare to a normal heart? What'd you find? Chieh-Yu Lin: This is a great question. Compared to normal heart, we have been talking about this accumulation of macrophages with scattered multinucleated giant cells. For the similar landscape, first and foremost, you do not see those type of accumulations in brain microscopy or by myeloid markers in the heart. Although, indeed, in even normal heart tissue we have rest and macrophages. It just doesn't form such morphological alterations. But then we dive deep into it, and then we found that from a different cell type perspective, we realized that the granuloma is composed by several different type of inflammatory cells, with most of the T cells and NKT cells kind of adding periphery. The myeloid cells, including the multinucleated giant cells also, are kind of in the center of the granuloma of the sarcoidosis. Then, we further dive in and realize that there are at least six different subtype of myeloid cells that is contributing to the formation of this very eye-catching distinctive granular malformations, and to just never feel first off and foremost, of course, is those multinucleated giant cells that is really distinct, even on the line microscopy] routine change stand. And then we have a typical monocyte that's more like a precursor being recently recruited to the heart, and we finally sent the other four different type of myeloid cell that carry different markers, and then improving the resident macrophages. Especially for me as a pathologist, I'm using my eye and looking at stand every day, is actually these six type of cells, myeloid cells, actually form a very beautiful special kind of distribution with the connections or special arrangement with all different type, kind of like multinucleated giant cell in the middle, flanked by HLA-DR positive epithelioid macrophages, kind of scatter, and then with dendritic cells and a typical monocyte at the peripheral, and then resident macrophage kind of like in the mix of the seas of granuloma information. All these are distinct from normal heart tissues that does carry a certain amount of macrophages, but just don't form this orchestrated architectural distinct structure that's composed of this very complicated landscape. Cindy St. Hilaire: Those images, I think it was figure six, it's just gorgeous to look at, the model you made. One of the questions I was thinking is there must be a significance between these cells that are on the periphery and those that are in the center of this granuloma. Do you have an idea or can we speculate as to are some more cause and some more consequence of the granuloma? Were you able to capture any more information about maybe the initiating steps of these from your study? Kory Lavine: That's a great question, and a question the field has had for a long time. Now, we know there's different populations of cells. The single cell data allows us to understand what are the transcriptional differences and distinctions between them to gain some insights. One thing that we do know from the field is that disease activity correlates with mTOR activity within these granulomas. We took advantage of phospho-S6 kinase staining as a downstream marker of mTOR activity, and Ki-67 is a marker of self proliferation. Which of these populations within the granuloma might be most active with respect to mTOR and respect to proliferation? If you ask most people in the field, they would jump up and say, "It's the giant cell in the middle." We found that that's not actually the case at all. It's the macrophages that surround the giant cell, the ones that are HLA-DR positive, the epithelioid macrophages, and the ones that are SYLT-3 positive that are scattered around them. That's really interesting and could make a lot of sense, and leads to hypothesis that perhaps activation mTOR signaling within certain parts of the granuloma might be sufficient to set up the rest of the architecture. That's something that we can explore in animal models, and are doing so to try to create a cause and effect relationship. Cindy St. Hilaire: Yeah, and I was actually thinking about this, too, in relation to kind of the resident macrophages versus infiltrating macrophages or even just infiltrating immune cells. Do you know the original source of the cells that make up the granuloma? Is it mostly resident immune, or are they recruited in? Kory Lavine: We can make predictions from the single cell data where you can use trajectory analysis to make strong predictions about what the origin of different populations might be. What those analyses predicted is that the giant cells and the cells that surround the giant cells, the HLA-DR positive and SYLT-3 positive macrophages, come from monocytes. That's the prediction, and, of course, resident macrophages do not. However, that prediction has to be tested, and that's the beauty and importance of developing animal models. The wonderful thing today is we now have genetic tools to do that. We can ask that question. Cindy St. Hilaire: I don't know. Maybe you don't want to spoil the lead of the next paper, but what kind of mouse model are you thinking about trying? Kory Lavine: Yeah. First of all, let me talk about the tools that are available, because they're published in Circulation Research, of course. We have a nice tool to specifically mark, track and delete in tissue resident macrophages using a CX3CR1 ERT pre-mouse, and taking advantage of the concept that tissue macrophages don't turn over from monocytes and turn over from themselves. We can give tamoxifen to label all monocytes macrophages in Dcs with that CRE, and then wait a period of time where only the resident macrophages remain labeled. We can use that trick to modulate mTOR signaling as a first step, and ask whether mTOR signaling is required in that population. We've now developed a new genetic tool to do the same thing in just recruited macrophages. Cindy St. Hilaire: What was the most challenging aspect of this study? There's a lot of moving parts. I'm sure probably the data analysis alone is challenging, but what would you say is the most challenging? Kory Lavine: I think you alluded to this early on, but the most challenging thing is collecting the right tissues to analyze, and that's not a small feat or a small effort here. All the technologies are a lot of fun, and everything works so well today compared to many years ago when we trained, so it's an exciting time to do science. The most challenging and time-consuming component was assembling a group of tissues that we could do single-cell sequencing on between our group and our colleagues at Duke, and then creating validation cohorts that we did across several different institutions, including our own as well as Stanford. That team effort in building that team is the most important, challenging, and honestly, enjoyable part of this. Chieh-Yu Lin: I cannot agree more what Kory just said. I think that that's the challenging and the fun part, and that we're very fortunate to really have a great team to tackle this questions in multiple from multiple institute. I just want to add one more thing that, particularly for me as a cardiopathologist, one of the hardest things is I've known how to look or diagnose sarcoidosis for years, but seeing the data emerging that is so complicated and then beyond my reliable eyes in understanding, it's kind of mentally very challenging but very fun to really open and broaden the vision. It's not just how it looks like just giant cells in macrophages. Cindy St. Hilaire: What do you think about in terms of diagnostics or even potential therapies? How do you think this data that you have now can be leveraged towards those objectives, whether it's screening for new cell types that are really key to this granuloma formation versus therapeutically targeting them? Kory Lavine: This study opens new doors, and right now, diagnosis of sarcoids islimited by trying to biopsy, which, in the heart, is limited by sample bias. You certainly can biopsy the wrong area because you don't know whether a granuloma is in the area or not. We do do some cardiac and other imaging studies like FDG-PET scans, which are helpful but are not perfect, and each of them has their individual limitations. One of the beauties of our study is it identifies new markers of macrophage populations that live within the granuloma, many of which are unique to this disease. That suggests that there's maybe an opportunity to develop imaging tracers that can identify those populations more specifically than our current PET imaging studies do, which rely simply on glucose uptake. It also opens up the possibility that we may able to take blood samples and identify some of these cell types within the blood, and have more simple testing for our patients. I think in terms of therapy, you alluded to it earlier, these concepts about mTOR signaling, that could be a new therapeutic avenue that needs to be rigorously explored in preclinical models. We're lucky already to have very good mTOR inhibitors available in clinical practice today. Cindy St. Hilaire: Obviously, opening new doors is amazing because it's more information, but often a good study leads to even more questions to be asked. What question, or maybe what questions, are you guys going to go after next? Chieh-Yu Lin: Well, that list is very long, and then that's actually the exciting thing about doing this research. There's no bad questions, in some sense. All the way from diagnosis, management, monitoring, therapeutic, how we predict where the patient can respond, that's the whole clinical side. Even the basic science side, we still haven't really answered the question, although our data suggests where that multinucleated giant cells coming from. It's very eye catching. How do they form, even though our data suggests it's from the recruited macrophages. But that's still a long way from the recruited macrophage, monocyte to that gigantic bag of nuclei in the very fluffy cytoplasm. And then, how the granuloma, as we discussed earlier in this discussion, really initially from a relatively normal background myocardium to form this disease process. There are just so many questions that we can ask. There are, of course, several fronts that we would like to focus on. Kory already nicely listed some of them. First and foremost is actually to establish animal model to enable us to do more details in mechanistic studies, because human tissue, as good as it is, it's kind of like a snapshot, just one time point, and it really limits our ability to test our hypothesis. Animal model, certainly, is one of the major directions that we are going forward, but also the other side, like more clinical science also to develop novel noninvasive methodologies to diagnose and to hopefully monitor this patient population in a better way. Cindy St. Hilaire: Well, it's beautiful work. I was actually reading this paper this weekend at a brunch place just next door to my house, and the guy sitting next to me happened to see over my shoulder the title and said that his father had passed away from it. This is hopefully going to help lots of people in the future, and really help to make the models that we need to ask, "What's happening in this disease?" Thank you so much for taking the time to speak with me, and congratulations on what seems to be a landmark study in understanding what's going on in this disease. Chieh-Yu Lin: Thank you so much. It's a pleasure. Cindy St. Hilaire: That's it for our highlights from the September 30th and October 14th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page, and follow us on Twitter and Instagram with the handle @CircRes, and hashtag Discover Circ Res. Thank you so much to our guests, Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover Circ Res, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors of the American Heart Association. For more information, please visit ahajournals.org.
Please join senior author Louise Olde Nordkamp, Editorialist Sana Al-Khatib, and Associate Editor Mark Link as they discuss the original research article Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in "Transvenous and Subcutaneous Implantable Defibrillators: An Analysis of All Appropriate Therapy in the PRAETORIAN trial" and the editorial "Just When We Thought the Debate About the Value of Anti-Tachycardia Pacing Was Over Perplexing Results from the PRAETORIAN Trial Emerged." 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, your host and Associate Editor from the National Heart Center and Duke National University of Singapore. And as you can tell, I am sorely missing my co-host, Dr. Greg Hundley, who cannot make it today, but yet I am so excited to tell you about the wonderful papers in today's issue. Now, right after these summaries, we will be discussing appropriate shocks and anti-tachycardia pacing in transvenous and subcutaneous implantable defibrillators. A really interesting analysis from the PRAETORIAN trials. The results may surprise you as they did for me. I really highly recommend you listen to the discussion, important clinical take home messages there. Now, though, let me tell you about some original papers in today's issue. We know that symptomatic children with catecholaminergic polymorphic ventricular tachycardia and that's a mouthful. Dr. Carolyn Lam: So, I'll abbreviate it as CPVT. They are at risk for recurrent arrhythmic events, beta blockers decreases risk, but are some types of beta blockers better than others in this regard? That's what coauthors and corresponding authors, Dr. Peltonberg and van de Werf from University Medical Center, Amsterdam and colleagues looked at. Studying 329 patients with RYR2 variant carrying symptomatic children from two international registries of patients with CPVT, these authors found that beta-1 selective beta blockers were associated with a higher risk for arrhythmic events, defined as syncope, appropriate ICD shock, sudden cardiac arrest, or sudden cardiac death. And this was compared with non-selective beta blockers. The difference in non-selective versus beta-1 selective beta blockers was driven by a significantly lower risk for arrhythmic events in patients treated with nadolol compared with metoprolol, bisoprolol, and atenolol. So, what are the clinical implications? Well, symptomatic children with catecholaminergic polymorphic ventricular tachycardia should preferably be treated with nadolol or another non-selective beta blocker such as propranolol should nadolol be unavailable. Dr. Carolyn Lam: The next paper deals with the super hot topic of myocarditis-related COVID-19 vaccination in adolescents and young adults. Now, suspected myocarditis temporarily related to COVID-19 vaccination has been reported in adolescents above 12 years old and young adults since the emergency use authorization of the Pfizer COVID-19 vaccine. And this is particularly in male adolescents and young adults. Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccine, of course, has important public health implications in the decision to vaccinate youth. So, these authors led by corresponding author, Dr. Truong from University of Utah and Primary Children's Hospital from Salt Lake City in Utah, retrospectively collected data on patients younger than 21 years old presenting before July 2021 with suspected myocarditis within 30 days of COVID-19 vaccination. And they found that in 139 adolescents and young adults with 140 episodes of suspected myocarditis, 49 of which were confirmed and 91 were probable. Dr. Carolyn Lam: And these were at 26 centers. Most patients were male and white with a median age of 15.8 years. Suspected myocarditis occurred in 98% following mRNA vaccine with 94% following the Pfizer vaccine, 91% occurring after the second dose. Symptoms started a median of two days after vaccination. The most common symptom was chest pain. 26 patients or 19% were in the ICU. Two were treated with inotropic vasoactive support and none required ECMO or died. The median hospital stay was two days. So, while the majority of patients with suspected vaccine associate myocarditis had normal ventricular systolic function on echocardiogram, many had abnormal findings suggestive of myocarditis on cardiac MRI in the setting of elevated troponin and electrocardiographic changes. The take home message is that despite lab and cardiac MRI evidence of cardiac injury, the majority of adolescents and young adults with suspected myocarditis following COVID-19 vaccination have rapid recovery of symptoms and a mild clinical course. Further studies are needed to better understand the timing of resolution of myocardial injury, mechanisms of myocardial injury, and the long term outcomes. Dr. Carolyn Lam: The next paper is the first study to look at examining the genetic architecture of the plasma protein using whole-genome sequencing in persons of African ancestry and really provides a chance to look at rare ancestry specific variation. Authors led by corresponding author, Dr. Gerszten from Beth Israel Deaconess Medical Center in Boston, Massachusetts performed proteomic profiling of 1,301 proteins in 1,852 black adults from the Jackson Heart Study using aptamer-based proteomics or the SOMAscan. Whole-genome sequencing association analysis was ascertained for all variants with minor allele count of five or greater. Results were validated using an alternative antibody-based proteomic platform, the Olink platform as well as replicated in the multiethnic study of atherosclerosis or MESA, and the HERITAGE family study. A huge amount of work. So, this large study added 114 novel genomic [inaudible 00:07:00] associated with protein levels and an additional 217 novel sentinel variant protein relationships. Novel cardiovascular findings included genetic variant associated with amyloidosis in persons with African ancestry shown to be associated with retinol binding protein four levels, even in those without cardiomyopathy implicating it as a potential biomarker. Dr. Carolyn Lam: Taken together, these results provide evidence of the functional importance of variants in non-European populations and suggest new biological mechanisms for ancestry specific determinants of lipids, coagulation, and myocardial function. And this is discussed in an excellent editorial by Professor Dr. Schunkert from German Heart Center, Munich. And the final original paper deals with high-salt intake, which we know to be the leading dietary risk factor for cardiovascular disease. We also know that clinical evidence suggests that high-salt intake is associated with non-alcoholic fatty liver disease. Now, could the two be linked, in other words, could hepatic steatosis induced by high-salt diet mediate cardiovascular damage and how? This is exactly what these authors did. Corresponding author, Dr. Zhu from Army Medical University in Chongqing, Institute of Hypertension in China and their colleagues in an elegant series of mouse experiments demonstrated that reduced SERT three expression in the liver is an important mediator of salt-induced hepatic inflammation and steatosis. Dr. Carolyn Lam: High-salt diet inhibits the transcription of SERT three through epigenetic modification mechanisms resulting in the persistence of hepatic inflammation in the liver. Notably, the over expression of SERT three in the liver using an adeno-associated virus eight vector or activation of SERT three by metformin effectively relieved the progression of persistent hepatic damage in mice and thus counteracted salt-induced cardiovascular damage. Taken together, these findings suggest that the MK SERT three pathway may be a promising interventional target for treatment of persistent cardiovascular damage in populations exposed to high-salt diet, and finally rounding up the other papers in today's issue, there's an AHA Update by Dr. Lloyd-Jones on the power of patient stories to inspire us to prevent cardiovascular disease and death, personal reflections on AHAs scientific sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30 years of no-touch saphenous vein harvesting, a timely jubilee gift. Dr. Carolyn Lam: There's a Frontiers paper by Dr. Rivard on a tremendous contribution on atrial fibrillation and dementia, a report from the AF Screen Interventional Collaboration. And finally a research letter from Dr. Joe on genetic proliferation tracing revealing a rapid cell cycle withdrawal in pre-adolescents cardiomyocytes. Well, that wraps it up for the summaries. Now, let's go on to our feature discussion. Dr. Greg Hundley: Welcome listeners to our feature discussion today on this February one. And we're very excited because we have three individuals that will be discussing this paper, Dr. Louise Olde Nordkamp from Amsterdam, Netherlands, the primary author. Dr. Sana Al-Khatib, who is our editorialist for this paper. And finally, Dr. Mark Link, who is our associate editor. Welcome to you all. Louise, we're going to start with you. Can you describe for us some of the background pertaining to why you formulated this study and then what was the hypothesis that you wanted to address? Dr. Louise Olde Nordkamp: Yes. Thank you very much for joining this podcast on our study. Our study was designed because in ICD therapy, antitachycardia pacing, ATP has been developed as a painless method to terminate ventricular arrhythmias, and it might decrease the number of appropriate shocks. But on the other hand, ATP might also be given unnecessarily for VTs that would've been ended spontaneously and might even accelerate VTs. The reported efficacy ranges from 52 to 81%, and some studies have observed even higher mortality in patients treated with ATP. The subcutaneous ICD has been developed 10 years ago approximately, and it's completely extra thoracic. And due to this extra thoracic design, it is incapable of providing pacing therapy including ATP. And this was a pre-specified analysis from the PRAETORIAN trial, which was a randomized trial comparing the transvenous and the subcutaneous ICD. And in this pre-specified secondary analysis, we're aimed to determine the efficacy of ATP, the safety of ATP and shocks by comparing appropriate therapies in both arms. So, both the SICD and transvenous ICD, and specifically, we investigated whether ATP reduced the number of appropriate ICD shocks. Dr. Greg Hundley: Very nice. And so describe for us a little bit more the study population and the design particularly of the PRAETORIAN trial. Dr. Louise Olde Nordkamp: Yeah. So, we published at PRAETORIAN trial in August 2020, in The New England Journal of Medicine and it was the first randomized trial to compare the subcutaneous ICD with the transvenous ICD in patients with a regular ICD indication, but without a pacing requirement. And in 39 census throughout Europe and US of 849 patients were randomized to either the subcutaneous and transvenous ICD in a one-to-one ratio. And during a median follow up of 49 months, the rate of the primary endpoint composite of device related complications and inappropriate shocks were similar between the subcutaneous ICD and the transvenous ICD arm. But here we looked at the appropriate therapy in the study. So, it was defined as both ATP or shock therapy and appropriate therapy was also defined as therapy for ventricular arrhythmias. The PRAETORIAN trial population in overall was, as I said before, regular ICD population with a median age of 63 years, 20% were female. Two-third of patients had an ischemic cardiomyopathy and 20% of patients had a secondary prevention indication. Dr. Greg Hundley: Very nice. And so tell us your study results. Dr. Louise Olde Nordkamp: Our findings were that in this trial, there was no significant difference in number of patients with appropriate therapy, so shocks and ATP. There were 86 patients in the SICD group and 78 patients in the transvenous ICD group. But patients in the subcutaneous ICD group were one and a half times more likely to be treated with at least one shock. So, if we look at shocks only, and that has a hazard ratio of 1.52 and that was statistically different of significance between the groups. The first shock efficacy was similar in the SICD and in the transvenous ICD. And the first ATP attempt successfully terminated 46% of all monomorphic VTs, but it accelerated through arrhythmia in 9.4%. And although, ATP successfully terminated 46% of all monomorphic VTs, the total of number of shocks, as I said before, was not statistically different between the two groups. Dr. Louise Olde Nordkamp: So, we looked at discrete episodes where ATP does reduce the number of appropriate shocks. But when we looked at storm episodes, which was defined as more than three shocks within 24 hours, we saw that there was a higher number of shocks in the transvenous ICD arm, despite a randomized design of the trial and the distribution of shocks between the discrete and the storm episode was there for opposites in the SICD, in the transvenous ICD. So, there was a high number of shocks in storm episodes in the transvenous ICD group, which can partly explain by the number of patients and electrical storms in this group, because there was 10 patients with an SICD who had an electrical storm and there were 18 patients with a transvenous ICD who had an electrical storm. So, patients with appropriate therapy had therefore almost twofold increased risk of an electrical storm in the transvenous ICD arm. Dr. Greg Hundley: Very nice. Listeners, next, we're going to turn to the associate editor for this paper, Dr. Mark Link, and Mark, you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Mark Link: Thanks, Greg. And thanks, Louise for contributing this papers. We were really very happy to have it. And the reason that we were happy to have it is that this is a very important question in our clinical practice. That is, should we give a patient a subcu ICD or a transvenous ICD? Then, there are risk and benefits of both. It's a discussion that I have multiple times a week with patients. And so getting data on the efficacy of shocks and the efficacy of ATP is very, very important for us as we will discuss this with our patients. So that's why we really like this paper, because we thought it was very clinically relevant to our readership and to the practicing EP community. Dr. Greg Hundley: Very nice. Next listeners, we're going to turn to our editorialist, Dr. Sana Al-Khatib from Duke University and Sana, help us put the results of this study in perspective with other research in the field of both subcutaneous and transvenous pacing. Dr. Sana Al-Khatib: Yeah, no, absolutely. I'd like to start by congratulating the authors on this paper, I really enjoyed reading it and thank you for sending it to circulation. I also enjoyed writing the editorial. So, certainly this paper provided results that have challenged some of the findings of prior studies, in the sense that several prior studies had shown that antitachycardia pacing reduces the risk of shocks, improves patients outcomes. And that's not at the expense of them having syncope or having adverse events. And this was the case in those trials even for faster ventricular tachycardia. So in this particular study, they excluded patients with slower ventricular tachycardia, but I would also say that several of the prior studies had looked at antitachycardia pacing for faster VT and showed better outcomes. Dr. Sana Al-Khatib: And so, this study certainly makes us question some of those findings, but really I feel like it will be a great impetus for different researchers to look at this question in relation to the newer generation of transvenous ICDs as well as even potentially looking at the combination of the subcutaneous ICD with perhaps leadless pacemakers that could deliver antitachycardia pacing, which is an area of research that we're going to hear more about. Dr. Greg Hundley: Very nice. And Sana, that really leads us into our next round of questions with our panelists. We'll start with you first, Louise, what do you see is the next focus of research that'll be performed in this space? Dr. Louise Olde Nordkamp: So, I think the efficacy and also the potential harm of ATP should be studied more thoroughly. So, I think a randomized trial with ATP as a main focus, because this was a secondary analysis, is the first step to do. And moreover as Dr. Al-Khatib already mentioned is that new innovations are ongoing with a leadless pacemaker in addition to a subcutaneous ICD and these clinical results will be gathered in the coming months and years. And that is really interesting to look at as well. Dr. Greg Hundley: And Mark, can you share your thoughts? Dr. Mark Link: Yeah. This study brings up many questions, tying in the leadless pacemaker with the subcu ICD is certainly one that's being explored by a number of manufacturers right now, ways to make shocks less painful also would be very critical. I mean, I think that the storms often are because of the catecholamine surges that occur with shocks, if you could make shocks less painful, that would be very keen. And that's been a focus of some researchers for quite some time without good results at the time. And then, increasing the efficacy of ATP because there was a signal here that ATP could, what did generate faster VPs and VFs. And so, the prevention of that I think is very crucial. Dr. Greg Hundley: Very nice. And Sana, do you have anything to add? Dr. Sana Al-Khatib: Yeah, no, absolutely. I completely agree with what was said. I truly feel that this is an area where we're going to see a lot of research being done. We have new algorithms of antitachycardia pacing, Greg, that are being developed and incorporated into devices that use machine learning, which is really exciting. So, trying to look at hard outcomes related to those and comparing them with, as I mentioned, the subcu ICD combination with a leadless pacemaker would be really interesting. And then, this whole question about the electrical storm, I commend the authors for looking at that, but as they pointed out this was a secondary analysis and the numbers that they had were pretty small. So, trying to look at those findings in a larger population of patients really designed to look at that question would be important. Dr. Greg Hundley: Very nice. Listeners, we want to thank our electrophysiology panelists today, Dr. Louise Olde Nordkamp, Dr. Sana Al-Khatib, and Dr. Mark Link for bringing us the results from this trial indicating that really there was no difference in observed shock efficacy of the subcutaneous compared with the transvenous ICDs. