Podcasts about atherosclerosis risk

Send us a textCan you provide feedback on my podcast (what you like?  what you want more of?  length?  Please answer a few questions here.  Can a simple habit like flossing really reduce your risk of stroke? In this episode, Dr. Bobby unpacks the headlines sparked by a recent presentation at the American Stroke Association's International Conference that claimed regular flossing could reduce stroke risk by 20–50%. Dr. Bobby begins with a refresher on the importance of stroke prevention. From there, he explores the biological plausibility of a connection between oral health and cardiovascular events. While Americans are fairly diligent about brushing (with 90% brushing once daily and 60% brushing twice a day per YouGov data), flossing habits lag significantly (NIH Oral Health Study—highlighting a clear opportunity if the flossing-stroke link is real.Dr. Bobby dives into the study behind the headlines, a new analysis from the long-running Atherosclerosis Risk in Communities (ARIC) study, which tracked over 6,000 individuals for 25 years. The preliminary finding: regular flossers had significantly lower risk of ischemic and cardioembolic strokes (Study Abstract). Surprisingly, brushing and dental visits showed no significant benefit in this analysis.So why isn't this flossing-stroke connection headline a "five-alarm fire" in medicine? Dr. Bobby explains the limitations: the results were shared via a conference abstract, not a peer-reviewed journal article. Without full access to the data or understanding how many other hypotheses were tested from this large dataset (which has already generated over 2,300 publications), we risk falling into the trap of correlation being mistaken for causation.To further evaluate the credibility of this association, Dr. Bobby introduces the Bradford Hill criteria—nine principles to assess causality in observational studies. While the biological plausibility is strong and the effect size notable, the study fails on criteria like replication, dose-response, and publication rigor (Bradford Hill Overview).In closing, Dr. Bobby affirms the benefits of flossing—not necessarily for stroke prevention, but for better oral health, which is valuable in its own right. He shares his personal oral care routine, including flossing nightly and using a water jet, while reminding listeners to stay evidence-informed in their health decisions.Takeaways Flossing likely improves oral health, but its role in stroke prevention remains unproven. Be cautious with headlines drawn from unpublished conference abstracts—they're a starting point for inquiry, not a reason to change behavior just yet."How to Live Long and Well" at DrBobbyLiveLongAndWell.com.

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances discusses a recently published original research paper on vital exhaustion and biomarkers associated with cardiovascular risk, part of the Atherosclerosis Risk in Communities (ARIC) Study.

This week, please join author Bruce Wasserman and Associate Editor Mercedes Carnethon as they discuss the article "Intracranial Atherosclerotic Disease and Incident Dementia: the Atherosclerosis Risk in Communities Study (ARIC)." For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240906.944975

Links: Go to episode page Subscribe to Premium See recommended resources Receive the Sigma email newsletter About This Episode: The question of whether dietary fat quality causally affects atherosclerosis risk has been a subject of extensive research and debate within the field of nutrition and cardiovascular health. Atherosclerosis, the build-up of plaque in arteries, is a key factor in the development of cardiovascular diseases, including heart attacks and strokes. Traditionally, dietary fat has been implicated in contributing to atherosclerosis, with a focus on reducing overall fat intake. However, recent studies have shifted the focus towards the quality of dietary fats rather than their quantity. Not all fats are created equal, and researchers are now paying closer attention to the types of fats consumed in the diet. Saturated fats, commonly found in animal products and some tropical oils, have long been associated with increased cholesterol levels and atherosclerosis. On the other hand, unsaturated fats, including monounsaturated and polyunsaturated fats found in olive oil, nuts, and fish, have been linked to potential cardiovascular benefits. Research suggests that replacing saturated fats with unsaturated fats may have a positive impact on blood lipid profiles and reduce the risk of atherosclerosis. Additionally, genetic factors and individual responses to different fats may play a role in how dietary fats impact atherosclerosis risk. In this episode, Dr. Jacob Christensen discusses the research in this area and some conclusions about whether we can say dietary fat quality causally increases atherosclerotic cardiovascular disease (ASCVD) risk. This includes looking at the relationship between low-density lipoprotein (LDL) particles and ASCVD, the link between dietary fat quality and LDL particles, and then finally the relationship between dietary fat quality, LDL particles, and ASCVD. About the Guest: Jacob J. Christensen is a clinical dietitian and researcher at University of Oslo. His research interests include cardiovascular diseases, lipid metabolism, nutrition, genomics and data science.