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinion expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This month on Episode 27 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the July 23rd and August 6th issues of Circulation Research. This episode also features an in-depth conversation with Drs Ana Gomez and John Pierre Benitah, from INSERM and the Paris-Saclay University, about their study, Impaired Binding to Junctophilin 2 and Nanostructural Alterations in CPVT Mutation. Article highlights: Glasenap, et al. Imaging Inflammation and Fibrosis in Heart Failure Shi, et al. Cardiomyocyte Pyroptosis Aggravates MI/R Injury Koenis, et al. SPM Temper Phagocyte Responses in COVID-19 Zhang, et al. Common Origin of Heart and Extraembryonic Lineages Cynthia St. Hilaire: Hi, and welcome to Discover CircRes, the podcast to the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'll be highlighting articles presented in our July 23rd and August 6th issues of Circulation Research. I also will speak with Drs Ana Gomez and John Pierre Benitah, from Inserm and the Paris-Saclay University, about their study, Impaired Binding to Junctophilin 2 and Nano-structural Alterations in CPVT Mutation. Cynthia St. Hilaire: The first article I want to share comes from the July 23rd issue of Circ Res, and it's titled Molecular Imaging and Inflammation and Fibrosis in Pressure Overload Heart Failure. The first author is Aylina Glasenapp and the corresponding author is James Thackeray, and they're from Hanover Medical School in Germany. After a heart attack, inflammation and fibrosis of the heart alter cardiac contraction and can lead to its failure. Currently, for ischemic heart failure, doctors use imaging techniques such as positron emission tomography, and cardiac magnetic resonance imaging, to measure the inflammation and fibrosis to provide a prognosis. Cynthia St. Hilaire: However, whether these imaging techniques are useful for non-ischemic heart failure was unknown. To find out, this group performed transverse aortic constriction on mice, which is a commonly used method to model non-ischemic heart failure, and then they analyzed the animal's hearts with positron emission tomography to assess the inflammation and cardiac magnetic resonance imaging to quantify scar tissue. Compared with Sham-operated animals, those that underwent TAC exhibited increased heart inflammation for at least three weeks and significant fibrosis for at least six weeks. The degree of scarring and inflammation was inversely correlated with heart function. The team also found that reversal of TAC led to reduced inflammation and fibrosis over time. Together, the results confirm that these imaging modalities are valuable for monitoring fibrosis and inflammation in non-ischemic heart failure, and they could potentially be useful for assessing the effectiveness of interventions. Cynthia St. Hilaire: The second article I want to share is titled GSDMD Mediated Cardiomyocyte Pyroptosis Promotes Myocardial Ischemia Reperfusion Injury. The first author is Huairui Shi and the corresponding author is Junbo Ge, and they're from Fudan University in China. After myocardial infarction, restoring blood flow is essential to saving muscle function. However, restoration of flow itself causes damage by inducing inflammation and cell death. This study found that the cell death aspect of a reperfusion injury occurs via a process called pyroptosis, which is a controlled form of necrosis that is due to excessive inflammation. Cynthia St. Hilaire: The team developed an in vitro model of reperfusion injury, where cultured cardiomyocytes are starved and then resupplied with oxygen. Using this model, they found that cells exhibited features of pyroptosis, including the release of inflammatory factors, increased production of the pyroptotic factor gasdermin D and cell death. Cardiomyocytes lacking gasdermin D did not display signs of pyroptosis under these same conditions. The team went on to show that gasdermin D was significantly increased in the hearts of mice following ischemia reperfusion. And compared with control animals, mice whose cardiomyocytes were engineered to lack gasdermin D, suffered less necrosis and smaller reperfusion injuries in their hearts. Together, these findings provide insights into the mechanisms that should be targeted to minimize pyroptosis and subsequent ischemia reperfusion injury, following myocardial infarctions. Cynthia St. Hilaire: The next article I want to share is titled Disruptive Resolution Mechanisms Favor Altered Phagocyte Responses in COVID-19. The first authors are Duco Steven Koenis, Issa Beegun and Charlotte Camille Jouvene, and the corresponding author is Jesmond Dalli. And they're from Queen Mary University of London. Inflammation is essential in the early stages of battling and invading pathogen, but at the same time, inflammation can become damaging to the host if it is not resolved in a timely manner. Prolonged and unresolved inflammation is responsible for the hospitalizations and deaths of many COVID-19 patients. An excess of circulating pro-inflammatory cytokines is one of the key features of severe COVID-19. And now, Koenis and colleagues show that certain pro-resolving factors are out of balance in these severe patients. Cynthia St. Hilaire: Blood samples from patients with mild COVID-19 showed an increase in specialized pro-resolving lipid mediators. However, blood from patients with severe COVID-19 had lower levels of these pro-resolving lipid factors. Expression of specialized pro-resolving lipid mediator receptors on phagocytes was also higher in patients with mild disease than those with severe COVID-19. And, in line with this, the proportion of activated pro-inflammatory phagocytes was higher in patients with severe disease. Cynthia St. Hilaire: When patients were treated with the steroid dexamethasone, they subsequently inhibited the increased levels of the specialized pro-resolving lipid mediators in the blood. Together, these results reveal specialized pro-resolving lipid mediators are dysregulated in severe cases of COVID-19, and the findings suggest increasing these pro-resolving lipid mediators could promote resolution of out-of-control inflammation. Cynthia St. Hilaire: The last article I want to share is titled Unveiling Complexity and Multi Potentiality of Early Heart Fields. The first authors are Qinqguan Zhang and Daniel Carlin, and the corresponding authors are Sylvia Evans, Joshua Bloomekatz, and Neil Chi, and they're from UC, San Diego. The developing heart is thought to originate from two populations of cells; the first and the second heart fields. And these are first identifiable at stages E 7.5 in the mouse, or on day 15 in the human embryo. Genes controlling the development of these fields have been linked to congenital heart defects, but interestingly, congenital heart defects are also sometimes linked to placental abnormalities. However, the mechanisms underlying this link have been unclear. Now this study has gone on to discover an unexpected link between the first heart field and extra embryonic tissues, which give rise to the yolk sack and the placenta. Cynthia St. Hilaire: Through lineage tracing experiments and single cell transcriptomics, the team discovered that the first heart field consists of two sources of mesoderm progenitor cells, one source that is embryonic in nature and the other source arises from the interface between the extra embryonic and the embryonic tissue of the early gastrula. This latter population of progenitor cells, which is defined by the expression of the transcription factor hand one, gives rise to extra embryonic mesoderm cells in addition to the two Hartfield cell populations. The discovery of this shared source of mesodermal progenitors not only blurs the lines between the embryo and its supporting tissue but may also explain the link between placental abnormalities and congenital heart defects. Cynthia St. Hilaire: Today I have with me Drs Ana Gomez and Jean-Pierre Benitah, and they're from Inserm and the Paris-Saclay University. And today we'll discuss their study Impaired Binding of Junctophilin 2 and Nano-structural Alterations in CPVT Mutation. And this article is in our July 23rd issue of Circulation Research. So thank you both very much for joining me today. Jean-Pierre Benitah: Thank you. Ana Gomez: Thank you. Cynthia St. Hilaire: You're in Paris, so we're trying to match it so we're all meeting our normal workday on a Friday. So I very much appreciate you taking the time to meet with me. So this study is investigating a rare disease called Catecholaminergic Polymorphic Centricular Tachycardia, or CPVT. So can you describe to us what is CPVT and how does this disease present in patients? Ana Gomez: Okay, so CPVT stands for Catecholaminergic Polymorphic Centricular Tachycardia. So it is a genetic disease that appears mainly in childhood and youth with sudden death. So the patients don't have any remarkable problem, either in the electrocardiogram or arteries, or in the cardiac structure by echocardiography, and they seem healthy. But when they have stress, it can be emotional or it can be physical, so during exercise, it presents with syncope or sudden cardiac arrest. So the problem is that, many of the times, the first symptom is the death of a child playing soccer or doing exercise and then the only treatment that they, so far, it's beta blockers, to avoid this stress, and also flecainide and propafenol. But these treatments are still not completely efficacious, or sometimes the people need to get implant defibrillator. It's a big cost and it's also stressful because if the patient feels that they have to recharge, that supposes stress, and this stress is bad for them. Cynthia St. Hilaire: Right, so it's like if they feel a flutter, it makes them more stressful, which can exacerbate. That is terrifying. And so the goal, I guess, regarding gaps in knowledge that are leading to your investigation, what was known about this disease before you started your study? And where did you leap off from that? Jean-Pierre Benitah: Up to now, what we know about the disease is an alteration of the calcium homeostasis in cardiac myocyte. That could induce trivial activity, and then arrhythmia and cardiac sudden death. So mainly the mutation related to an intracellular calcium channel called Ryanodine receptor. So it's up to 60% of the patient with this mutation, but also you have a mutation related also to proteins that are in-buried in the control of the Ryanodine receptor activity, priadine, calmodulin. Cynthia St. Hilaire: Yeah, that was actually going to be my next question. So I know this cardiac Ryanodine receptor 2, or RYR2, it's obviously the channel component that helps to release that calcium signal, but it's part of a larger complex. I believe it's called the Calcium Release Unit. Can you talk about what is in that unit in terms of proteins and then where those other genetic mutations fit into that? Ana Gomez: Yeah, so the Calcium Release Unit is formed by a cluster of Ryanodine receptors. So in the reticular cardiomyocytes, these are mostly in the junction of sarcoplasmic reticulum that is very close to the sarcoplasmic reticulum membrane inside the cardiomyocyte, inside the cell. So the channel is internal. But it's very close to the sarcolemma in the T-tubule invaginations where the L-type calcium channels are located. So this is... The channels are very important to activate contraction, so it's heartbeat. The calcium entry through the attached calcium channel on the surface makes some calcium get into these very restricted spaces, like 20 nanometers, and in this space this calcium activates the Ryanodine receptor. So the Ryanodine receptor is activated by calcium and these release much more calcium than is needed for the contraction. So the problem of the CPVT is that the channels may release calcium during diastole, so when calcium should be low because they had to relax. Ana Gomez: For your new question, which proteins? So the main proteins are the Ryanodine receptor. But Ryanodine receptors are a very big macro complex. They are the biggest channels that are known and they have a big cytoplasmic portion with proteins that can bind to them, and most of them just keep the channel quiet. So this may be calmodulin, FKPB 12.6, or 12, sorcin. And then there are also some other proteins that scaffold kinases, like PKA and CaM kinase. And also they have some proteins that moderate the channel from the luminal side. So, calsequestrin, triadin and junctin. And this agents to fill in that we will speak later. It's important because it binds to the L-type calcium channel and to the ryanodine receptor. So it's important to keep the dyad structure. It's not only a structural role. Cynthia St. Hilaire: Yeah, that is so interesting. So your study focused on a very specific mutation. It's the RYR2 arginine in the 420 spot to glutamine mutation. So I guess my first question is based on the patient population, how common is this specific mutation? How common is that? Ana Gomez: Yeah. So in fact, I'm going to say that it's very common, because normally CPVT is one mutation, one family. Cynthia St. Hilaire: I see. Ana Gomez: Even if they are located in hotspots, but these particular mutations, we were approached by a cardiologist working in Spain who had this family with a child that died at the age 14, playing soccer game. And so Dr Zorio in Valencia, she found this RyR2 420Q mutation. And at this time this was the first mutation in this site. I mean, not really in the site, there was already RyR2 420W that was already, so it was the same spot, but different. Cynthia St. Hilaire: That was my next follow up question to that. My PhD was biochemistry, so this brought back having to memorize the amino acid structure. So arginine is large and positively charged to glutamine is neutral. So what were the experiments that you designed to help determine the functional causes of this mutation? You know, in addition to just, okay, obviously there's a charge change, so there's probably a structural or a binding change, but how did you determine the functional consequences of this mutation? Ana Gomez: The structure, as you say, this has been shown. In fact, they was the first family, but then also in this region, there was another family and in Israel also there is another family. So there are three, but the structural limitations that these arginine is neutral. It has been shown by a laboratory, who works in Vancouver, in a structural and the end terminal has like three logs and these are 420. It's important to hold a chloride that in the middle and, and to hold the position. So, but this is not the functional, the functional is what we were going to analyze. So the first thing that we did is to analyze calcium sparks because calcium sparks is the functional, let's say elementary event, of calcium release to RyR2 receptors. So we start analyzing calcium sparks in the cells and we found strange things, like very long calcium sparks that was not so clear in other CPVT models, even one that we studied earlier. And so then we started to continue to know why we have longer calcium sparks and different kind of analysis. So we also collaborate with some other laboratories to do the ultrastructure of the dyad by electromicroscopy. Ana Gomez: And then we found that the sarcoplasmic reticulum, junctional sarcoplasmic reticulum, was enlarged. So we thought, well, maybe the channel, the calcium spark is longer because locally they delayed depletion. So we did another kind of experiment changing the volume of the SR and it was not so concluded so we found that it may contribute to longer calcium sparks, but it doesn't explain for it. So then we start with to analyze different proteins candidates, also the phosphorylation of course. And then we didn't find in most of these proteins, like FKVP. Cynthia St. Hilaire: Kind of a standard go-tos. None of them were involved. Yeah. Ana Gomez: Yeah. And then, because there is this ultrastructural alteration, we thought of junctophilin and that is how we found that junctophilin binding was impaired. Cynthia St. Hilaire: That's a perfect segue. You're hitting all of my next questions. So can you tell us a little bit about, what did you find regarding junctophilin and the RyR2 channel? Jean-Pierre Benitah: So mainly, junctophilin act to us the good structural design between the ryanodine receptor and the trigger L-type calcium channel. And people say that junctophilin binds to both proteins to keep them close to each other. So mainly what we found is that we don't have activation of the expression of junctophilin, but it seems that with this mutation the junctophilin is less in contact with ryanodine receptor. But it's not the case for the L-type calcium channel. It seems that coimmunoprecipitation experiments that we've done show that junctophilin stayed still with the L-type calcium channel, but have a lower affinity to the ryanodine receptor when you have this mutation. What was really important is that we saw that not only in the mouse model where we induce this mutation, but also in cardiomyocytes derived from induced pluripotent stem cells from patients that have this mutation. Cynthia St. Hilaire: I think that's one of the great strengths of your study. You know, I like how you took a multi-faceted approach, you know, using these IPS cells from the patients and also created a knock in model. Previous studies had used more global or whole exon deletions. So how is your knock-in able to identify additional information that built upon those former studies? Ana Gomez: Maybe this is not an exact answer to your question, but what I think is that the strength of our study or one of the strengths of our study is that we have the patients with electrocardiograms working, we have the cells from the patients. So we have...Our IPS cell is from one of the persons that have been patient, and the control line is from his brother. So we have the two brothers. They are still living, and we have the mice and everything is in the same point mutation. So in this thing, because there is a lot of, let's say, critics to the IPS cells studies because they are not mature and they don't look like an adult cardiomyocyte. And I think that besides CPVT, we can also show that of course cardiomyocytes derive from IPS cells. They are not adult, but they are still a good model because we recapitulate the same thing. Ana Gomez: So we can mix the human context to really have what happened in patients, because that is the important thing, but we also need to manipulate the in vivo animals and there are some things that we cannot do. We cannot get adult cardiomyocytes from patients, so for that, we have the mice and we can also analyze from in vivo to the molecular level. So I think that it's a big strong point from our study that you take compared to others, that they are only in mice or only in IPS, cannot do this correlation. Then, each mutation, we think that it may, or at least each region of the mutation, may have different mechanisms. So if we find these longer calcium sparks in these R420Q mutation, it doesn't mean that because we also have other studies in C-terminal mutation, and we don't find longer calcium sparks, we just find more. So this is not because of the design of the study, but because the mechanism of the mutation is different. Cynthia St. Hilaire: In terms of translational potential, what do your findings suggest about either the ability to screen patients potentially for the development of CPVT or actually more importantly, you know, therapies to help treat these patients when they're identified? Jean-Pierre Benitah: Yeah. It's one of the big problems with the CPVT, especially since when you look at the different mutations, those are different mutations that have been reported on the ryanodine receptor located on different hotspots on the ryanodine receptor. And it's seems that each hotspot could have a different type of mechanism behind that. So, for example, we show, there you see, you know, different mutations in collaboration with CPVT or 420Q mutation. So the mechanism was related to an alliteration of the sensitivity of the ryanodine receptor to the calcium. So the group of branching show that in other mutations, in other spots, hot spots, it was related in fact, to a modification of this. Also the sensitivity of calcium of the ryanodine receptor calcium, but from the luminal side. Ana Gomez: Regarding your first question was diagnosis. I think that after our work, we may also include junctophilin, because so far there has not been any link to junctophilin for sensitivity. So when a patient has CPVT, they start screening for mutations in the ryanodine receptor, since it was found that this child was involved and then in other proteins. So I think now if they don't find in a patient, because there are still like 40% of CPVT patients that the mutation has not been found. Ana Gomez: For therapeutic side maybe find a molecule that stimulates the binding of junctophilin to ryanodine receptor, but also maybe some smaller molecule that may interact between the N-terminal and the core solenoid because we found that in the interim molecular structure, they show tighter association between the N-terminal and the core solenoid. So maybe it's more of a tide or something that can be in between too. I mean, I don't know, but it's first line there. Cynthia St. Hilaire: Potential, but still far off. That's wonderful. So are some of these mechanisms, I assume, they would also be relevant in non-genetic forms of tachycardia? Is that the case? Could some of your findings also perhaps be applied to the tachycardia related to heart failure or other types of disease states? Ana Gomez: I think it's actually, for example, junctophilin binding to ryanodine receptor in heart failure. It has not been yet studied, but we want to do it. It's something because as you say heart failure, it's a very common disease. So it's also very relevant to the public health. This is something that we need to know. Jean-Pierre Benitah: One of the things that happens in heart failure is that it seems also that you are a dissociation between the calcium channels and the ryanodine receptor because you have less tissue formation. So perhaps this is difficult to try to figure out whether it would be the same, but perhaps this activation between the communication between the two channels is one of the main points that we have in CPVT and in heart failure related to tachycardia. Ana Gomez: Yeah. In fact, many years ago we showed that. We showed that in heart failure there is a defect in calcium channel and ryanodine receptor. So in this study it was only functional. We didn't do the structure, but of course it is something that we have to keep in mind, continue investigating. Cynthia St. Hilaire: Yeah. Well that sounds like a great future project. Well, I want to thank you so much for joining me today and helping to discuss your paper. I love it when we take rare diseases and figure out the mechanism with hopefully applying it to more common disease states. That's what I do in my lab with vascular calcification, and so thank you so much for joining me and for this great publication. And we look forward to your future work that is hopefully in Circ Res. Jean-Pierre Benitah: Thank you for the invitation. Ana Gomez: Yeah, thank you very much for your time. Cynthia St. Hilaire: That's it for the highlights from the July 23rd and August 6th issues of Circulation Research. Thank you for listening. Cynthia St. Hilaire: Please check out the Circ Res Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, doctors Ana Gomez and John-Pierre Benitah. Cynthia St. Hilaire: This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.
In this episode of the Heart podcast, Dr James Rudd is joined by Dr Greg Mellor from Royal Papworth Hospital, Cambridge. They discuss LQTS, Brugada and CPVT syndromes - diagnosis, risk stratification, patient education and therapeutic options. If you enjoy the show, please subscribe to the podcast to get episodes automatically downloaded to your phone and computer. Also, please consider leaving us a review at https://itunes.apple.com/gb/podcast/heart-podcast/id445358212?mt=2 Link to published paper: https://heart.bmj.com/content/early/2021/02/14/heartjnl-2019-316026
This month on Episode 21 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the February 2 and February 19 issues of Circulation Research. This episode also features an in-depth conversation with Konstantinos Drosatos and Ioannis Kyriazis from Temple University to discuss their study, KLF5 is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy. Article highlights: Wittenbecher, et al. Lipidomics and Heart Failure Risk Kryshtal, et al. Flecainide Directly Inhibits RYR2 Ca Release Chen, et al. Klotho and Heart Aging Grootaert, et al. SIRT6 Deacetylase Protects Against VSMC Senescence Dr Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'll be highlighting four articles from the February 5th and 19th issues of CircRes. After the highlights, Dr Konstantinos Drosatos and Ioannis Kyriazis from Temple University will join me to discuss their study, KLF5 is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy. Dr Cindy St. Hilaire: The first article I want to share is Lipid Profiles and Heart Failure Risk: Results from Two Prospective Studies. The first author is Clemens Wittenbecher, and the corresponding author is Frank Hu from Harvard's Chan School of Public Health in Boston, Mass. Heart failure affects tens of millions of people worldwide, and as the prevalence grows, prevention strategies are becoming ever more important. While factors including age, obesity, and hypertension influence one's risk of developing heart failure, robust biomarkers that are able to pinpoint which individuals will develop heart failure are lacking. Changes in cardiac lipid metabolism predispose animal models of heart failure. Dr Cindy St. Hilaire: This group hypothesized that blood lipid profiles might be useful to serve as a heart failure biomarker. The team examined 216 blood lipids from a cohort of individuals with various cardiovascular risk factors, but who, at the time of enrollment and blood collection, did not have heart failure. Over the observation period, which averaged out to over 12 years, 331 of the subjects developed heart failure. Dr Cindy St. Hilaire: When compared to the baseline lipid profiles of individuals who didn't develop heart failure, the group identified two particular lipids, ceramide and phosphatidylcholine, and several networks of lipids and metabolites that were strongly predictive of developing heart failure. Importantly, the findings were corroborated in the second cohort, in which 87 individuals developed heart failure. Together, the results reveal early biomarkers for identifying at-risk individuals and point to particular lipid alterations that may yield insights into heart failure pathology and prevention. Dr Cindy St. Hilaire: The second article I want to share is titled, RyR2 Channel Inhibition Is a Principal Mechanism of Flecainide Action in Catecholaminergic Polymorphic Ventricular Tachycardia. The first authors are Dmytro Kryshtal and Daniel Blackwell, and the corresponding author is Bjorn Knollmann, from Vanderbilt University School of Medicine in Nashville, Tennessee. Flecainide is a drug that is commonly used to treat various heart arrhythmias. Flecainide works by blocking sodium channel activity. However, the drug also has been found to reduce symptoms of catecholaminergic polymorphic ventricular tachycardia, or CPVT, a condition in which mutations affecting the function of a calcium channel ryanodine receptor, called RyR2, are to blame. In vitro studies have suggested that flecainide can in fact block RyR2 activity, but some researchers have argued that flecainide's inhibition of this receptor is too weak to be clinically relevant, and suggest its sodium channel inhibition instead provides an indirect benefit. Dr Cindy St. Hilaire: To test that claim, this group synthesized analogs of flecainide that lack RyR2 inhibitory activity, yet retained sodium channel blocking ability. They compared the analogs with the original drug, both in vitro and in vivo. Experiments in cardiomyocytes confirmed flecainide, but not the analogs, could reduce RyR2-mediated calcium release and experiments in catecholaminergic polymorphic ventricular tachycardia model mice showed flecainide, but not the analogs, could suppress induced ventral tachyarrhythmias. These findings suggest that RyR2 inhibition is the principal mechanism of action of flecainide in treating catecholaminergic polymorphic ventricular tachycardia, and therefore, RyR2 may be a valid therapeutic target for the development of additional antiarrhythmia drugs. Dr Cindy St. Hilaire: The third article I would like to share is titled, Klotho Deficiency Causes Heart Aging via Impairing the Nrf2-GR Pathway. The first author is Kai Chen, and the corresponding author is Zhongjie Sun, and they're from the University of Tennessee Health Science Center in Memphis, Tennessee. Age is a risk factor for many disease states, including heart failure. Even in healthy individuals, the heart size increases and its function declines with age. Aging in humans has also been associated with a decrease in circulating levels of the protein Klotho, which is thought to have anti-aging properties. Previous studies have shown, in a murine model of cardiac hypertrophy, that mice that lack Klotho fare worse than those with normal levels of the protein. Dr Cindy St. Hilaire: This group, therefore hypothesized that Klotho decline may contribute to age-related heart changes. Similar to humans, heart function declines with age in otherwise healthy mice. Injection of Klotho into old mice reduced the size of the animal's hearts and improved cardiac function. Klotho injections also improve heart size and function in young Klotho-lacking mice with pharmacologically induced cardiac hypertrophy. The team found that Klotho induces these effects by inhibiting the accumulation of damaging reactive oxygen species, and by reducing apoptosis in aged-Klotho deficient heart cells. From these data, they suggest that perhaps boosting Klotho levels may be a strategy to prevent age-related heart failure. Dr Cindy St. Hilaire: The last article I want to share before our interview is titled, SIRT6 Protects Smooth Muscle Cells from Senescence and Reduces Atherosclerosis. The first author is Mandy Grootaert, and the corresponding author is Martin Bennett from the University of Cambridge in Cambridge, United Kingdom. Vascular smooth muscle cells reside in the medial layer of vessels. They contribute to atherosclerotic plaque progression, as well as to the fibrous cap that helps to stave off plaque rupture. Over time, however, the increased proliferation and differentiation of plaque smooth muscle cells causes them to accumulate DNA damage, senesce, and ultimately die, leading to the destabilization of the plaque. Dr Cindy St. Hilaire: Functional disruption of the enzyme SIRT6 has been implicated in DNA damage senescence and apoptosis, and certain polymorphisms of the SIRT6 encoding gene are linked to atherosclerosis. From these premises, the team wanted to examine the role of SIRT6 in plaque smooth muscle cells. Compared with healthy aortas, aortas from atherosclerotic mice and humans have lower levels of SIRT6 protein. Inhibiting the activity of SIRT6 and smooth muscle cells caused damage to the telomeres and induced early senescence. By contrast, overexpression of SIRT6 preserved telomeres and prevented senescence. ApoE knockout mice were then engineered to over express SIRT6, specifically in their smooth muscle cells, and these mice showed reduced severity of atherosclerosis compared to control mice. Together, these findings implicate SIRT6 suppression as a cause of plaque senescence, and suggest reversing it may in fact slow disease progression. Dr Cindy St. Hilaire: Okay, so today we have Dr Konstantinos Drosatos and his postdoctoral fellow, Dr Ioannis Kyriazis from Temple University in Philadelphia, Pennsylvania, and they're here to discuss their study, KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy. And this is in our February 5th issue of Circulation Research. So, thank you both so much for being with me today. Dr K. Drosatos: Thank you for the invitation and for helping to draw attention to our study. Dr Cindy St. Hilaire: Absolutely. And thank you for doing this at what? What is it, eight o'clock where you are? Dr Ioannis Kyriazis: It is eight o'clock at night. Dr Cindy St. Hilaire: Okay. Well, thank you for taking the- Dr Ioannis Kyriazis: But it's okay, it's okay. It's quite early to be in Greece. Dr Cindy St. Hilaire: Okay, good. Dr K. Drosatos: Maybe we need to clarify that Ioannis is a former postdoc. I don’t have a lab at Temple and in Greece. Dr Cindy St. Hilaire: Former postdoc. Thank you for clarifying that. So I want to start with a question about cardiomyopathy. What is it and how prevalent is it? And what's the different pathogenesis of cardiomyopathy? And how does it differ from diabetic cardiomyopathy? Dr K. Drosatos: So usually cardiomyopathy arises after heart infracts, after myocardial ischemia, and it actually reflects the reduced ability of the heart to pump blood to the rest of the body, in simple words. Diabetic cardiomyopathy has some unique features. One of those is that it's not related to coronary artery disease, so it does not start with ischemia, but it's still the heart cannot do what it is supposed to. Dr Cindy St. Hilaire: So it's kind of its own unique driver then, the diabetic cardiomyopathy? Dr K. Drosatos: Yeah. And there is a lot of, I wouldn't say debate, but there's a lot of discussion in the field about how to best define diabetic cardiomyopathy. It's a different kind of cardiac dysfunction. It has some certain features like oxidative stress, which is the stuff that we work with. It has fibrosis, primarily perivascular fibrosis. Diastolic dysfunction is more prevalent than systolic dysfunction. So there's a number of features that actually define diabetic cardiomyopathy. Dr Cindy St. Hilaire: I know it's highly prevalent in patients with diabetes, but the inhibitors that people are using to try and treat the diabetic portion, I'm thinking about the sodium glucose transporter SGLT2 inhibitors, those are obviously very good at helping regulate the blood glucose, but they don't appear to alleviate the heart failure. And so what do you think about the pathogenesis or the pathophysiology between the glucose regulation and the cardiomyopathy? Is it kind of like a cliff and it gets too far and is it unrepairable? Dr K. Drosatos: It's certainly a very trendy question. I mean, you are a scientist so you know that in science will have several trends. So SGLT2 inhibition is one of those right now. And from time to time, there are several, I would say miraculous drugs that do a number of good things, which we're not very certain about the mechanism that underlies the effect. So the SGLT2 inhibitors, which is something that we had also started in a previous paper in Circulation Research four years ago, in relation to KLF5, what it actually does, it targets a transporter in the kidney and this transporter normally returns glucose back to the bloodstream. But when it is inhibited, the extra glucose that we observe in diabetes goes out through the urine. So this is what the drug does, but it has been shown that the drug has its own effects in cardiac function, which do not necessarily pertain to the effect that the drug has in the kidney. And actually I was reading yesterday very interesting paper about using SGLT2 inhibitors in heart failure patients that do not have diabetes. Dr Cindy St. Hilaire: Oh, interesting. So it might actually have a secondary function that we're just not aware of right now. Dr K. Drosatos: We do believe that at least in part the beneficial effects has to do with the removal of the extra glucose from the system. My training has been in labs that work on lipid metabolism, so I believe that fatty acid oxidation is the best thing that can happen to the heart. So removing the glucose out of the system is definitely beneficial and actually, Ioannis, before he returned back to Greece, he had performed some experiments showing that removing glucose is definitely beneficial. Dr Cindy St. Hilaire: That's great. Can you describe the study? What was the former research that the question you were asking in this study was on? Dr K. Drosatos: That was a study that I started in the lab of Ira Goldberg at Columbia University when I was a postdoc, and we had come up with an interesting observation that in the heart, the protein interception factor, named KLF5, follows an oscillating pattern of expression. So at the early stage of the abyss, it goes down and then it goes up. So we believe that the levels of glucose in the plasma may be one of the defining factors for affecting the expression of KLF5. So this is how it started, why KLF5 goes down and then up. And at that time we observed that KLF5 is an important transcriptional regulator of cardiac PPAR-alpha, a protein that's another transcriptional factor, which seems to be a very important factor that orchestrates gene expression for fatty acid oxidation. So there is more than 20 genes that are important for fatty acid oxidation, and the expression of which has been shown to be affected by PPAR-alpha. Dr K. Drosatos: So we started working with KLF5 and PPAR-alpha, and that was the paper we published in Circulation Research in 2016, and then Ioannis joined my lab and he works on the effect of KLF5 per se in diabetic cardiomyopathy. And one of the interesting findings from the new study is that the KLF5 has a separate effect on diabetic cardiomyopathy that does not involve PPAR-alpha. Dr Ioannis Kyriazis: And the whole idea, when I joined Dr Drosatos’ lab, the initial idea was that something is happening initially in the heart and that's why we see KLF5 goes down and we believe initially that has to do with subject utilization. And that's why KLF5 is coming down and then comes up. But after several studies, we figured out that it's actually a big tie in the transcriptional factors that act synergistically and like FOXO1, KLF5, and PPAR-alpha, and KLF5 and PPAR-alphas have distinct roles on regulating diabetic cardiomyopathy. So starting from one point of view, we transferred to a different aspect and we tried to see how KLF5 is involved in that system. And this is two stories in one, actually. And that's why we have this follow up study about glucose, that Dr Drosatos said, before I leave. We try also to make it bigger. Dr Cindy St. Hilaire: Yeah, it's always complex, but I feel like this story got very complex as it's really interesting. You used a large amount of different mouse models. Can you talk about some of the different mouse models you used and why you had to use them? You had different drivers of CRE, but also over expression, knockout models. Can you maybe give a quick summary of all the different models you use to really test your hypothesis really thoroughly? Dr K. Drosatos: Are you asking Ioannis why I am forcing him to do a lot of experiments? Dr Ioannis Kyriazis: No, no. Dr Cindy St. Hilaire: But they're really well done, so. Dr Ioannis Kyriazis: I think the answer has to do with how the research community is able to tackle biological questions. You need to use knockout animals and conditional transgenic animals in order to answer biological questions that you are asking. So because we have in front of us a triangle of transcriptional factors that regulate the diabetic myopathy, we were obliged to use all these mouse models to answer all these questions. And we have to understand what is the driving force behind all these systems? Is it FOXO1? Is it KLF5? Is it PPAR-alpha? Do these all add together? So that's why we had two knockout-specific mouse lines for FOXO1 and KLF5. We have the global PPAR-alpha knockout mice, we have transgenic KLF5 specifically in the cardiomyocyte mouse line, and we also have gene therapy. Dr Ioannis Kyriazis: We construct an AAV that drives KLF5 expressions, specifically in the cardiomyocytes, under the Cardiac Troponin T Promoter. So all these actually helped us combination of therapies to tackle all these biological questions that we wanted to have and to answer. Dr K. Drosatos: So this is how it's done. So Ioannis started from this point. We were hopeful that there was a flux FOXO1 mouse. So he started working with that, and then we started making more questions. Okay, after we figured out that, yes, FOXO1 regulates KLF5, so the question then was, okay, is it an effective KLF5 through PPAR-alpha? This is where the next mouse model came. When we said, no, it's not PPAR-alpha, we said, okay, what it is then? Dr Cindy St. Hilaire: What is it? Dr K. Drosatos: And started thinking about different mechanisms that activate diabetic cardiomyopathy. We started with oxidative stress. I was not very ecstatic about this possibility because antioxidant therapies in diabetic patients did not really improve survival. And actually, we were right not to be so excited about this possibility because we only saw a partial improvement. So then we said, okay, what else? And this is where we started doing high throughput analysis, where we ran out of possible answers to questions. So this is when we did look at dogs and we came up with the observation that ceramides are effective. Dr Ioannis Kyriazis: And one more thing to add is that, as Dr Drosatos said, that this study, I think, it's one of a lot of studies out there. But I think this is how we, I believe, as an early scientist, the science to know the biological systems, especially in mice. We use the transgenic models and the knockout models and we see in our study that black and white is not good. So in Kosta's, in Dr Drosatos's study in 2016, Circulation Research, he showed that KLF5 knockouts, specifically in the cardiomyocytes, actually is not good for a long time. Initially, we believed that the transgenic KLF5 mouse model will do better in diabetes. Dr Ioannis Kyriazis: And when we saw that there actually has an accelerated cardiac dysfunction, we were like, okay, this is an interesting phenotype. We need to see how this goes, because we believe in our initial hypothesis that if we induced KLF5 in the early diabetes, then we will have something like we alleviate diabetes. But this was not the case. And I believe that the fine tuning of some proteins will be the future. It's not black, it's not white. If we knock out completely KLF5, it's not good. If we over express KLF5, it's not good. We need some physiological levels. Dr Cindy St. Hilaire: Yeah. You need to be able to tighter it a bit and tighten it up here or loosen it up there and, yeah. Well, this is a great study to really highlight the intricate dynamics of it all. One of the interesting results, it was just one of the shorter sections, but when KLF5 was increased, you also saw a decrease in mitochondrial DNA integrity in the cardiomyocytes, which I thought was a really interesting finding. It was just a little portion of the paper, but I just thought that was really interesting, and I was wondering if you could expand on it. What does that mean? And do we know what KLF is doing to the mitochondria? Dr K. Drosatos: We believe that this is an effect of the oxidative stress and the increase of ceramides. It's a secondary effect. But this is something we would like to pursue further because when we did... And Ioannis nicely mentioned about that. In the 2016 paper, in Circ Research, we actually saw that prolonged exhibition of KLF5 results in diabetic cardiomyopathy. So we don't want to inhibit it completely. And in that case, mitochondria number also goes down. Dr Cindy St. Hilaire: And then, once it's down, it doesn't go back up? Dr K. Drosatos: We believe that in the most recent papers case, it is the oxidative stress that actually targets mitochondria. Dr Cindy St. Hilaire: I think, if I got it correctly, the time course of these events happening in the mice is about a 12 week time span you're doing your treatments for? Dr K. Drosatos: That's correct. Dr Cindy St. Hilaire: So obviously that's much more accelerated than humans. What do you think about these dynamics on a human scale in terms of KLF being up and then being down? Do we know how this mechanism would translate to humans or is that still kind of a black box? Dr K. Drosatos: I think that it's a black box. If I know correctly, we still don't know how fast type one diabetes is occurred in humans. And also the majority of people that have diabetes, diabetic cardiomyopathy is not everything. So maybe their cardiac function is bad, and KLF5 is induced, but these patients do not know that they have actually diabetic cardiomyopathy. And the majority, most probably, of the samples of the research community might have is like a endpoint type 1 diabetic patients. And with the help of Professor Kyriazis, it gave us human samples that we have in our study, we saw that KLF5 is increased in isolated cardiomyocytes. So in terms of how KLF5 is induced in human samples, I think it is high, but we don't know if this 12-week timeframe that we put in the mice to have lack of an overt cardiac dysfunction is actually mimicking completely what is happening to humans. Dr Cindy St. Hilaire: So what do you think about leveraging your findings for the development of potential therapies? What would you want to target first, or how do you think this could potentially move to the clinic setting? Dr K. Drosatos: So regarding the previous question, first, I think it's important that in our case we observe in both type 1 and type 2 diabetes mice, that KLF5 is going now. And the result of correcting cardiac function, when we see a bit of KLF5, either genetically and specifically cardiomyocytes or pharmacologically, identifies KLF5 as a potential barrier. This is how I see. Dr K. Drosatos: You know that in the drug discovery world, transcriptional factors are not very popular therapeutic therapies. So right now the lab is investing on identifying what do they regulate? So we are pursuing a proteomic analysis, we are pursuing sequencing analysis to see what may be happening one step earlier. This is how we envision in potential therapeutic approaches in the future. So this is how we see. Dr K. Drosatos: For me, it's not really a black box. There is a lot of information in the last 20 years on diabetic cardiomyopathy, and you mentioned earlier the SGLT2 inhibition and we don't know how this works, but we have some ideas. I believe we are getting there. And our hope is that the piece of our work we were able to identify any important, novel points of the mechanisms, because it was actually miraculous. I mean, the experiment that excited more than any other experiment in Ioannis's paper was when he started the treatment with the KLF5 inhibitor after diabetic and after cardiac dysfunction had occurred. And the cardiac function became back normal. Dr Cindy St. Hilaire: Do you think this KLF5 mechanism is operative in kind of traditional cardiomyopathy, kind of non-diabetic cardiomyopathy? Dr K. Drosatos: We just published a paper in Circulation. This was the work of Matthew Hoffman and Ioannis was also a co-author in that paper. Matthew and Ioannis were working together in the lab. So Matthew showed that KLF5 is increasing ischemic cardiomyopathy as well. And this was shown both in human samples and mouse experiments. And when KLF5 was inhibited, dilated cardiomyopathy was actually the first. KLF5 was such an underappreciated transcriptional factor and when I was doing my postdoc and started working with that, I always say that I took the risk to generate the cardiomyopathy-specific mouse models because by that time there was only one study showing that it was only fibroblast KLF5 that actually protects from a pressure overload cardiomyopathy. Where they knocked out KLF5 and cardiomyocytes they did not see any protection in pressure overload-driven hypertrophy. So they said, because KLF5 has low RNA copy number, probably it's not important. And I still remember when I first presented this data to KLF meeting, and they will all say, "Yeah, but the expression is very low," but we had the results, so. Dr Cindy St. Hilaire: Yeah. Well, good for you for sticking to your guns. And it's really, really a wonderful study and I want to congratulate you both on this. And it was a huge undertaking with all those mice. Dr K. Drosatos: Thank you. Dr Ioannis Kyriazis: Thank you very much. Dr Cindy St. Hilaire: That's it for the highlights from the February 5th and February 19th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and @DiscoverCircRes and #DiscoverCircRes. Thank you to our guests, Kostas Drosatos and Ioannis Kyriazis. This podcast is produced by Rebecca McTavish and Ashara Ratnayaka, edited by Melissa Stoner, and supported by the Editorial Team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire. And this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research.