Hearing loss affects roughly 15.5% of Americans 20 years and older. While the majority of these individuals experience mild hearing loss, the prevalence and severity of hearing loss increases with age. What does this sensory change mean for dementia risk, and can this risk be prevented through interventions like hearing aids? Dr. Frank Lin joins the podcast to discuss the relationship between hearing loss and dementia and share findings from the Aging and Cognitive Health Evaluation in Elders, or ACHIEVE, study. Guest: Frank Lin, MD, PhD, director, Cochlear Center for Hearing and Public Health, Professor of Otolaryngology, Medicine, Mental Health, and Epidemiology, Johns Hopkins University Show Notes Read more about Dr. Lin's study, “Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial,”  in The Lancet. Learn more about the Atherosclerosis Risk in Communities (ARIC) study, mentioned at 20:01, through the National Heart, Lung, and Blood Institute and Johns Hopkins Bloomberg School of Public Health's websites. Read more about U.S. regulations surrounding over-the-counter hearing aids, mentioned at 34:00, in “‘A New Frontier' for Hearing Aids,” by The New York Times. Learn more about Dr. Lin at his bio on the Johns Hopkins Bloomberg School of Public Health website. Learn more about the ACHIEVE study on their webpage. Connect with us Find transcripts and more at our website. Email Dementia Matters: dementiamatters@medicine.wisc.edu Follow us on Facebook and Twitter. Subscribe to the Wisconsin Alzheimer's Disease Research Center's e-newsletter. Enjoy Dementia Matters? Consider making a gift to the Dementia Matters fund through the UW Initiative to End Alzheimer's. All donations go toward outreach and production.

Commentary by Dr. Valentin Fuster

Welcome to the Olink® Proteomics in Proximity podcast! Below are some useful resources mentioned in this episode: Olink tools and software• Olink® Explore 3072, the platform utilized by the UK Biobank to measure ~3000 proteins in plasma: https://olink.com/products-services/explore/• Olink® Explore HT, Olink's most advanced solution for high-throughput biomarker discovery, measuring 5400+ proteins simultaneously with a streamlined workflow and industry-leading specificity: https://olink.com/products-services/exploreht/ UK Biobank Pharma Proteomics Project (UKB-PPP), one of the world's largest scientific studies of blood protein biomarkers conducted to date, https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/news/uk-biobank-launches-one-of-the-largest-scientific-studies Research articles• Dhindsa, R.S., Burren, O.S., Sun, B.B. et al. Rare variant associations with plasma protein levels in the UK Biobank. 2023 Nature, DOI: 10.1038/s41586-023-06547-xhttps://www.nature.com/articles/s41586-023-06547-x• Sun, B.B., Chiou, J., Traylor, M. et al.  Plasma proteomic associations with genetics and health in the UK Biobank. 2023 Nature, DOI: 10.1038/s41586-023-06592-6 https://www.nature.com/articles/s41586-023-06592-6• Ticau S, Sridharan G, Tsour S, et al. Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis 2021 Neurology, DOI: 10.1212/WNL.0000000000011090https://n.neurology.org/content/96/3/e412.long• Zannad F, Ferreira JP, Butler J, et al.  Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program. 2022 European Heart Journal, DOI: 10.1093/eurheartj/ehac495                https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehac495/6676779• Eldjarn GH, et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature. 2023 Oct;622(7982):348-358. doi: 10.1038/s41586-023-06563-xhttps://www.nature.com/articles/s41586-023-06563-x#Sec44• [PREPRINT] Carrasco-Zanini et al 2023 Proteomic prediction of common and rare diseases MedRxiv https://www.medrxiv.org/content/10.1101/2023.07.18.23292811v1• Michaëlsson E, Lund LH, Hage C, et al. Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF. 2023 JACC. Heart Failure, DOI: 10.1016/j.jchf.2023.03.002https://www.sciencedirect.com/science/article/pii/S2213177923001257• Girerd N, Levy D, Duarte K, et al.  Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study. 2023 Circulation Heart Failure, DOI: 10.1161/CIRCHEARTFAILURE.122.009694https://www.ahajournals.org/doi/abs/10.1161/CIRCHEARTFAILURE.122.009694Subscribe to the podcast on your favorite player or app:Apple Podcasts: https://apple.co/3T0YbSm Spotify Podcasts: https://open.spotify.com/show/2sZ2wxO... Google Podcasts: https://podcasts.google.com/feed/aHR0... Amazon Music: https://music.amazon.com/podcasts/d97... Podcast Addict: https://podcastaddict.com/podcast/409... Deezer: https://www.deezer.com/show/5178787 Player FM: https://player.fm/series/series-3396598 In case you were wondering, Proteomics in Proximity refers to the principle underlying Olink technology called the Proximity Extension Assay (PEA). More information about the assay and how it works can be found here: https://bit.ly/3Rt7YiY For any questions regarding information about Olink Proteomics, please email us at info@olink.com or visit our website: https://www.olink.com/Interested in a specific podcast topic or guest? Reach out to us at PIP@olink.comWHAT IS PROTEOMICS IN PROXIMITY?Proteomics in Proximity discusses the intersection of proteomics with genomics for drug target discovery, the application of proteomics to reveal disease biomarkers, and current trends in using proteomics to unlock biological mechanisms. Co-hosted by Olink's Cindy Lawley and Sarantis Chlamydas.