Paul J. Wang: Welcome to the monthly podcast On the Beat for circulation, arrhythmia, and electrophysiology. I'm Dr. Paul Wang, Editor In Chief, with some of the key highlights from this month's issue. Elizabeth Wang and Associates examined the relationship between acute precipitants of atrial fibrillation and long-term recurrence of atrial fibrillation, AF, from a multi-institutional, longitudinal electronic medical record database. Among 10,723 patients with newly diagnosed Afib, age 67.9 years, 41% women, the authors found that 19% had an acute AF precipitant, the most common of which were cardiac surgery in 22%, pneumonia in 20% and non-cardiothoracic surgery in 15%. The cumulative incidence of AF recurrence at five years was 41% among individuals with a precipitant, compared to 52% in those without a precipitant. Adjusted hazard ratio 0.75 P < 0.001. The lowest risk of recurrence among those with precipitants with postoperative atrial fibrillation, five-year incidence 32% in cardiac surgery and 39% in non-cardiothoracic surgery. Regardless of the initial precipitant, recurrent atrial fibrillation was associated with an increased adjusted risk of heart failure, hazard ratio of 2.74 P < 0.001, Stroke, hazard ratio 1.57 P < 0.001 and mortality, hazard ratio 2.96 P < 0.001. Thus, the authors found that atrial fibrillation after acute precipitant frequently recurs and the recurrence is associated with substantial long-term morbidity and mortality. In the next paper, Jacob Koruth and associates examine the effect of pulse field ablation on the esophagus in a novel in-vivo porcine esophageal injury model. The authors studied 10 animals under general anesthesia while the lower esophagus was deflected towards the inferior vena cava using an esophageal deviation balloon and ablation was formed from within the inferior vena cava at areas of esophageal contact. Six animals received eight pulse field ablation applications per site and four animals received six clusters of irrigated radio frequency ablation applications at 30 Watts for 30 seconds. All animals survived to 25 days, sacrificed, and the esophagus was submitted for a pathological examination including 10 discreet histological sections of the esophagus. The authors found that zero out of six pulse field ablation animals demonstrated esophageal lesions while esophageal injury occurred in all four radio frequency ablation animals, P = 0.005. A mean of 1.5 mucosal lesions per animal, length 21.8 millimeters with 4.9 millimeters were observed, including one esophageal pulmonary fistula, and deep esophageal ulcers in the other animals. Histological examination demonstrated tissue necrosis surrounded by an acute and chronic inflammation and fibrosis. The necrotic radio frequency ablation lesions involved multiple esophageal tissue layers with evidence of arteriolar medial thickening and fibrosis of peri-esophageal nerves, abscess formation and full thickness esophageal wall disruption were seen in the areas of perforation or fistula. In our next paper, Peter Noseworthy and associates examine whether the ability of deep learning algorithms to detect low left ventricular ejection fraction using the 12 lead electrocardiogram varies by race or ethnicity. The authors used a retrospective cohort analysis and included 97,829 patients with paired electrocardiograms and echocardiograms and used a convolutional neural network to identify patients with a left ventricular ejection fraction less than or equal to 35% from the 12 lead electrocardiogram. The convolutional neural network was previously derived in a homogeneous population, 96.2% non Hispanic white, N = 44,959 which demonstrated consistent performance to detect low left ventricular ejection fraction across a range of racial ethnic subgroups in a separate cohort of 52,870 patients (Non-Hispanic white 44,524 patients with an AUC of 0.93; Asian 557 with an AUC of 0.96; Black/African American N = 651 with an AUC of 0.937; in Hispanic/Latino N = 331 AUC of 0.937; in Native American/Alaskan N = 223 AUC of 0.938). In secondary analysis, a separate neural network was able to discern racial subgroup category, Black/African American AUC 0.84 and white non-Hispanic AUC 0.75 in a five-class classifier. In a network trained only in non-Hispanic whites, from the original derivation cohort, performed similarly well across a range of racial ethnic subgroups in the testing cohort with at least an AUC of 0.93 in all racial ethnic subgroups. The authors concluded that while ECG characteristics vary by race, this did not impact the ability of a convolutional neural network to predict low left ventricular ejection fraction from the ECGs. They recommend reporting of performance against diverse ethnic, racial, age, and gender groups for all new artificial intelligent tools. In our next paper, Benjamin Shoemaker and associates examine the association between atrial fibrillation or AF genetic susceptibility and recurrence after de novo AF ablation, using a comprehensive polygenic risk score for AF in the 10 centers from the AF genetics consortium. AF genetic susceptibility was measured using a previously described a polygenic risk score, N = 929 snips. The overall arrhythmia recurrence rate between 3 and 12 months was 44% in 3,259 patients. Patients with a higher AF genetic susceptibility were younger and have fewer clinical risk factors for atrial fibrillation. Persistent atrial fibrillation has a ratio of 1.39, left atrial size has a ratio of 1.32, and left ventricular ejection fraction per 10% has a ratio of 0.88, were associated with increased risk of occurrence. In unit varied analysis, the authors found that AF genetic susceptibility had a hazard ratio of 1.08 P = 0.07 and in multivariate analysis hazard ratio 1.06 with a P value 0.13. In our next paper, Mohit Turagam and associates reported the outcomes of the first inhuman value trial, which uses low intensity collimated ultrasound or LICU guided anatomical mapping in robotic ablation to isolate the pulmonary veins for atrial fibrillation ablation. In 52 paroxysmal atrial fibrillation patients, ultrasound M-mode based left atrial anatomies were successfully created and ablation was performed under robotic control along an operated defined lesion path. The operatives found that acute pulmonary vein isolation was achieved in 98% of pulmonary veins using LICU only in 77% of pulmonary veins and requiring touch-up with a standard radio frequency ablation catheter in 23% of the pulmonary veins. The touch up rate decreased to 5.8% in patients undergoing LICU ablation with an enhanced software. Freedom from atrial relational recurrence was 79.6% at 12 months or 92.3%, 12 out of 13 patients with the enhanced software. Major adverse events occurred in three patients or 5.8%. One had transient diaphragmatic paralysis, one vascular access complication and one had transient ST segment elevation from air-embolism without sequelae. In our next paper, Miguel Rodrigo and associates mapped electrical patterns of disorganization and reasons of reentrant activity in atrial fibrillation, or AF, from the body surface using electrocardiographic imaging. The author examined the bi-atrial intracardiac electrograms of 47 patients at ablation (30 persistent, 29 males, age 63 years) obtained using 64-pole basket catheters while simultaneously recording 57-lead body surface electrocardiogram. The authors found the body surface mapping showed greater atrial fibrillation organization near intracardiac detected drivers and elsewhere, both in phase singularity density in numbers of drivers, they found that complexity defined as a number of stable AF reentrant sites was concordant between the noninvasive and invasive methods. The subset receiving targeted ablation, AF complexity, showed lower values in those in whom AF terminated than in those in whom AF did not terminate, P < 0.01. The authors concluded that AF complexity, assessed noninvasively, correlates well with organized, disorganized regions detected by intracardiac mapping. In our next paper, Krystien Lieve and Veronica Dusi and associates examined whether heart rate reduction immediately after exercise is regulated by autonomic reflexes, particularly vagal tone and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia, CPVT. In a retrospective observational study, the authors studied 187 patients mean age 36 years, 68 or 36% symptomatic before diagnosis, pre-exercise stress test heart rate and maximal heart rate were equal amongst symptomatic and asymptomatic patients. Patients that were symptomatic prior to diagnosis had a greater delta HRR one prime after a maximum exercise, 43 versus 25, P < 0.001. Corrected for age, gender, and relatedness, patients in the upper tertile for Delta HRR one prime had an odd ratio of 3.4 of being symptomatic before diagnosis, P < 0.001. In addition, Delta HRR one prime was higher in patients with complex ventricular arrhythmias at exercise stress test, off antiarrhythmic drugs. After diagnosis, patients with a Delta HRR one prime in the upper tertile of its distribution, had significantly more rhythmic events as compared to patients and other tertiles, P=0.045. The authors concluded that CPVT patients with a larger heart rate reduction following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during first exercise stress test off antiarrhythmic drugs. In our next paper, Balvinder Handa and associates examined whether low spatial resolution, sequentially acquired data can be used to examine the global fibrillation organization, characterizing dominant propagating patterns and identifying rotational drivers. The authors employed ranger causality analysis, an econometric tool for quantifying causal relationships between complex time series, which was developed as a novel fibrillation mapping tool and adapted to low spatial resolution sequentially acquired data. Ventricular fibrillation, or VF, optical mapping was performed and Langendorff-perfused Sprague Dawley rat hearts, N = 18. And novel algorithms were developed using Granger causality analysis to quantify causal dependence of neighboring signals and plot Granger causality analysis vectors, quantify global organization using causality pairing index, a measure of neighboring causal signal pairs, and localize rotational drivers by quantifying the circular interdependence of neighboring signals with the circular interdependence value. Granger causality analysis based mapping tools were optimized for low spatial resolution by down sampled optical mapping data validated against high resolution phase mapping analysis and further tested in previous VF optical mapping recordings of coronary perfused donor heart LV wedge preparations, N = 12, and adaptive for sequentially acquired intracardiac electric Grande during human persistent atrial relation mapping, N=16. The authors found that global VF organization quantified by causality pairing index showed a negative correlation at progressively lower resolutions in organized VF with high causality pairing index values. Ranger causality analysis vector mapping characterize dominant propagating patterns and localized stable rotational drivers with the circular interdependence value showing a significant difference in driver versus non driver regions, P = 0.0002. These findings were further confirmed in human VF in persistent atrial fibrillation, a positive correlation was found between causality peri-index and presence of stable rotational drivers. 50% of patients had rotational drivers with a low incidence of 0.9 rotational drivers per patient. In a special report, Piotr Futyma and associates report on the use of bipolar radiofrequency ablation of ventricular arrhythmias originating in the vicinity of the His bundle. Bryce Alexander and associates report in a research letter the patient acceptance of cybersecurity upgrade in ICDs. That's it for this month. We hope that you'll find the journal to be the go to place for everyone interested in the field. See you next time. This program is copyright American Heart Association 2020.
Asistanlık yıllarımdan bir nöbet. Kırklı yaşlarında bir kadın hasta 112 tarafından nöbet diye getirilmişti. Yakınlarından hastanın kasılma ve morarması olduğunu öğrendik, hasta bu kısmı hiç hatırlamıyordu ve özgeçmişinde bilinen başka bir hastalığı yoktu. Hastanın bilinci açık, GKS 15, nörolojik muayenesi doğaldı. Benim de aklıma ilk olarak nöbet geldi, hastanın tetkiklerini istedim, orderını verdim, bunlar yapılırken hasta tekrar nöbet geçirdi. Çok kısa sürmüştü ve postiktali olmamıştı. İkinci kez nöbeti olunca hastayı tomografiye gönderdik. Tabii öncesinde EKG çektik, çektiğimiz sırada hasta nöbet geçirmiyordu ve EKG o anki değerlendirmemle normaldi ve herhangi bir aritmi yok idi. Hasta BT’den döndüğünde ekip, hastanın çekim sırasında da nöbet geçirdiğini söyledi. BT’de akut patoloji yoktu. Mükerrer nöbetleri olunca hastayı monitorize ettik, nörolojiye haber verdik ve fenitoin yüklemeye başladık. Fenitoin devam ederken hasta VF'ye girdi ancak birkaç saniye sürmüştü ve defibrile etmeden hasta normal ritme geri döndü. Fenitoin infüzyonunu durdurduk, hastayı monitörize izlemeye devam ediyoruz, bu arada nöroloji de geldi. Hasta tekrar VF'ye girince tabiri caizse bizde jeton düştü. Hasta nöbet geçirmiyor VF’ye girip çıkıyordu. Zaten postiktal dönemi de yoktu. Dış merkeze koroner YBÜ’ye sevk edildi. Sonrasında aileye yapılan genetik taramada Na kanalopatisi saptandığını ve hasta ve çocuklarına ICD takıldığını öğrendik. Bu da bana ders olsundu. Aradan 8 yıl geçti, şimdi de belki bu yazı meslekte yeni arkadaşlarıma yol gösterici olur. Kalıtsal aritmi sendromları nadir görülüyor olmalarına rağmen, erken tanı ile ölüm riski ciddi oranda azaltılabileceğinden oldukça önemli bir başlıktır. Kırk yaş altında ani kardiyak ölüm insidansı yıllık 3/100.000’dir ve yapılan araştırmalar bu ölümlerin çoğuna, kalıtsal kalp hastalıklarının neden olduğunu göstermiştir. Bu vakaların %70’inde neden, primer aritmi sendromları, %30’unda ise aritmi riski oluşturan yapısal kalp hastalıklarıdır. En sık karşılaşılan primer aritmi sendromları1: Uzun QT sendromu (LQTS)Katekolaminerjik polimorfik ventriküler taşikardi (CPVT)Brugada sendromu (BrS)Daha nadirende,Kısa QT sendromu (SQTS)Erken repolarizasyon senromu (ERS)ve idiopatik ventriküler fibrilasyon (IVF)’ dur. Aritmi riski oluşturan yapısal kalp hastalıkları arasında ise1: Hipertrofik (Obstruktif) Kardiyomiyopati (HOCM, HCM)Dilate kardiyomiyopati (DCM)Ve Aritminojenik sağ ventrikül kardiyomiyopatisi/displazisi (ARVC/D) sayılabilir. Ani kardiyak ölüm dışında bu hastaların tipik başvuru şikayetleri çarpıntı, spontan geri dönen kısa bilinç kaybı (senkop) ve spesifik tetikleyicilerin uyardığı aritminojenik nöbetlerdir. LQTS ve CPVT’de senkop genellikle fiziksel efor, psikolojik stres veya saat alarmı gibi ani yüksek seslerden sonra olur. BrS’de ise aritmi genellikle uyku ve ateşlenme sırasında görülür. Hasta öyküsünde, genç aile bireylerinde açıklanamayan ani ölüm veya akrabalarında bilinmeyen nedene bağlı senkop ataklarından bahsediyorsa kalıtsal kardiyak aritmiler (KKA) akla gelmelidir. KKA için bir diğer risk faktörü, başka bir nedenle açıklanamayan EKG anomalileridir. Bu anomaliler: Uzamış QT intervaliStres EKG ‘de ventriküler ekstrasistollerPrekordiyal derivasyonlarda ST segment elevasyonuNegatif veya anormal T dalgaları olabilir. Bu hastalarda tanısal amaçlı ilk değerlendirme 12 derivasyonlu EKG, stres EKG ve EKO muayenesi ile yapılır. Klinik şüphe durumunda aşağıdaki algoritmaya göre genetik inceleme yapılması önerile bilinir. Hastalıkların çoğu otozomal dominanttır (OD), daha nadiren otozomal resesif (OR) kalıtım veya de nova mutasyonlar gözlenebilir. Beckmann BM, Pfeufer A, Kääb S. Inherited cardiac arrhythmias: diagnosis, treatment, and prevention. Dtsch Arztebl Int. 2011 Sep;108(37):623-33; quiz 634. doi: 10.3238/arztebl.2011.0623. 1 Ancak unutulmamalıdır ki, genetik testin NEGATİF çıkması, klinik şüphenin devamı halinde tanının tamamen dışlanmasını ...