This week, host Andy Bellavia is joined by two researchers from the Cochlear Center for Hearing and Public Health at Johns Hopkins University. Nicholas Reed, AuD, and Kening Jiang, MHS, discuss their research into the complex relationships between hearing loss, fatigue, sleep disturbances, and cognitive decline. Kening Jiang discusses her study on the connection between hearing loss and self-reported fatigue, exploring future research possibilities including the impact of addressing hearing loss on fatigue. The pair emphasize the need to understand individual factors and interactions contributing to cognitive health in the complex relationship between hearing loss and fatigue. References: * Sleep Characteristics and Hearing Loss in Older Adults: The National Health and Nutrition Examination Survey 2005–2006 https://academic.oup.com/biomedgerontology/article/77/3/632/6327644) *Associations of sleep characteristics in late midlife with late-life hearing loss in the Atherosclerosis Risk in Communities-Sleep Heart Health Study (ARIC-SHHS) https://www.sciencedirect.com/science/article/abs/pii/S235272182300133X) * Hearing Loss and Fatigue in Middle-Aged and Older Adults https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2806828) More information about the research taking place at the Cochlear Center can be found here: https://jhucochlearcenter.org/ Be sure to subscribe to our channel for the latest episodes each week and follow This Week in Hearing on LinkedIn and Twitter. - https://twitter.com/WeekinHearing - https://www.linkedin.com/company/this-week-in-hearing - https://hearinghealthmatters.org/thisweek/