Asistanlık yıllarımdan bir nöbet. Kırklı yaşlarında bir kadın hasta 112 tarafından nöbet diye getirilmişti. Yakınlarından hastanın kasılma ve morarması olduğunu öğrendik, hasta bu kısmı hiç hatırlamıyordu ve özgeçmişinde bilinen başka bir hastalığı yoktu. Hastanın bilinci açık, GKS 15, nörolojik muayenesi doğaldı. Benim de aklıma ilk olarak nöbet geldi, hastanın tetkiklerini istedim, orderını verdim, bunlar yapılırken hasta tekrar nöbet geçirdi. Çok kısa sürmüştü ve postiktali olmamıştı. İkinci kez nöbeti olunca hastayı tomografiye gönderdik. Tabii öncesinde EKG çektik, çektiğimiz sırada hasta nöbet geçirmiyordu ve EKG o anki değerlendirmemle normaldi ve herhangi bir aritmi yok idi. Hasta BT’den döndüğünde ekip, hastanın çekim sırasında da nöbet geçirdiğini söyledi. BT’de akut patoloji yoktu. Mükerrer nöbetleri olunca hastayı monitorize ettik, nörolojiye haber verdik ve fenitoin yüklemeye başladık. Fenitoin devam ederken hasta VF'ye girdi ancak birkaç saniye sürmüştü ve defibrile etmeden hasta normal ritme geri döndü. Fenitoin infüzyonunu durdurduk, hastayı monitörize izlemeye devam ediyoruz, bu arada nöroloji de geldi. Hasta tekrar VF'ye girince tabiri caizse bizde jeton düştü. Hasta nöbet geçirmiyor VF’ye girip çıkıyordu. Zaten postiktal dönemi de yoktu. Dış merkeze koroner YBÜ’ye sevk edildi. Sonrasında aileye yapılan genetik taramada Na kanalopatisi saptandığını ve hasta ve çocuklarına ICD takıldığını öğrendik. Bu da bana ders olsundu. Aradan 8 yıl geçti, şimdi de belki bu yazı meslekte yeni arkadaşlarıma yol gösterici olur. Kalıtsal aritmi sendromları nadir görülüyor olmalarına rağmen, erken tanı ile ölüm riski ciddi oranda azaltılabileceğinden oldukça önemli bir başlıktır. Kırk yaş altında ani kardiyak ölüm insidansı yıllık 3/100.000’dir ve yapılan araştırmalar bu ölümlerin çoğuna, kalıtsal kalp hastalıklarının neden olduğunu göstermiştir. Bu vakaların %70’inde neden, primer aritmi sendromları, %30’unda ise aritmi riski oluşturan yapısal kalp hastalıklarıdır. En sık karşılaşılan primer aritmi sendromları1: Uzun QT sendromu (LQTS)Katekolaminerjik polimorfik ventriküler taşikardi (CPVT)Brugada sendromu (BrS)Daha nadirende,Kısa QT sendromu (SQTS)Erken repolarizasyon senromu (ERS)ve idiopatik ventriküler fibrilasyon (IVF)’ dur. Aritmi riski oluşturan yapısal kalp hastalıkları arasında ise1: Hipertrofik (Obstruktif) Kardiyomiyopati (HOCM, HCM)Dilate kardiyomiyopati (DCM)Ve Aritminojenik sağ ventrikül kardiyomiyopatisi/displazisi (ARVC/D) sayılabilir. Ani kardiyak ölüm dışında bu hastaların tipik başvuru şikayetleri çarpıntı, spontan geri dönen kısa bilinç kaybı (senkop) ve spesifik tetikleyicilerin uyardığı aritminojenik nöbetlerdir. LQTS ve CPVT’de senkop genellikle fiziksel efor, psikolojik stres veya saat alarmı gibi ani yüksek seslerden sonra olur. BrS’de ise aritmi genellikle uyku ve ateşlenme sırasında görülür. Hasta öyküsünde, genç aile bireylerinde açıklanamayan ani ölüm veya akrabalarında bilinmeyen nedene bağlı senkop ataklarından bahsediyorsa kalıtsal kardiyak aritmiler (KKA) akla gelmelidir. KKA için bir diğer risk faktörü, başka bir nedenle açıklanamayan EKG anomalileridir. Bu anomaliler: Uzamış QT intervaliStres EKG ‘de ventriküler ekstrasistollerPrekordiyal derivasyonlarda ST segment elevasyonuNegatif veya anormal T dalgaları olabilir. Bu hastalarda tanısal amaçlı ilk değerlendirme 12 derivasyonlu EKG, stres EKG ve EKO muayenesi ile yapılır. Klinik şüphe durumunda aşağıdaki algoritmaya göre genetik inceleme yapılması önerile bilinir. Hastalıkların çoğu otozomal dominanttır (OD), daha nadiren otozomal resesif (OR) kalıtım veya de nova mutasyonlar gözlenebilir. Beckmann BM, Pfeufer A, Kääb S. Inherited cardiac arrhythmias: diagnosis, treatment, and prevention. Dtsch Arztebl Int. 2011 Sep;108(37):623-33; quiz 634. doi: 10.3238/arztebl.2011.0623. 1 Ancak unutulmamalıdır ki, genetik testin NEGATİF çıkması, klinik şüphenin devamı halinde tanının tamamen dışlanmasını ...
This week's episode is co-branded with SADS.ORG and we review a paper on the clinical presentation of those who have conditions associated with sudden cardiac death. Are there questions about the patient and family history and physical examination signs that can improve the identification of those at risk before an event of cardiac arrest? We review this important question and others with Assistant Professor of Pediatrics at Washington University in St. Louis, Dr. Aarti Dalal. Referenced also in this discussion is the following webpage: https://www.sads.org/Library/School-Materials/Risk-Assessment#.XW25gy2ZOu4.DOI:10.1016/j.jpeds.2016.06.088
This week's episode is co-branded with SADS.ORG and we review a paper on the clinical presentation of those who have conditions associated with sudden cardiac death. Are there questions about the patient and family history and physical examination signs that can improve the identification of those at risk before an event of cardiac arrest? We review this important question and others with Assistant Professor of Pediatrics at Washington University in St. Louis, Dr. Aarti Dalal. Referenced also in this discussion is the following webpage: https://www.sads.org/Library/School-Materials/Risk-Assessment#.XW25gy2ZOu4.DOI:10.1016/j.jpeds.2016.06.088
In this special episode # 71 co-presented with the SADS Foundation (SADS.ORG) we speak with the president of the foundation, Professor Michael Ackerman of The Mayo Clinic about a recent work he co-authored on a novel approach to assessing patients with possible CPVT. How should the phenotype help to inform genotype results? Can a novel CPVT scorecard help to improve our understanding of genetic test results? How are genes determined to be 'benign', 'likely disease causing' or a variant of uncertain significance (VUS)? We discuss these issues and more with Dr. Ackerman who provides great insights into this fascinating topic that affects all cardiologists who use genetic testing as part of their practice. doi: 10.1161/CIRCGEN.119.002510
In this special episode # 71 co-presented with the SADS Foundation (SADS.ORG) we speak with the president of the foundation, Professor Michael Ackerman of The Mayo Clinic about a recent work he co-authored on a novel approach to assessing patients with possible CPVT. How should the phenotype help to inform genotype results? Can a novel CPVT scorecard help to improve our understanding of genetic test results? How are genes determined to be 'benign', 'likely disease causing' or a variant of uncertain significance (VUS)? We discuss these issues and more with Dr. Ackerman who provides great insights into this fascinating topic that affects all cardiologists who use genetic testing as part of their practice. doi: 10.1161/CIRCGEN.119.002510
Jane Ferguson: Hi, everyone. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. It's May 2019, and this is episode 28. So let's see what papers we have in the journal this month. First up, a paper from Mengyao Yu, Nabila Bouatia-Naji and colleagues from the Inserm Cardiovascular Research Center in Paris, entitled GWAS-Driven Gene-set Analyses, Genetic and Functional Follow-Up Suggest Glis1 as a Susceptibility Gene for Mitral Valve Prolapse. In this paper, they set out to characterize the genetic contributions to mitral valve prolapse, or MVP, to better understand the biological mechanisms underlying disease. They applied the gene-set enrichment analysis for QWAS tool and the pathway enrichment tool DEPICT to existing GWAS for MVP in a French sample to identify gene sets associated with MVP. They find significant enrichment of genes involved in pathways of relevance to valve biology and enrichment for gene expression in tissues of relevance to cardiovascular disease. They zeroed in a Glis family zinc finger gene Glis1 with consistently strong pattern of evidence across the GWAS enrichment and transcription analyses. They replicated the association between Glis1 and MVP in a UK biobank sample. They found that Glis1 is expressed in valvular cells during embryonic development in mice, but is mostly absent at later times. They targeted two Glis1 orthologs in zebrafish and found that knockdown of Glis1 B was associated with a significant increase in the incidence of severe atrioventricular regurgitation. These data highlight Glis1 as a potential regulator of cardiac valve development with relevance for risk of mitral valve prolapse. Next up is a paper from Gina Peloso, Akihiro Namuro, Sek Kathiresan and colleagues from Boston University, Kanazawa University, and Mass General Hospital. In their paper, Rare Protein Truncating Variance in APOB, Lower LDL-C, and Protection Against Coronary Heart Disease, the team was interested in understanding whether protein truncating variance in APOB underlying familial hypobetalipoproteinemia confer any protection against coronary heart disease. They sequenced the APOB gene in 29 Japanese families with hypobetalipoproteinemia as well as in over 57,000 individuals, some with early onset CHD and some without CHD. They found that presence of an APOB truncating variant was associated with lower LDL cholesterol and lower triglycerides, and also with significantly lower risk for coronary heart disease. This study confirms that variance in APOB, leading to reduced LDL and triglycerides are also protective against coronary heart disease. : The next paper entitled Mortality Risk Associated with Truncating Founder Mutations in Titin comes to us from Mark Jansen, Dennis Dooijes, and colleagues from University Medical Center Utrecht. They analyzed the effect of titin truncating variance on mortality in Dutch families. Titin truncating variants are associated with dilated cardiomyopathy, but have a very variable penetrance. In this study, the authors looked at three titin truncating variants, established to be founder mutations, and traced the pedigrees back to 18th century ancestors. They looked at 61 individuals on the transmission line and 360 of their first-degree relatives. They find no evidence for excess mortality in variant carriers overall. However, when they restrict it to individuals over 60 years of age, they did find a significant difference in mortality, which was also observed in individuals born after 1965. What these data tell us is that these titin truncating variants have a relatively mild phenotype with effects on mortality only manifesting later in life in many carriers. Given increases in life expectancy over the past several decades, the prevalence of morbidity and mortality attributable to titin truncating variants may increase. Genetic screening may identify genotype-positive, phenotype-negative individuals who would benefit from preventative interventions. Continuing on the theme of genetic variance, we have a paper from John Giudicessi, Michael Ackerman, and colleagues from the Mayo Clinic, Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. In this paper, they aim to find a better way to classify variants of unknown significance, of VUS, in the RYR2 gene. Variants in this gene are commonly associated with catecholaminergic polymorphic ventricular tachycardia, or CPVT. They examined 72 distinct variants in 84 Mayo Clinic cases and find that 48% were classified as VUS under ACMG guidelines. The rate was similar in a second sample from the Netherlands, with 42% of variants originally classified as VUS. They developed a diagnostic scorecard to incorporate a pretest clinical probability of CPVT, which included various clinical criteria, including symptoms and stress test results. Application of the phenotype enhanced ACMG criteria brought the VUS rate down to 7% in Mayo Clinic and 9% in the Dutch samples. The majority of VUS were reclassified as likely pathogenic. This study highlights how incorporation of disease-specific phenotype information can help to improve variant classification and reduce the ambiguity of reporting variants of unknown significance. We also have a number of research letters in the journal this month. From Karine Ngoyen, Gilbert Habib, and coauthors from Marseilles, we have a paper entitled Whole Exome Sequencing Reveals a Large Genetic Heterogeneity and Revisits the Causes of Hypertrophic Cardiomyopathy, Experience of a Multicentric study of 200 French Patients. In this study, they examined the genetic contributions to hypertrophic cardiomyopathy, or HCM, in 200 individuals as part of the HYPERGEN study and compared the benefits of whole exome sequencing compared with targeted sequencing of candidates' sarcomeric genes. All subjects had HCM documented by echocardiography. In the whole exome sequencing data, they first looked for mutations within 167 genes known to be involved in cardiomyopathies or other hereditary diseases. Of these 167 virtual panel genes, they find variants in 101 genes. Following whole exome sequencing, over 87% of the patients had an identified pathogenic, or likely pathogenic, mutation compared with only 35% of patients who only had targeted sequencing of sarcomeric genes. This highlights the generic heterogeneity of HCM and suggests that whole exome sequencing has utility in identifying variants not covered by sarcomeric gene panels. The next letter is from Wouter Te Rijdt, Martin [Vandenberg] and colleagues from University Medical Center Groningen and states that [dissynchronopathy] can be a manifestation of heritable cardiomyopathy. They hypothesized that left bundle branch block, also designated as dissynchronopathy, may be a manifestation of familial cardiomyopathy. They analyzed patients from a database of cardiac resynchronization therapy and identified super-responders whose left ventricular dysfunction was normalized by therapy. They carried out targeted sequencing in 60 known cardiomyopathy genes in 16 of these super-responder individuals and identified several variants, including a pathogenic variant in troponin T in one individual and variants of unknown significance in nine individuals. Pedigree analysis identified multiple family members with dilated cardiomyopathy. This study highlights that dissynchronopathy can be a manifestation of DCM, but that affected individuals may still benefit from cardiac resynchronization therapy. The next letter entitled Targeted Long-Read RNA Sequencing Demonstrates Transcriptional Diversity Driven by Splice-Site Variation in MYBPC3 comes from Alexandra Dainis, Euan Ashley, and colleagues from Stanford University. They set out to understand whether transcriptome sequencing could improve the diagnostic yield over genome sequencing in patients with hypertrophic cardiomyopathy. In particular, they hypothesized that long-read sequencing would allow for identification of alternative splicing linked to disease variance. They used long-read RNA and DNA sequencing to target the MYBPC3 gene in an individual with severe HCM who carried a putative splice-site altering variant in the gene. They were able to obtain heart tissue for sequencing and included several HCM and control subjects in addition to the patient with the MYBPC3 variant. They identified several novel isoforms that were only present in the patient sample, as well as some additional isoforms, including retained introns, extended exons, and an additional cryptic exon, which would not have been predicted based on the DNA variant. While the effects on protein function is not known, the transcripts are predicted to be translated. This analysis highlights the effect of a rare variant on transcription of MYBPC3 and provides additional evidence to link the variant to disease. This is a really nice approach, which could be used to probe causality and mechanisms, not only for cardiovascular disease, but for other rare variants in many disease settings. We finish with a perspective piece from Nosheen Reza, Anjali Owens, and coauthors from the University of Pennsylvania entitled Good Intentions Gone Bad, The Dangers of Sponsored Personalized Genomics. They present a case of a 23-year-old woman who presented for genetic counseling and evaluation after discovering she carried a likely pathogenic MYH7 variant associated with cardiomyopathy. She had no significant medical history, but had participated in employer-sponsored genetic testing motivated to identify potential variants related to cancer given a family history of cancer. After receiving her results, she experienced considerable anxiety and stopped exercising out of fear of cardiac complications. She visited an ER after experiencing chest pain, something she had not experienced previously. There was no appropriate counseling available at her institution for her genetic test results, leading her to seek out the additional counseling. Thus, while she was initially motivated to complete genetic testing because her employer offered it free of change, she ended up incurring costs related to the followup evaluation and counseling. Ultimately, she had no significant clinical findings. Although the variant had been listed as likely pathogenic, other sources consider it to be of unknown significance. This story highlights the psychological and financial impact that genetic testing can have on individuals, particularly when carried out without any pretest counseling or accessible post-test support when variants are identified. Despite the considerable promise of personalized medicine, there are many complexities to be considered, particularly with direct-to-consumer testing and employer-sponsored testing. This perspective highlights the ethical considerations and urges caution to maintain the best interests of patients. That's all for this month. Thanks for listening. I look forward to bringing you more next month. This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.
Jane Ferguson: Hi, everyone. Welcome to Episode Four of Getting Personal: -Omics of the Heart." I'm Jane Ferguson, an assistant professor at Vanderbilt University Medical Center. This month, we have a special feature from early career member, Andrew Landstrom, who went to the Heart Rhythm Scientific Sessions in Chicago earlier this month and talked to some of the scientists who presented their research. So listen on for interviews Andrews conducted with Anneline te Riele, discussing the challenges and opportunities related to incidental findings in genetic testing, with Ernesto Fernandez, describing his research into whole exome sequencing and Long QT syndrome, and with David Tester, discussing novel variance and pathway analysis in Sudden Infant Death Syndrome. Andrew : My name is Andrew Landstrom and I am from the Baylor College of Medicine Department of Pediatrics' section on Cardiovascular Disease. I'm here at the 2017 Heart Rhythm Society Scientific Sessions. Anneline, will you tell us a little bit more about yourself, and what brought you to HRS? Anneline: Sure. So my name is Anneline Te Riele, I am a physician from The Netherlands. I finished my medical training in 2012 basically, in The Netherlands, and I started doing a PhD on ARVC in a combined project of our Netherlands patient as well as a group at Hopkins. So what brought me to HRS? I think of course the science. There's a lot of very good science. Actually, I think it's the best meeting for my purposes. Andrew : Absolutely. So will you just start by telling us a little bit about the spectrum of genetic testing in the clinic and about both the opportunities and the challenges that it brings? Anneline: Sure. So what we do in clinic, and I think this is really the challenge that we're facing currently, is we have moved from just testing on gene or one small panel of genes to bigger panels and then to whole exome or even whole genome sequencing. And I think the good part of that is that in certain cases, certain well-selected cases, you'll get a higher change of actually finding that gene that is responsible for disease. On the contrary, it also leads to a lot of incidental findings. So findings that you were not expecting based on the phenotype of the patient and then you need to deal with those abnormalities that you've found and that brings on a lot of challenges as well for the family but also for us as physicians. Do we then need to screen those families, what do we do with this patient, do we treat them with medical therapies or drugs or do we give them ICDs? That kinds of question. So that I think is a virtually important part of what we're currently dealing with in clinical practice. Andrew : It does seem to be a very widespread problem. And here in the US of course we have the American College of Medical Genetics guidelines about reporting a variance. How do you think that that plays into the increased genetic uncertainty here in the US at least? Anneline: So that's a great questions. In 2013, the ACMG produced a guideline on which genes to report if you find these incidental findings. So 24 of these genes, and that's actually a big number, 24 of these genes are cardiovascular genes and that's mainly because changes in cardiovascular genes may detrimental effects down the line and really cause death or certain morbidities that are really important for the patient so we do need to deal with that. And the problem with the ACMG guidelines and especially the pathogenicity guidelines is that they require two aspects. They basically require first that the variant was seen before in other cardiomyopathies or in this case other patients with disease. And that's really difficult for cardiomyopathy genes because these are large genes, they have a lot of novel or private mutations in there, so it's really hard to fulfill that requirement of having been seen before. And the second thing is that the ACMG guidelines require functional studies as another proof of evidence of pathogenicity and of course, I think we would all like to do that in all of our patients, but it's just not feasible for financial purposes and all that. So that's a problem that we're facing. There are options and solutions but I think we'll talk about that later, but yeah, I think that's a problem that we're facing. Andrew : So on the one hand you have the ability to make a diagnostic decision based on a clear finding, but oftentimes the threshold to calling it a clearly pathologic variant is very high and oftentimes it never rises to that so it becomes more genetic uncertainty. Anneline: Yeah. I think that's basically right. And of course in an ideal world, we'll have certainty and say this is likely or this is definitely pathogenic, and this is likely or definitely benign, but in the real world, really, I think maybe even 80, 90% of the cases were in that gray zone in between and we need to deal with that. Andrew : Yeah, yeah. And you had some great resources that both scientists and clinicians alike can apply to these unknown, uncertain variants that might clarify things at least a little bit, and what are these tools? Anneline: So of course, from a traditional perspective, we have always looked at in silico predictive programs, we'll look at segregation data, and I think they're all very important, but they all have limitations, so for example, in silico predictive programs, they likely overcall mutations deleterious and segregation data is nothing more than evidence of pathogenicity of a locus to a disorder, not necessarily that variant, so the new things that are on the horizon, and a thing that could be the future of [inaudible 00:06:04] interpretation is collaborative project so really we should be collaborating, we should not be having our own little islands. The collaboration is the key here. And collaborative efforts in the US have been for example, ClinVar and NHLBI funded effort, as well as ClinGen and ClinGen, or Clinical Genome, is perhaps the, at least it claims to be, the authoritative central resource to go back to that curates variants as being pathogenic yes or no. And I think these databases, ClinVar finally has a database entry, so the variants will be in ClinVar, but ClinGen provides an expert panel of individuals who will curate these variants as being pathogenic yes or no. I think that is a central resource that we should all be aware of. I know these are not the only ones, there are other collaborative efforts out there. I mean, there are ways to connect clinicians, so for example, Match Maker Exchange is a website that you could use to enter your variant and the phenotype of the patient and you submit your own information and then you'll get matches in other databases, but not only your own match shows up. So if, say, two years later, another physician comes up and looks for the same variant, you'll get a pop up, which will actually be very nice for these clinicians to get in touch. So that's, I think, the feature ... future of variant interpretation is collaboration. That's basically my, I think my main important message here. Andrew : I think that's absolutely right. I think this has become sort of a big data question that requires many perspectives, and a lot of resources to be able to curate accurately. What are some of the limitations of these tools that you've seen that kind of, you have to keep in mind in terms of trying to determine whether a variant is truly pathologic or not with a patient that you have sitting in front of you? Anneline: So that is, I mean, of course, there's many limitations in the things that we currently do because there's so much that we don't know. But for example, to give you an example, ClinVar I think, is one central resource that we should all be aware of and if you go to ClinVar, there is actually data from two years ago, and I'm sure the numbers are high if we would look now, but if we look in ClinVar two years ago, we already saw that of the, say 120,000 variants that were in the database, 21% of these variants were called VUSes but if you look at these variants, 17% of the cases, the labs or the individual submitters of ClinVar didn't agree on the actual classification of that variant. So the limitations that we all should be aware of is that there is not one single solution and you should look for evidence and really research your variants. So look at Popmap, look at what is out there, look the patient of course, look at the clinical phenotype, does it match what you think the gene should be doing or not, or is it completely unrelated? And then of course search these databases but be aware of the fact that there may be errors there. Another thing I want to highlight too is that we typically go to population databases, so Exome Variant Server, ExAC, I think these are very popular databases that we use to look at the frequency of variants in a selected population. But really these databases may have sub-clinical disease patients, so I know ExAC has three NYBPC-3 mutations that are known to cause HCM, so this is something to keep in mind. There's not a gold standard truth if you open these databases, but you should have multiple pieces of information when interpreting your variant. Andrew : And that's a good point. I think with a lot of these cardiomyopathies and channelopathies, particularly some of the more frequent ones, when you have a database of 60,000 people, at least a couple of them are going to have disease. Anneline: Yeah. I think that is part of the problem. I mean HCM is pretty prevalent, I mean one in 500 individuals likely, I mean these are recent numbers, has the disease. So I think the cutoff of a minor allele frequency of five percent, which is in the ACMG guidelines, I think is way too high for this disease. So this is what the cardiovascular expert panel of ClinGen has done, so they ... This is, ClinGen, as you might know, Clinical Genome, is a one-on-one team of curators that know the framework of ClinGen and then there is disease experts that are very well accustomed with the disease and the genes associated with it. So they provide teams and these teams work together, and the cardiovascular expert group has recently published a modified, or customized, ACMG guidelines on how to deal with the intricacies of the cardiomyopathies and for example, NYH-7 which is the first genotype deposed in ClinGen or in ClinVar finally. So they modify that cutoff, the minor allele frequency of five percent, which is the BA-1 ACMG guideline cutoff, they changed that to 0.1% and I think that's exactly what you were saying, that is important to keep in mind, some of the cardiomyopathies are way more prevalent so you should not consider that if you see it in a population database that you think that it's, then it's normal, it's not necessarily the case because this is a prevalent disease. Andrew : Yeah, and particularly when commercial genetic testing companies all can't agree that a variant is bad, and we all can't agree that a healthy variant may or may not be good, there is definitely a lot of genetic uncertainty there. Anneline: Exactly, exactly. Andrew : Now, whole-exome sequencing certainly has its role clinically, even with that genetic uncertainty that we spoke about, but it has a clear role in genetic discovery as well. Anneline: Sure. Andrew : And you were part of a very recent paper, and you led a very long list of authors, speaking more about your collaborative approach to genetics research that evaluated a novel substrate for ARVC, is that correct? Anneline: Yes. So this is something I'm actually pretty proud of. As you said, it's a collaborative effort, so it literally take a village to do these kind of studies and we're lucky enough to collaborate with a lot of people who are interested in the same topic. So what we did ... and I metnioned to you in the beginning, I come from the ARVC field ... So what we did is we had one ARVC patient that was discovered by whole-exome sequencing to carry an SCN5A variant and we, in and of itself, found that that was very interesting, because SCN5A, as you know, has been associated with Brugada syndrome predominantly but many other cardiomyopathies as well, so DCM, even ACM. There's been a lot of controversy about SCN5A in that matter. So the computational data, the population data, it all pointed to the fact that this variant may be pathogenic, but we weren't really able to connect those dots just yet. So we then collaborated with the group in NYU with Mario Delmar, who did, first of all, functional studies on the sodium channel, but what was nice is that he was able to use his novel method of super-resolution microscopy which is a way in which we can look at the nano-scale structure of the cardiomyocytes, or really the small, small levels of molecules that you see in these cells. And what we did is we found that not only NAV1.5 which is the gene product of SCN5A but also [inaudible 00:13:53] which is an adherence structure molecule, which links the cells together was actually less present in our ARVC patient compared to the control. And this was in the IPS so cardiomyocyte molecule, which we corrected using CRISPR-Cas9 technology so I think at least in current practice, on of the best pieces of evidence that we can get. So I think this shows that our SCN5A variant, I mean, in this case, probably really was pathogenic, but also in a pathophysiological standpoint, explains to us how SCN5A mutations, which are typically thought to be only affecting the sodium channel, can also lead to cardiomyopathy phenotype which has implications beyond the ARVC world, but also in DCM I think this is a nice finding of collaboration that I think ... I hope more people will look into this. Andrew : Absolutely I think the trouble with SCN5A is exactly like you were saying, it's been implicated in Long QT, Brugada Syndrome, SIDS, [inaudible 00:14:57], now ARVC, and even nodal disease, like sinus syndrome and things like that. So the ability to show sort of mechanistically, that while you have a change in your sodium channel gating that you also have a change in the way that the cells can connect with each other and form contractile force is, I guess, key to your study. Anneline: Yeah, yeah. I think this really, I mean, I'm hoping at least, it was also finally published in a journal that looks more into functional studies, so not necessarily only genetics, and I think we need to work closely not only on the genetic side, but look closely at the pathophysiological standpoint for gene discovery purposes because this will really explain to us why one gene is implicated in one disease, and also it points to possible directions to perhaps stop the disease process and treat these patients, which I think is vital in our clinical practice. Andrew : So are SCN5A mutations in ARVC a common finding or are they rare? Anneline: So they are pretty rare. I mean, we do find them every now and then and maybe they're modifiers. So what we did to follow up on that one individual, we check 281 ARVD patients who were screened just by regular screening, not by whole-exome but we did a targeted screening of SCN5A and we found five variants in these 281 patients, so that's two percent. I mean, it's still rare, but it is as rare as any other minor gene causing ARVC, but it is a rare feature, so I mean, I think it could be a player. And interestingly, the phenotype didn't change much. It wasn't really different from the ARVC patients without an SCN5A mutation which is reassuring. What we also saw is that the prevalence of mutations in those with desmosomal mutations. So ARVC is, as you know, typically associated with diseases or mutations in the desmosome. It was more often seen in those without a desmosomal mutation. That was almost double as frequent as in those with a desmosomal mutation. So it does give us some direction to the fact that this may be a player out there. I mean of course it's not Plakophilin-2 which is the major player, I think, in ARVC, but I think it may cause a, at least a certain form of cardiomyopathy of arrhythmogenic cardiomyopathy that we need to be aware of. Andrew : And how do you think your new discovery of SCN5A being associated with ARVC, how do you think that plays into the bigger discussion we were having about expansive genetic testing and what that may mean for a patient as far as diagnostic utility but also limitations of variant interpretation? Anneline: That's a great question. So I think we should be cautious of saying this gene causes only this disease, and I think this is a common feature not only in ARVC but in a lot of cardiomyopathies and even in channelopathies. I think the concept of one gene causes one disease is outdated. We know that multiple genes have multiple effects and this SCN5A, of course the gene product is NAV1.5 which is the major alpha subunit of the sodium channels so it is really not the canonical function of SCN5A or NAV1.5 that causes cardiomyopathy here but it's a non-canonical function so I think we should be aware of the fact that gene products have different functions and that there can be overlap of the cardiomyopathies. So of course I think we should be screwing SCN5A in our ARVC patients and I'm hoping a lot of labs and a lot of physicians are already doing that, but it's really not the only thing that is associated with ARVC. So that's important to keep in mind. Andrew : What do you think the next steps are for sort of broadening the implication of your finding? Anneline: So what we are doing currently, and is a little bit of a sneak peek, because this data is not really out there yet, but we have, in this cohort, we found these five variants in 281 individuals, and we're currently working on one of these individuals to get another IPSO cardiomyocyte cell line and look into the functional components to that. And interestingly, this variant, that exact variant in that ARVC patient was also found in a Brugada Syndrome patient. So wouldn't it be nice to actually set them side by side and see what the differences are? Of course this is a little bit of a future music, if you know what I'm saying, like this is something that we don't have just yet, but I think what we need to figure out is how epigenetic or environmental factors play into this field and to explain how one gene or one variant, even, can cause opposite functional effects in different phenotypes. Andrew : What do you think is needed to help clarify some of the genetic uncertainty you see clinically? Anneline: I think a lot of collaboration, a lot of money, quite frankly. I think we need to ... I mean, the functional data is really helping us not only for understanding that single variant, but also for gene discovery, and as I said, for treatment down the line, that is necessary, and I think the variant of uncertain significance, I mean, if we all live on our little islands and only do our little practices, then we're not going to go a lot further. So we need to work together to understand what your patient has in this variant, my patient had in that variant, and this is our phenotype, so we need to connect those dots to be able to make certain conclusions. Andrew : Well, I'm all for collaboration, as well as additional money, that's good. Anneline: Good. Andrew : Well, thank you so much for spending time with us. Anneline: Sure. Andrew : And again, congratulations on a wonderful presentation. Anneline: Thank you very much. Andrew : I'm joined by Dr. Ernesto Fernandez from the Baylor College of Medicine to talk about his research project. Ernesto, I'm wondering if we can just start by introducing yourself and what your project is. Ernesto: I am a second-year pediatric resident, I'm applying to a cardiology fellowship right now and I'm interested in, obviously, all aspects of pediatric cardiology. We're trying to figure out whether testing for Long QT genes or Long QT syndrome is actually warranted in otherwise healthy individuals. We're trying to see what the yield is on these testings, specifically whole-exome sequencing. Andrew : And I think this project really hits on an important point, whereby, because we've been able to interrogate the genome more comprehensively with clinical testing, that we've run into more incidentally identified variants. And these variants can pop up in genes, like the genes responsible for Long QT syndrome. Talk a little bit more about these variants, what the implication is of finding these variants incidentally, and what your project hoped to target as far as the diagnostic value of these variants. Ernesto: Yeah. So I guess the answer to your first question is that we are coming up with these marvelous new techniques of analyzing the genome and now we're using whole-exome sequence testing to look up is someone has any exome that's abnormal and this has caused a huge problem whereby we're now finding all these variants that we don't really know what they mean. We call them variants of undetermined significance. Our study is basically premised by the fact that if you have no underlying suspicion for any arrhythmic disease, there's really no need or no indication to be referred for whole-exome sequencing testing, given that the most likely result is a variant that we don't really know what it means. And it's probably going to be benign. Andrew : So on the one hand, you have a well-established gene panel that's being used for diagnostic purposes with you index of suspicion being high for Long QT syndrome versus something like a whole-exome gene screen where somebody may not be thinking about Long QT syndrome as a diagnosis and have low pre-test suspicion but then comes back with a variant found in these genes sort of incidentally. Is that sort of the dichotomy you're drawing? Ernesto: Yeah. I think the best way of explaining it is through Bay's Theorem whereby if you have someone with a high index of suspicion when you start off to have sudden cardiac death, a family history of an arrhythmic disease, and you get a test for it, such as a gene panel for Long QT syndrome, and they come up with a positive test result, then you're going to say, "Oh. I should probably evaluate this further," whereas if you have someone who has some dysmorphism, they have delay, they might have seizures, but there's no family history of sudden cardiac death, no personal history of syncope, then there's really no need to send off this big gun, the whole-exome sequence, because you're likely to either get a normal variant or you're likely to get a variant that we don't know what to make of. Andrew : So I think, Ernesto, that nicely summarizes the clinical question that you had in mind. What was your hypothesis going into the study, and how did you seek to approach that hypothesis, sort of experimentally? Ernesto: So we came up with the hypothesis that if you have an incidentally identified variant within the whole-exome sequencing tests without any other clinical suspicion, it's likely to represent a benign finding. We went about by analyzing the data from the Baylor Miraca labs on the whole-exome sequencing data that they achieved, and we looked specifically at individuals who had gotten these tests and found to have a variant of undetermined significance, or had a pathologic variant for either one or all 17 of the genes for Long QT syndrome. We compared them to individuals who had known Long QT syndrome that had undergone genotype testing, and we [inaudible 00:25:21] these individuals from the literature. And we wanted to compare the whole-exome sequencing cohort to individuals who were otherwise healthy and had obtained a whole-exome sequence. So these are patients or individuals from the well-established ExAC database that are believed to be ostensibly healthy individuals. Andrew : So if I understand you correctly, you're comparing this unknown cohort, that being the rare variants found in whole-exome sequencing, against a positive control cohort of pathologic cases versus a negative control cohort of healthy individuals derived from the ExAC database to look for whether those west variants are more similar to the cases or the controls. With regards to the west cohort, what was the prevalence of individuals with these incidentally identified variants, how many did you find? Ernesto: So we actually found just about 49% of individuals had some variant in Long QT syndrome gene, and noted that about 12% of them had a mutation in the major causes of Long QT syndrome, and just over a third, or 36% had a mutation in the more rare causes of long QT syndrome. Andrew : That's a pretty surprising finding. So you're saying that one in two individuals who get whole-exome sequencing sent for whatever reason, have a variant in a Long QT-associated gene? Ernesto: That's what the data suggests. Andrew : And where did you go from here? Ernesto: So from there, we went onto compare the variant frequency between the case's cohort, those individuals with known Long QT syndrome, those individuals in our west cohort from the Baylor Miraca labs, and those individuals from the ExAC database who are otherwise healthy. So we noted that in our west cohort, there was about 13% of individuals who had a positive variant in the Long QT syndrome one through three genes, the major causes of Long QT syndrome. When we compare that to the ostensibly healthy individuals from the ExAC database, it was 12% in that study that had some variant in Long QT syndrome genes that are major causes of Long QT syndrome itself. This was statistically similar, it was indistinguishable. And then when we compared it to the pathologic cases, it was actually about 50% of those cases who had a positive variant in a Long QT syndrome gene one through three. Andrew : So there was a relatively low frequency of individuals who had variants in one of the big three Long QT genes in both controls and the west cohort, and was obviously much higher among individuals with a diagnosis of Long QT syndrome. Ernesto: Yep. That's exactly what we found. Andrew : And where did you go from here? Ernesto: And then from there, we had a good idea that there was probably a big difference between cases and west, but we wanted to make sure, gene by gene, that there was no difference between our west cases and the ExAC database, the control cases. So we mapped each variant frequency by gene for the major causes of Long QT syndrome. There was no statistically significant difference between the west and the controls. Andrew : So the gene frequencies between the controls and the west were indistinguishable and very much different, both of them, it would seem, to the pathologic cases. Ernesto: Correct. Andrew : And you then looked at the position of these variants, the actual amino acid residues, correct? Ernesto: Yeah. So we looked at, for KCNQ1, KCNH2, and SCM5A, the three major causes of Long QT syndrome, one, two, three respectively, and we mapped out the amino acid positions where there was actually a mutation for each individuals. So the cases, controls, and