Welcome to Olink Proteomics in Proximity Podcast!  Below are some useful resources from this episode:  Highlighted publication:Girerd N, et al. Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study. Circ Heart Fail. 2023 May;16(5):e009694. doi: 10.1161/CIRCHEARTFAILURE.122.009694 https://pubmed.ncbi.nlm.nih.gov/37192292/ Large-scale cardiovascular studies:·         Heart “OMics” in AGEing (HOMAGE), a European-based consortium investigating biomarkers to predict heart failure and as drug targets for prevention: https://www.homage-hf.eu/·         Atherosclerosis Risk in Communities (ARIC) consortium, a prospective epidemiologic study to investigate the causes of atherosclerosis and its clinical outcomes: https://sites.cscc.unc.edu/cscc/projects/ARIC·         Framingham Heart Study, a study identifying common factors or characteristics that contribute to cardiovascular disease across three generations: https://www.framinghamheartstudy.org/'·         EMPEROR-Preserved trial, a cohort of patients who had chronic heart failure and a left ventricular ejection fraction of more than 40% : https://www.wikijournalclub.org/wiki/EMPEROR-Preserved High-throughput platforms mentioned during the podcast or used in this study that measure tens to thousands of proteins simultaneously: ·         Olink® Target 96: https://olink.com/products-services/target/ ·         Olink® Explore 3072: https://olink.com/products-services/explore/·         Olink® Explore HT: https://olink.com/products-services/exploreht/ Podcast mentioned during this podcast:Cooper, Peter M, host. Easter Island – Where Giants Walked. Fall of Civilizations, Episode 6, July 2019, https://fallofcivilizationspodcast.com/ Books mentioned during the podcast:·         Attia, Peter. Outlive: the science & art of longevity. New York: Harmony, 2023. https://www.goodreads.com/en/book/show/61153739·         Hood, Leroy and Price, Nathan. The Age of Scientific Wellness: Why the Future of Medicine Is Personalized, Predictive, Data-Rich, and in Your Hands. Cambridge, MA and London, England: Harvard University Press, 2023. https://doi.org/10.4159/9780674293465 Would you like to subscribe to the podcast on your favorite player or app? You can do so here:  Apple Podcasts: https://apple.co/3T0YbSm  Spotify Podcasts: https://open.spotify.com/show/2sZ2wxO...  Google Podcasts: https://podcasts.google.com/feed/aHR0...  Amazon Music: https://music.amazon.com/podcasts/d97...  Podcast Addict: https://podcastaddict.com/podcast/409...  Deezer: https://www.deezer.com/show/5178787  Player FM: https://player.fm/series/series-3396598   In case you were wondering, Proteomics in Proximity refers to the principle underlying Olink Proteomics assay technology called the Proximity Extension Assay (PEA), and more information about the assay and how it works can be found here: https://bit.ly/3Rt7YiY  For any questions regarding information Olink Proteomics, please email us at info@olink.com or visit our website: https://www.olink.com/ WHAT IS PROTEOMICS IN PROXIMITY?Proteomics in Proximity discusses the intersection of proteomics with genomics for drug target discovery, the application of proteomics to reveal disease biomarkers, and current trends in using proteomics to unlock biological mechanisms. Co-hosted by Olink's Dale Yuzuki, Cindy Lawley and Sarantis Chlamydas.

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis? Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion. Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address? Dr. Carolyn Lam: Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine. And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan. However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials. Dr. Greg Hundley: Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find? Dr. Carolyn Lam: In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure. Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña. Dr. Greg Hundley: Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis. So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition. And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage. So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression. Dr. Carolyn Lam: Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex. They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models. So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression. Dr. Carolyn Lam: Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension. So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence. Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development. As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age. So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results. Dr. Greg Hundley: Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models? Dr. Carolyn Lam: Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension. The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration." So lots of translational implications of this paper. Dr. Greg Hundley: Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe. Dr. Carolyn Lam: Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants." There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea." In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature. Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity. There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study. Dr. Greg Hundley: Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion? Dr. Carolyn Lam: Let's go. Thanks. Dr. Greg Hundley: Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen. Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Amil Shah: Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today. So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality. Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes. Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation. Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction. And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals. But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults. And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease. To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life. Dr. Greg Hundley: So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population? Dr. Amil Shah: Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota. Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age. We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally. And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion. Dr. Greg Hundley: Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results? Dr. Amil Shah: So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair. And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort. And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes. Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest. Dr. Greg Hundley: Now, did you find similar results for men and for women? Dr. Amil Shah: So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar. Dr. Greg Hundley: And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions? Dr. Amil Shah: Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages. So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly. So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings. For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that. Dr. Greg Hundley: Very nice. Well, thank you so much, Amil. And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper? Dr. Ntobeko Ntusi: Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle. And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms. We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex. And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution. The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease. And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations. So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg. Dr. Greg Hundley: Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research? Dr. Amil Shah: So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life. And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in. I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients. Dr. Greg Hundley: Very nice. Ntobeko, do you have anything to add? Dr. Ntobeko Ntusi: Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward. The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease. Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time. And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events. Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. 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, please visit ahajournals.org.