pathologic cohorts. We determined the percent overlap between the west cohort and the controls and the percent overlap between the west cohort and the cases and noticed that for all three, there is a huge preference for west and control versus west and cases. Andrew : So if you're a west variant you're more likely to reside in the residue also occupied by a healthy individual variant as opposed to a pathologic variant? Ernesto: Yeah. Exactly. Andrew : And so what did you do next? You retrospectively looked at some of the charts of the patients who were seen at Texas Children's Hospital, correct? Ernesto: Mm-hmm (affirmative). So then we had 223 total individuals that had an incidentally identified variant within one of the major three genes, the Long QT syndrome genes. We looked at the reasons for their referrals and noticed that the vast majority of individuals were referred for some developmental delay, for some dysmorphism, for a non-cardiac cause, and then it was only about 23% of these individuals that actually had a reason for referral that was cardiac in nature. And less than on percent of individuals were referred for a solely cardiovascular reason. And we concluded that it's unlikely that these individuals were referred for a cardiac reason, as the data suggests, and that as a result, the index of suspicion for an arrhythmia is likely lower in these individuals. Andrew : And what did you find when you looked at the charts of those individuals? Ernesto: We had EKG data for a good number of them, and we excluded individuals who obviously had no EKG data, and we excluded individuals who had some congenital abnormality and then anyone with any other arrhythmia that would make the QTC interpretation more difficult, such as interventricular conduction defects. We ended up with 62 individuals and 61 of them had a normal QTC, so there was no evidence of QT prolongation at all. There was one individual who was left who had borderline elevated QTC of 460, which was our cutoff for borderline elevation and this individual had actually been seen by pediatric cardiology at Texas Children's Hospital and found to have ... a history of syncope and it was found to be non-cardiogenic in nature. Andrew : So matching the variant data which suggested that you had likely found background variation in the west, you found no evidence of Long QT syndrome in these individuals who had variants in Long QT genes. Ernesto: That's correct. So, the overall percent was very similar between the healthy individuals and the west individuals. The variant frequencies were almost indistinguishable, and then the variant co-mapping for all, for both the west and the controls, was preferential to the western cases. So that kind of matched what we found in our study, that there was no clinical suspicion or clinical diagnosis of Long QT syndrome in these individuals who had been found incidentally. Andrew : Well that sounds to me to be a pretty big finding. Ernesto: Yeah. I think it's pretty important to get this information out there. Andrew : So what do you think the take home message for your study is? Ernesto: I think the take home message is if you don't have a suspicion of Long QT syndrome or of an arrhythmia, there's low likelihood that such a big gun test as the whole-exome sequence is likely going to change your mind. Andrew : So Ernesto, what would you advise a cardiologist who maybe gets a patient in clinic with a chief complaint of a VUS in a Long QT associated gene picked up on west, what would you advise based on your study findings? Ernesto: They're going to have to determine their own pre-test suspicion. They're going to have to get a good history and physical, probably get a baseline EKG to determine what the QTC intervals are, and if there's really no other clinical suspicion for Long QT syndrome, they're likely to be able to provide reassurance at that point in time. Andrew : Ernesto, what do you think the next steps are for this project, and what do you think still needs to be done in the field to reinforce your conclusions? Ernesto: I think my study is one of the early studies of this field, so getting more studies like this and other channelopathies, getting not just looking at Long QT one through three but looking at all of them, and in patients who've been evaluated at Texas Children's or any other institution would be helpful. And then moving forward to give more credence to the idea that if you have history that's reassuring and physical exam that's reassuring, then you probably don't need to have further testing. Andrew : What do you recommend if your index of suspicion is high for Long QT syndrome, so maybe a QTC in the low 480s, maybe a family history of syncope or seizures, do you think whole-exome sequencing is the way to go? Ernesto: Right now, that's probably not the best test, given all these incidental findings that we don't really know what to do with. There's other tests that are more high-tailored for those specific diseases, like Long QT syndrome panel among others, that are probably more likely to give you a positive post-test probability. Andrew : So testing for the disease you're suspicious for as opposed to testing indiscriminately? Ernesto: Yeah. Andrew : So Ernesto, thank you so much for taking the time our of your day to speak with us. Ernesto: Thank you, Andrew. Andrew : I'm here with David Tester, senior research technologist working with Mike Ackerman at Mayo Clinic, and he just gave a wonderful talk on whole-exome sequencing and next-generation sequencing as an unbiased look to determine underlying causes of Sudden Infant Death Syndrome, or SIDS. So David, I'm wondering if you can introduce yourself and talk a little bit about your project. Dave: Sure. I'm Dave Tester and I'm at the Mayo Clinic, again with Mike Ackerman. Dr. Ackerman and I have been together for about 18 years now, with a real focus on genetics of sudden cardiac death disorders. So this latest study was looking at whole-exome sequencing in a population of SIDS cases in collaboration with Dr. Elijah Behr at St. George's University in London. And really the approach, what we were aiming for is really kind of two-fold. First we were looking to determine what is the yield of ultra-rare variance within genes that have been implicated in cardiovascular disorders? These would be the cardiac channelopathies and some of the cardiomyopathies such as ACM or ARVC, for example. And the second thing that we were wanting to look at was can we use this to search for sort of novel candidate genes for Sudden Infant Death Syndrome susceptibility? And so we took that aim and really the main result was to show that about 14% of our SIDS cases had what we term potentially informative variants. And those are going to be variants that were within sort of the major channelopathy genes that are implicated in Long QT syndrome or CPVT as well as loss of function variants within the 90 ICC genes that we had examined. Using the ACMG guidelines for determining the pathogenicity of variants, about 4.3% of our SIDS cases hosted an ACMG guideline predicated likely pathogenic to pathogenic variant. And most of those variants represent either a frame shift or splice site error variance really in minor cardiomyopathy genes and channelopathy genes. So there's still a lot of work that needs to be done in terms of looking at specifically missense variance within channel genes and that sort of thing, and really kind of functionally characterizing those to determine whether or not they truly are pathogenic or if they should remain variants of uncertain significance. Andrew : And so you took a very complex disease like SIDS with probably a number of differens ideologies and found a pretty good percentage have suspicious variants, that 14% or so, and then 4% had variants that were so suspicious they would meet American College of Medical Genetics guidelines for being a possible or likely pathologic variant. Where do you think this study lies in sort of the continuum of identifying the genetic ideology of SIDS, and what do you think these findings sort of add to that overall picture? Dave: Well I think these findings in general really just kind of show the complexity of SIDS. Whether or not SIDS is really truly genetic or not, or perhaps it just, if it's not monogenic, perhaps it's polygenic, and so those are some things that we should be considering and looking at. Now some of those questions might be able to be answer through our whole-exome sequencing data set that we have, and I think those are really going to be kind of the next phases. We can also take and do some pathway analyses of the exome sequencing data, for example, and see our variance kind of lining up on certain pathways that may contribute to certain pathologies that could contribute to SIDS. Andrew : And in your study, you had a few genes where the number of variants that were found in SIDS cases were higher than in your controls. Can you speak some more about what those genes may tell you in the context of pathway analysis for SIDS? Dave: Yes. So there was ... There were not genes that came out with sort of a genome-wide significance level. But there were at least 400 genes that had a p-value of 0.05 over representation in SIDS versus our ethnic match controls and 17 of those genes have a p-value of 0.005 and we're really kind of focused on some of those that have a little bit higher p-value for us to assess. A few of those genes may represent biologically plausible candidate genes for SIDS and we were kind of actually going through and considering which ones we'd like to follow up on in terms of function. Some of these genes do play a role in, say, cardiorespiratory system and function of the heart as well as in the brain. Andrew : So then given all these findings, and the fact that you may have some candidate genes and candidate pathways that might be interesting to look at further, what are the next steps that you think would help this project move forward, and what do you think the field of Sudden Infant Death Syndrome and Sudden Unexplained Death Syndrome needs to kind of move forward? Dave: Well I think from a genetic standpoint, the study that we just complete was really on a large set of unrelated infants that had died suddenly. We did not have access to parental DNA and so moving forward in terms of the genetics, I think incorporating sort of a trio analysis I think would get at the question of sort of [inaudible 00:42:01] variance for example. The other things, in terms of genetic standpoint is perhaps looking at different genetic mechanisms. Whether these are copy number variance that may be missed by exome sequencing, perhaps some of the SIDS could be due to epigenetic abnormalities or even small chromosomal abnormalities that perhaps may not be detected on certain arrays on there being used. So I think going forward, kind of taking those approaches to look for sort of unique genetic variation. Andrew : Well Dave, thank you so much for taking the time to speak with me and congratulations on a great project. Dave: All right, great, thank you. Jane Ferguson: Thanks to Andrew for highlighting the interesting precision medicine research presented at HRS and thanks to you all for listening. We'll be back with more next month.
Dr. Wang: Welcome to the monthly podcast On The Beat for Circulation, Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, editor-in-chief, with some of the key highlights from this month's issue. We'll also hear from Dr. Suraj Kapa, reporting on new research from the latest journal articles in the field. This month's issue of Circulation: Arrhythmia and Electrophysiology has a number of fascinating and important articles. Let's start with the first article by Philip Halbfass and Associates, which describes the use of esophageal endoscopy in patients undergoing atrial fibrillation ablation. Of 1,802 patients undergoing afib ablation, 832 underwent post-procedural esophageal endoscopy. All patients were ablated using a single tip re-circular ablation catheter. Category one lesions described as erythema erosion were seen in 98 out of these 295 patients, while in 52 out of the 295 patients, ulceration was seen. In three of the 832 patients, esophageal perforation occurred, and in two of the 832 patients, atrial-esophageal fistula occurred. Esophageal perforation only occurred in patients with category two lesions with an absolute risk of 9.6%. The authors concluded that post-ablation esophageal endoscopy is able to identify patients with high-risk lesions. One out of 10 patients with post-ablation esophageal ulcers progressed to perforation, while no patients without esophageal ulcers showed evidence of perforating complications. In the next article by Christian Sohns and Associates describes the relationship between atrial fibrosis identified with magnetic resonance imaging and atrial rotor activity identified by noninvasive electrophysiological mapping. Ten patients underwent pulmonary vein isolation for persistent atrial fibrillation. Late gadolinium enhancement using magnetic resonance imaging, which projected onto the anatomy used for noninvasive electrophysiologic mapping. The noninvasive electrophysiologic mapping identified 410 rotors evenly distributed between the left atrium and the right atrium. This study found that there was no statistically significant association between the presence of late gadolinium enhancement and the presence of rotors. In the next article written by Jereon Venlet examines the endocardial unipolar voltage that best identifies abnormal epicardial electrograms. Thirty-three patients underwent endocardial epicardial right ventricular electro-anatomical mapping in ablation of right ventricular scar-related ventricular tachycardia. Eighty-six percent of abnormal epicardial electrograms had corresponding endocardial sites with bipolar electrogram less than 1.5 millivolts. The remaining abnormal epicardial electrograms could be identified by endocardial unipolar voltages of less than 3.7 millivolts. The authors concluded that this use of endocardial unipolar voltage cut off at normal bipolar voltage sites improves the identification of all abnormal epicardial electrograms where there is less than 1 millimeter of fat. The next article by Alan Bulava and Associates examines the outcomes of hybrid epicardial and endocardial radial frequency ablation, a persistent atrial fibrillation. Seventy patients underwent the epicardial thoracoscopic procedure followed by endocardial mapping ablation two to three months later. At the time of catheter ablation, 76% of patients were in sinus rhythm. All four pulmonary veins were found to be isolated in 69% of the patients and the left atrial posterior wall was isolated in 23% of the patients. In the 12 months after the catheter ablation, 77% were arrhythmia-free, off antirrhythmic drugs. The majority of arrhythmia occurrences occur during the first 12 months following catheter ablation. Using previously ineffective antiarrythmics drugs and re-ablation procedures, arrhythmia-free survival increased to 97% during a mean followup of 936 days. Left atrial volume greater than 165 milliliters, the absence of sinus rhythm before catheter ablation and induce-ability of any sustained tachyarrhythmia at the end of catheter ablation predicted atrial fibrillation recurrence. The authors concluded that the majority of patients after epicardial ablation required endocardial catheter ablation to complete the linear ablation or pulmonary vein isolation lesion sets. In the next article, Jason Roberts and Associates studied the clinical phenotype of Type 6 Long QT Syndrome, stemming from mutations in the KCNE2 encoded voltage gated channel beta subunit. The authors examined individuals reported pathogenic KCNE2 mutations collected from inherited arrhythmia clinics in the Rochester LQTS registry as well as previously reported LQT6 cases identified through a med-line database search. Of 44 probands studied, 16 probands had resting QTC intervals and only developed QT prolongation and malignant arrhythmias following exposure to QT prolonging stressors. Ten had other Long QT pathogenic mutations and 10 did not have a Long QT phenotype, with the remaining eight subjects having a Long QT phenotype, but with evidence suggesting that the KCNE2 variant was not the underlying culprit. The authors noted that the collective frequency of KCNE2 variance implicated in Long QT6 syndrome in the exome aggregation consortium database was 1.4%, in comparison with the 0.0005% estimated clinical prevalence of LQT6 syndrome. Thus, the authors concluded that based on clinical phenotype, the high allelic frequencies of LQT6 mutations in the exome consortium database, in absence of prior documentation of genotype phenotype segregation, many KCNE2 variants, and perhaps all have been erroneously designated as long QT syndrome causative mutations. Instead, KCNE2 variants may confer pro-arrhythmic susceptibility when provoked by additional environmental acquired or genetic factors. In the next article, Alexander Quinn and Associates examine how mechanically-induced ectopy may cause ventricular fibrillation, the mechanism of commotio cordis. It is known that the block of stretched sensitive ATP inactivated potassium channels limits ventricular fibrillation occurrence in a porcine model of commotio cordis. In isolated rabbit heart preparations using optical voltage mapping combined with pharmacological block of potassium ATP or stretch activated cation nonselective channels, the authors showed that the mechanical stimulation reliably triggers premature ventricular excitation at the contact site with induce-ability predicted by local tissue indentation. Mechanically-induced premature ventricular excitation induction is decreased by stretch activated cation nonselective channel block. The authors also found that mechanically-induced premature ventricular excitation resulted in ventricular fibrillation only if the mechanical stimulation site overlaps the re-polarization wave edge in hearts where T-waves involve a well-defined re-polarization edge traversing the epicardium. This defines a narrow subject-specific vulnerable window for commotio cordis-induced ventricular fibrillation in both time and space. In the next article Matthias Seidl and Associates examine the gene expression required for development of atrial fibrillation in a transgenic mouse model. Recent studies showed that atrial fibrillation susceptibility is associated with down regularization of target genes of the CREB/CREM family of transcription factors. CREB/CREM refers to cyclic and P-response element binding protein modulator. Short CREM repressor isoforms like CREM-IbΔC-X bind to cyclical A&P responsive elements preventing transcriptional activation. Messenger RNA for CREM-IbΔC-X is up-regulated in atrial biopsies from patients with paroxysmal or chronic atrial fibrillation. The authors examined transgenic mice expressing CREM-IbΔC-X, which spontaneously developed atrial fibrillation proceeding to permanent fibrillation with age. The authors found that the most prominent alterations of the gene program linked to CREM-induced atria modeling were identified in expression of genes related to structure, metabolism, contractility and electrical activity regulation. In the next article by Takumi Yamada and Associates electrophysiologic characteristics of the idiopathic ventricular arrhythmias originating from the parietal band, one of the muscle bands of the right ventricle, were examined. Of 294 consecutive patients with right ventricular origins, 14 patients had ventricular arrhythmia origins in the parietal band. All patients have left bundle block pattern with 12 inferior and two superior axis. All patients had the notch in the middle of the curess in all cases. Seven patients had precordial transition before lead V3 and four patients had a slow curess onset. Far field ventricular electrogram with an early activation was always recorded in His bundle region regardless of the location of the ventricular arrhythmia origin. During the catheter ablation, a mean number of 10.4 radio frequency of applications with a mean duration of 1,099 seconds were delivered. Catheter ablation was successful in 10 patients and ventricular arrhythmias recurred in four with a mean followup of 41 months. In the Advances in Arrhythmia and Electrophysiology section, the Buza and Associates have reviewed cancer treatment-induced arrhythmias. The authors describe ECD advances in arrhythmias associated with individual cancer chemotherapeutic agents. Now here with a review of the highlights from the articles from journals throughout the world in the past month, is Dr. Suraj Kapa. Dr. Kapa: Hello. Today we're going to be going over several hard hitting articles we have identified that seem to stand out in the electrophysiological literature from the month of July 2017. The first area we will be delving into is that of atrial fibrillation. Specifically related to cardiac mapping and ablation. The first article in this area that we've chosen was published by Samuel et al. in the Journal of Cardiovascular Electrophysiology entitled Catheter Ablation for the Treatment of Atrial Fibrillation Is Associated with a Reduction in Healthcare Resource Utilization. Samuel et al. reviewed data from a large population base cohort in Quebec, Canada including over 1,500 patients undergoing cardiac ablation for atrial fibrillation. They demonstrated that healthcare resource utilization including hospitalizations, emergency room visits and cardioversions were significantly reduced both 12 months as well as 24 months after the next ablation. These findings seem to suggest that catheter ablation has a sustained overall impact on resource utilization amongst patients with atrial fibrillation. While the study was not randomized and was a retrospective evaluation of outcomes, these findings are provocative. Certainly as we wait for the results of the Cabana trial in about one year we hope to see whether or not cardiac ablation carries the weight of potential beneficial impacts both in terms of long-term care as well as long-term outcomes. Of course being a retrospective evaluation, one question that lies with regards to these findings is whether or not the reduction in resource utilization might be a byproduct of improved ambulatory care of these patients or whether it's a byproduct of patients understanding their disease process better, and thus perhaps not seeking emergency room care or hospitalization as frequently. The next publication we'll focus on was published by Anselmino et al. in The International Journal of Cardiology entitled Conduction Recovery Following Catheter Ablation in Patients with Recurrent Atrial Fibrillation and Heart Failure. This publication synergizes with several other publications that have come out in the month of July. Focusing on the publication by Anselmino et al., they reviewed retrospectively patients undergoing redo atrial fibrillation ablation in the setting of underlying heart failure. What they demonstrated was that nearly a third of patients had no pulmonary vein reconnection, but tended to have more persistent forms of atrial fibrillation suggesting more extensive atrial substraights. This study is complimentary to a publication by [inaudible 00:15:23] et al., published in JACC EP. this past month where they evaluated the longterm outcomes of patients who, when presenting for redo atrial fibrillation ablation had persistent pulmonary vein isolation. In that article, they found that nearly 17% of patients presenting for redo ablation had persistent pulmonary vein isolation. Moreover, these patients tended to perform significantly worse in terms of longterm outcomes than those who presented with PV reconnection, with about a 56% freedom from affiliate swipe after we do ablation in the setting of persistent pulmonary vein isolation as opposed to 76% when there was PV reconnection seen. So the question becomes if we see this greater atrial substraight, should we automatically be doing more ablation? Of course as we all know, there have been many studies performed trying to tease out whether additional ablation in patients who might have more significant atrial substraight carries benefits. In this regard, Fink et al. in last month's edition of Circulation, Arrhythmia and Electrophysiology demonstrated that in fact as an index procedure of performing a stepwise concomitant café plus linear ablation on top of pulmonary vein isolation in persistent and long standing persistent atrial fibrillation patients did not necessarily confer an increased likelihood of longterm success over pulmonary vein isolation alone. Thus, the jury continues to still be out as far as what the right strategy is in many of these patients. However, these studies highlight the importance of continued evaluation and understanding of how we can use information about atrial substraight to guide our ablation procedures more successfully. Changing gears, we'll move on the pathophysiology mechanisms of disease within atrial fibrillation. The article we will choose to focus on here was published by Die et al. in The Journal of Cardiovascular Electrophysiology entitled The Effects of Extrinsic Cardiac Nerve Stimulation on Atrial Fibrillation Induce-ability: The Regulatory Role of the Spinal Cord. Over the course of the last several years many investigators have sought to show that modulation of the autonomic nervous system can successfully alter cardiac electrophysiology and provide antiarrythmic benefits. However, when subject to prospective trials such as the recently published Defeat HF Trial, they have not necessarily found clear benefit. Thus, a critical question becomes how we translate our animal models into human treatment. The interesting results from Die et al. lie in the fact that they looked at the effects of spinal cord stimulation and spinal cord block in addition to concomitant stimulation of other centers such as the venous nerve, the stellate ganglion and ganglionated plexi. They demonstrated that spinal cord stimulation enhanced the effects of venial nerve stimulation while attenuating the effects of stimulating the left stellate ganglion or ganglionated plexus. In turn, the combinations of these different levels of stimulation had different effects on affiliate swipe induce-ability, whether significantly increasing or decreasing the potential. The reason this article is important is it highlights the extensive cross linking and synergy that exists within the autonomic nervous system and that attention paid to only a single center of autonomic innovation may not be sufficient for certain paradigms of care. This past month there were also two reviews summarizing the role of the autonomic nervous system and modulation of that nervous system and the treatment of arrhythmias. The first was by Witt et al. and Europace. The other by Schwartz et al. in the International Journal of Cardiology. These articles help the reader understand the extensive crosslinking and cross communication that might occur, that might sometimes defeat our efforts to use a single element of the autonomic nervous system to modulate cardiac arrhythmias. Changing gears yet again, we'll move on to risk stratification and management for atrial fibrillation. Perino et al. in last month's edition of The Journal of the American College of Cardiology published an article entitled Treating Specialty in Outcomes in Newly Diagnosed Atrial Fibrillation from the Treat AF Study. They present data based on a very large cohort of over 180,000 veterans regarding the effect of treating specialty on atrial fibrillation outcome. Interestingly they demonstrated that when a cardiologist was involved in the care of the patient, there was an overall decrease in stroke and mortality. Albeit with a concomitant increase in hospitalization for AF. The stroke reduction seen was also seen to be secondary to better anticoagulation prescription within 90 days of diagnosis when those patients were seen by a cardiologist as compared with a general internist. This earlier prescription anticoagulation however did not mediate the mortality reduction. These data presented by a Perino et al. are provocative in this era of rising healthcare costs. The question is, as atrial fibrillation rates rise, as the general population ages, how quickly and how aggressively we should engage specialty care early on in patient evaluation. The data by Perino et al. suggests that maybe this engagement should occur earlier. Part of the reasons for this might be improved understanding of current evidence regarding treatment of such patients or better systems of care that allow for providers to identify patients who might need alterations and care faster. However, if anything this is hypothesis-generating. Why anticoagulation prescriptions are delayed when patients are not seen by a specialist or why there would be a difference in mortality are important factors to review further. In this past month Hernandez et al. in Stroke published an article discussing the large degree of geographic variation that exists with regards to appropriate anticoagulation prescription in patients with atrial fibrillation. They demonstrated that there's extensive inhomogeneity across the United States in terms of how and in whom anticoagulation gets prescribed. Thus, how much of these outcomes are specialist-driven, geographically-driven or based on elements of access to care or other issues are going to be important features that have to be evaluated. The next article in risk stratification was published by Mostofsky et al. in Heart, entitle Chocolate Intake and Risk of Clinically Apparent Atrial Fibrillation: The Danish Diet, Cancer and Heart Study. In this study they demonstrated in a population of over 55,000 patients that when accounting for as many variables as they could, higher chocolate intake, more than once per month, was associated with a decreased atrial fibrillation risk when compared with those consuming less chocolate than once per month. Of course, they note that despite these attempts to account for multiple confounding variables, residuary confounders cannot be accounted for. The relevance of this article lies in the question of lifestyle choices patients are asked to make when thinking about how to either prevent themselves from having atrial fibrillation or trying to even treat their atrial fibrillation risk. Chocolate has been shown to have multiple potential beneficial effects in multiple areas of cardiology, however, how to counsel patients with data like these becomes very difficult. The questions lies in how chocolate might mediate arrhythmia risk and how it might also modulate other potential risks such as weight gain or other factors. Thus while important to consider this in light of patients often asking what they can and cannot have, it is important to further consider that we don't understand the full story. The other key element to understand is that really when they say that chocolate intake reduces risk of clinically apparent atrial fibrillation they are speaking about moderate chocolate intake and not necessarily having it for three meals a day. Changing gears away from atrial fibrillation, we will next focus on the area of ICDs pacemakers and CRT. Aberi et al. in Nature's Scientific Reports published regarding inductively power wireless pacing via miniature pacemaker and remote stimulation control system. Their approach provides potential novel opportunities beyond currently available both lead-based and leadless pacemakers and improving battery and allowing for further miniaturization of such devices. They noted by creating a very novel inductive power supply they're able to miniaturize the pacing components and also significantly reduce the power requirements. In fact, they suggested that they could create a leadless device that could be as small as being delivered out of the anterior ventricular vein. This is the first report of such an inductively powered miniaturized pacing system with low enough power consumption that may prove viable for ambulatory human use. The desire to create improved pacing and fibrillation systems is further highlighted by an article published by [Kalu 00:25:41] et al. in JACC Clinical Electrophysiology this past month where they demonstrated initial results of percutaneous epicardially delivered partially insulated defibrillator lead. Work like these holds the potential to improve options for patients and in traditional vascular access is not desired, or an identifying new ways of delivering pacing therapy that exists outside the traditional lead base or even somewhat miniaturized leadless approaches. We'll next focus on the area of sudden death and cardiac arrest. The first article we'll focus on was published by Stecker et al. in The Journal of The American Heart Association entitled Health Insurance Expansion and Incidence of Out of Hospital Cardiac Arrest: A Pilot Study in the US Metropolitan Community. This article looked at the results of The Affordable Care Act, mainly health insurance expansion, on the rate of out of hospital cardiac arrest in a large US metropolitan community of over 600,000 people. They separately studied a middle aged population that might have been affected by healthcare expansion versus an older population, above 65, who would have had relatively stable insurance plans having been covered by Medicare both prior to and after this change in healthcare plans. They demonstrated that there was a significant decrease in overall out of hospital cardiac arrests amongst middle age people without any significant change amongst the more elderly Medicare population in the same time period. The time period studied was relatively short, nearly less than a decade. Of course, whether there were other events that might have occurred to alter this risk such as improvements in care beyond the combination of availability and mandates plus carrying health insurance, it remains to be seen. However, the data is very suggestive. Further evaluation at the national level in varying communities however would be useful, as well as consideration of population level cost benefit analysis. The next article published by Shen et al. in the New England Journal of Medicine entitled Declining Risk of Sudden Death in Heart Failure. They presented data across 40,000 patients from multiple clinical trials over two decades regarding the changing rates of sudden death amongst heart failure patients. Interestingly they noted there was an overall 44% reduction in sudden death rates across these trials over time dating from the 1990s to 2014. In the earliest trials considered, the mortality rate within 90 days after randomization was as high as 2.4% while the most recent trials suggest that that rate is more like 1.0%. This profound decline was attributed to improved usage and prescription of medications early on in the heart failure course, which may modulate outcomes. The relevance of these findings lies in trials that have been published recently and met analysis that we've discussed regarding utility of defibrillators in nonischemic cardiomyopathy or even ischemic cardiomyopathy. The recently published Danish study suggested that ICDs might not confer an equivalent mortality risk as what would have been expected years ago. However, this publication by Shen et al. is particularly provocative because it calls into question whether the same mortality benefit we anticipated from earlier heart failure trials should still be the rubric by which current defibrillator trials are powered. Namely, if we consider that Danish saw the 25% difference in mortality, with a 44% overall reduction in sudden death seen in trials over time for heart failure, seeking a 25% reduction might be excessive. Thus, this highlights the need to potentially power trials for ICDs and the benefit of such ICDs better. This importance of better stratifying better heart failure patients for sudden death risk has been raised in multiple articles this month, including in a review by Holiday et al. in Circulation and in the series of reviews published in Volume 237 of The International Journal of Cardiology. The last article we choose to focus on in the role of sudden death and cardiac arrest was published by Vehmeijer in Circulation: Arrhythmia and Electrophysiology entitled Prevention of Sudden Cardiac Death in Adults with Congenital Heart Disease: Do the Guidelines Fall Short? They reviewed outcomes amongst 26,000 adults with congenital heart disease in light of existing guidelines for risk prediction and prevention of sudden death. They demonstrated that less than half of the patients with sudden cardiac death actually had a guideline basis recommendation for an ICD on the basis of either the 2014 consensus statement on arrhythmias or the 2015 European Society of Cardiology Guidelines. These findings are very provocative in suggesting that we don't really understand who requires treatment amongst adults with congenital heart disease. With improved care paradigms, both with improvements in surgical outcomes as well as ambulatory care of these patients and recognition of need for interventions, arrhythmias are becoming a greater and greater problem amongst patients with adult congenital heart disease. However, large scale studies are limited in stratifying overall risk of arrhythmias. The risk is certainly present as many of these patients have ventricular scar often attributable to cardiac surgeries or have hemodynamic insults that may result in progressive fibrosis of the ventricles. In addition, the basal abnormalities of cardiac formation itself may lend itself to a sudden increased risk of arrhythmias. Thus, the question remains as how to best risk stratify these patients in order to reduce these overall sudden death rates. Changing gears yet again, we'll focus on two articles within the realm of cellular electrophysiology. The first article was published by Cerrone et al. in Nature Communications entitled Plakophilin-2 is Required for Transcription of Genes that Control Calcium Cycling and Cardiac Rhythm. They demonstrated that plakophilin-2, or PKP2, which is known to mediate arrhythmogenic right ventricular cardiomyopathy due to abnormalities in the desmosomes actually has other direct electrical effects independent of substraight effects that are seen. Specifically PKP2 plays a significant role in maintaining gene transcription for several genes that mediate normal electrophysiologic activity, such as the ryanodine receptor, calsequestrin and others. They demonstrated that this reduced expression of other genes secondary to PKP2 absence or abnormality leads to increased isoproterenol or adrenaline-induced arrhythmias that in turn can be suppressed with Flecainide. These findings are provocative in the fact that they suggest that it is possible for patients to have abnormalities of genes such as PKP2 that result in electrical abnormalities independent of the structural abnormalities. Furthermore, it suggests that manifestation of the disease such as catecholaminergic polymorphic ventricular tachycardia may be immediate upstream of typical channels associated with the disease. For example, if PKP2 reduces expression of the ryanodine receptor, this might result in manifestations similar to CPTB in some patients. Along the same lines, Hewitt et al. published in Science Advances regarding deregulated calcium cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. Obscurins are a relatively growing area of interest as these are cytoskeletal proteins that have be associated with both hypertrophic and dilated cardiomyopathy. Similar to the story we just told about PKP2 however, they demonstrated that obscurins, likely through circa 2 and pentameric phospholamban can cause abnormal calcium handling. In fact, they demonstrated that the principle phenotype associated with obscurin abnormalities is one of an electrical abnormality, namely frequent PVCs. In turn, mechanical phenotypes such as cardiomyopathy result in the setting of chronic pathologic stress such as increased afterload, thus these findings demonstrate that genes such as obscurin or PKP2, which are commonly associated with structural or mechanical myopathic processes might have direct independent electrical effects. The story with obscurin raises further question into how this may apply to conditions of PVC-related cardiomyopathy or other such conditions. The other key point about these two areas of interest lie in the fact that it is possible as these genetic abnormalities mediate not just direct substraight elements, but arrhythmogenesis via abnormal channel expression, whether in all patients presenting with such specific genetic abnormalities substraight-based ablation alone will result in reduction of arrhythmia tendency. Of course this remains to be seen and is primarily hypothesis-generating. Next we'll focus on three articles within the area of genetic channelopathies. The first paper was published by Rohatgi et al. in The Journal of the American College of Cardiology entitled Contemporary Outcomes in Patients With Long QT Syndrome. In a large single center practice, they reviewed the results of over 600 patients predominantly affected by LQT1 or LQT2 and demonstrated that after initial evaluation along with treatment based on the individual, done at a highly skilled center, 92% of patients did not experience any breakthrough cardiac events over longterm followup. It was noted however, that the incidence of breakthrough cardiovascular events over longterm followup were far more common in patients who were symptomatic prior to their first evaluation than asymptomatic. In other words, if you were symptomatic prior to your first evaluation, the likelihood of a breakthrough cardiovascular event over longterm followup was as high as 25%, but if you were asymptomatic it was as low as 2%. These data suggest that our overall care of the Long QT patient is improving. However, it also supports that further improvements in care are needed as breakthrough cardiovascular events can continue to occur. It also highlights the importance of close followup of that symptomatic patient in the modern era. The second article was published by Kannenkeril et al. in JAMA Cardiology entitled the Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia. Flecainide currently carries a class 2A indication according to both the 2015 ENC guidelines and 2013 HRS AHRA APHRS consensus statement for treatment of patients with CPVT who fail max dose beta blockers. A lot of this evaluation however, has been based on retrospective evaluations. Kannenkeril reviewed in a prospective single blind placebo controlled crossover trial the effect of Flecainide on exercise associated arrhythmias in CPTV patients who were already on max tolerated beta blockers and had an ICD. Amongst the 14 patients included of whom 13 completed the study, they showed there was a significant reduction in median ventricular arrhythmia score during exercise and in fact there was complete suppression with Flecainide compared to the placebo of 85%. These findings thus add to the existing literature in terms the potential incremental value of Flecainide in achieving adequate arrhythmia suppression when used in conjunction with maximal tolerated beta blockers. The last article within the realm of genetic channelopathies we'll focus on was published by Yang et al. in The Journal of Physiology entitled A Multi-Scale Computational Modeling Approach Predicts Mechanisms of Female Sex Risk in the Setting of Arousal-Induced Arrhythmias. It is recognized that female gender can increase the risk of Torsades in the setting of both inherited and acquired prolonged QT syndromes. In a combination of experimental and computational approaches, Yang et al. demonstrated that hormone concentrations can partly mediate this risk, specifically as it relates to her-related mutations. They demonstrated testosterone and high progesterone levels provide a protective effect against Torsades. However, estrogen can enhance Torsadogenic potential, particularly in the setting sympathetic stress. They also demonstrated the mechanism by which this likely occurs is due to interaction of estrogen with pore loop or intracavity binding site of the her channel. In fact, on top of this they demonstrated that combined treatment with both estrogen and Dofetilide can simultaneously blockade the pore channel of her. These findings are provocative and hypothesis-generating. In terms of potential future research to further clarify risk for patients, particularly as it may apply to menstruating females who might have varying levels of estrogen, especially when being treated with concomitant QT prolonging agents such as Defetilide. Next we will focus on three articles within the realm of ventricular arrhythmias. The first article was published by Sapp et al. in JACC Clinical Electrophysiology entitled Real Time Localization of Ventricular Tachycardia Origin from the Twelve Lead Electrocardiogram. They presented a methodology for rapidly determining in real time the approximate origin of a ventricular tachycardia using the 12 lead during cardiac ablation. In 38 patients they used a variety of methods that involved multiple linear regression learning methods and demonstrated that a patient-specific regression method using at least 10 training set pacing sites in the individual patient can provide a localization accuracy of the exit site for VT of as much as five millimeters. Furthermore, with additional pacing sites that accuracy could improve further. These findings support the continued utility of the standard 12 lead ECG in localizing the exit site of ventricular tachycardia. Furthermore, it points out the importance of considering that the electrocardiogram can be patient-specific. By using multiple pacing sites, this helps an algorithm learn how a patient-specific heart exists in terms of its electrical propagation potential. Further informing based on a 12 lead of a specific VT approximately where it should be exiting from. The next article we will focus on was published by Muser et al. in again, JACC Clinical Electrophysiology entitled Longterm Outcomes of Catheter Ablation of Electrical Storm in Nonischemic Dilated Cardiomyopathy COMpared with Ischemic Cardiomyopathy. The summary point to this article is in a single center, large volume group of patients including about 267 total, the longterm outcomes of VT recurrence or mortality was no different between nonischemic and ischemic patients. This is important to note as most prospective studies and in fact retrospective studies of the role of ventricular tachycardia ablation have focused on ischemic patients where the substraight is relatively predicable. These findings highlight that ablation may provide a reasonably effective therapy irrespective of the cause of the myopathy. Finally, changing gears within the realm of ventricular arrhythmias, we'll focus on a translational article by Motloch et al. in JACC Basic to Translational Science entitled Increased Afterload Following Myocardial Infarction Promotes Conduction-Dependent Arrhythmias That Are Unmasked by Hypokalemia. They studied the role of increased afterload after myocardial infarction in a listing arrhythmias in a porcine infarct model. They demonstrated that in the setting of increased afterload there was increased widespread interstitial fibrosis. Interestingly, pacing -induced arrhythmias induced by a rapid burst pacing were mediated by hypokalemia associated conduction abnormalities rather than repolarization abnormalities. The reason these findings are potentially important lie in the fact that arrhythmias in the early stages after myocardial infarction, especially in a setting of increased afterload, might be considered to be secondary to either repolarization abnormalities or depolarization abnormalities. These findings suggest that in the setting of concomitant hypertension the primary problem really lies in hypokalemia associated conduction abnormalities. Thus, treatments that impair cardiac excitability, for example, even sodium channel blockade, may similarly confer an increased risk of ventricular arrhythmias when in the presence of increased afterload and myocardial infarction. It also calls into question whether interventions such as antitachycardia pacing in patients with hypertension, in other words increased afterload, might be more prone to acceleration of the ventricular arrhythmias than patients who are relatively better managed as far as afterload. Changing gears yet again, we will focus on EP relevant myopathies. [inaudible 00:44:19] et al. published in JACC Clinical Electrophysiology regarding use of the 12 lead electrocardiogram to localize regions of abnormal electron atomic substraight in arrhythmogenic ventricular cardiomyopathy. There were really two major articles in this regard that have been published both in the same month. The other article was published by Andrews et al. in Circulation, Arrhythmia and Electrophysiology entitled Electrical and Structural Substraight of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. The relevance of both of these articles lies in their statements about the potential utility of noninvasive approaches essentially using electrocardiograms to determine the distribution of substraight in arrhythmogenic right ventricular cardiomyopathy. The article by [inaudible 00:45:16] et al. specifically focused on fractionation of the QRS. They showed that patients with evidence of fractionation in the QRS on a 12 lead ECG had more extensive substraight. Furthermore, distribution of fractionation to specific leads such as inferior, anterior or basal superior leads, was 100% specific, but veritably sensitive for identifying substraight as it localizes to specific cardiac regions. In turn, the publication by Andrews et al. in Circulation, Arrhythmia and Electrophysiology reviewed how the addition of multiple leads by a noninvasive electrocardiographic imaging could be used to even more specifically hone in on the relevant substraights. Their further benefit was in the suggestion that repolarization abnormalities in fact co-localized with origination sites for ventricular ectopy in these patients. In combination, these sites highlight the utility of simple, noninvasive methods of electrocardiographic imaging in identifying and defining the arrhythmogenic substraight in the NRVC. The next article we will review was by Sommariva et al. in Nature's Scientific Reports published just this past month entitled MIR 320A as a Potential Novel Circulating Biomarker of Arrhythmogenic Cardiomyopathy. They did micro RNA analysis on 53 healthy controls, 21 idiopathic VT patients and 36 arrhythmogenic cardiomyopathy patients and demonstrated that the circulating micro RNA 320A was significantly higher in arrhythmogenic cardiomyopathy than in either other cohorts. It is recognized that some patients with idiopathic VT, especially right ventricular [inaudible 00:47:09] VT might reflect a cohort that might have what we call "concealed ARVC." The question thus becomes how to define why a patient has a specific manifestation of disease because longterm outcomes, if there is some underlying ARVC might be worse if the ARVC is not recognized and if cure is assumed based on treatment of the initial presenting rhythm. Thus identifying novel ways of defining the presence of a disease even in the absence of obvious structural abnormalities carries benefit in terms of suggestions on longterm followup. Complimentary to the previously discussed article on the role of PKP2 mutations on mediating electrical instability in the heart, the study by [inaudible 00:48:01] et al. does in fact suggest that there might be methods of distinguishing arrhythmogenic cardiomyopathy from whether it be controls or truly idiopathic ventricular tachycardia using a very specific circulating biomarker. On a completely different route, we'll finish our podcast today with a discussion of Bruner et al. published in European Heart Journal entitled Alcohol Consumption, Sinus Tachycardia and Cardiac Arrhythmias at the Munich Oktoberfest: Results from the Munich Beer-Related Electrocardiogram Workup Study or Munich Brew. Bruner et al. studied over 3,000 voluntary participants with a combination of breath alcohol concentration measurements and electrocardiographic recordings via smartphone throughout the Munich Oktoberfest. In addition, they sought to evaluate chronic alcohol consumption effects on arrhythmias in a separate cord of over 4,000 patients from the Cora S4 study. In the study regarding acute alcohol effects, they demonstrated that in line with increasing BAC, there was a greater occurrence of arrhythmias in particular sinus tachycardia in almost a third of patients. What was even further interesting was that respiratory sinus arrhythmia over the course of higher BAC is from baseline was reduced in the setting of alcohol use. Similarly, with chronic alcohol consumption there was an apparent significant association with the occurrence of sinus tachycardia. The reason these findings are important is in their suggestive element that the effects of alcohol intake in terms of whether it be acute or chronic arrhythmogenesis might somewhat lie in their effects on the basal autonomic states. As demonstrated by the reduction in overall sinus arrhythmia. These findings serve to further elucidate mechanisms by which alcohol may mediate arrhythmias in a large real world patient sample. Thank you for joining us on this edition of On The Beat. Tune in next month again for more articles that might be of interest to the general electrophysiologic community all summarized in a single location.
Commentary by Dr. David Wilber
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