A new research paper was published on the cover of Aging (listed as "Aging (Albany NY)" by Medline/PubMed and "Aging-US" by Web of Science) Volume 14, Issue 24, entitled, “Associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease biomarkers.” Capturing the genetic architecture of Alzheimer's disease (AD) is challenging because of the complex interplay of genetic and non-genetic factors in its etiology. It has been suggested that AD biomarkers may improve the characterization of AD pathology and its genetic architecture. Most studies have focused on connections of individual genetic variants with AD biomarkers, whereas the role of combinations of genetic variants is substantially underexplored. In this new study for the Alzheimer's Disease Neuroimaging Initiative, researchers, from Alexander M. Kulminski, Ethan Jain-Washburn, Elena Loiko, Yury Loika, Fan Feng, and Irina Culminskaya from Duke University and University of California examined the associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with cerebrospinal fluid (CSF) and plasma amyloid β (Aβ40 and Aβ42) and tau biomarkers. “Here, we examine the associations of the APOE ε2 and ε4 alleles and the AD-risk-differentiating compound genotypes comprising rs429358, rs2075650, and rs12721046 SNPs with Aβ40, Aβ42, and tau AD biomarkers measured in CSF and plasma using data from three studies: the AD Neuroimaging Initiative (ADNI), the Atherosclerosis Risk in Communities (ARIC) study, and the Framingham Heart Study (FHS).” Findings from this study support associations of the ε4 alleles with both plasma and CSF Aβ42 and CSF tau, and the ε2 alleles with baseline, but not longitudinal, CSF Aβ42 measurements. The researchers found that the ε4-bearing polygenic profiles conferring higher and lower AD risks are differentially associated with tau but not Aβ42. Modulation of the effect of the ε4 alleles by TOMM40 and APOC1 variants indicates the potential genetic mechanism of differential roles of Aβ and tau in AD pathogenesis. “Our primary finding is that the ε4-bearing polygenic profiles conferring higher and lower AD risks are differently associated with tau but not Aβ42. The other main results of our work are characterizations of the associations of the APOE ε2 and ε4 alleles with Aβ40, Aβ42, and tau biomarkers in ADNI-1, ADNI-2/GO, ARIC, and three FHS cohorts.” DOI: https://doi.org/10.18632/aging.204384 Corresponding Author: Alexander M. Kulminski - kulminsk@duke.edu Keywords: aging, apolipoprotein E polymorphism, Alzheimer's disease, haplotypes, Alzheimer's disease biomarkers Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204384 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Atrial Fibrillation (AFib) and Venous Thromboembolism (VTE) have a risky bidirectional relationship. Hear from Carol Patrick, RNFA, ACNP-BC, FPCNA, as she explores this relationship and the different management and prevention techniques. Learn also about how cancer can increase a patient's risk for AFib and VTE. PCNA AFib Resources: https://pcna.net/clinical-resources/provider-tools/atrial-fibrillation-provider-tools/ PCNA VTE Resources: https://pcna.net/clinical-resources/patient-handouts/vte-and-blood-clot-tools-and-handouts/Atherosclerosis Risk in Community (ARIC) Study: https://onlinelibrary.wiley.com/doi/10.1111/jth.13974Pulmonary Embolism and Atrial Fibrillation: Two Sides of the Same Coin? A Systematic Review: https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0036-1598005Differential Presentations of Arterial Thromboembolic Events Between Venous Thromboembolism and Atrial Fibrillation Patients: https://www.frontiersin.org/articles/10.3389/fcvm.2021.775564/fullAmerican College of Cardiology, Atrial Fibrillation: Guideline For the Management of Patients: https://www.acc.org/guidelines/hubs/atrial-fibrillationAmerican College of Chest Physicians (CHEST): https://www.chestnet.org/Anticoagulation FORUM, DOAC Playbook: https://acforum-excellence.org/Resource-Center/downloads/DOAC%20Playbook%20_07-2021.pdfNational Blood Clot Alliance: stoptheclot.orgNational Heart, Lung, and Blood Institute (NHLBI): https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-heart-lung-blood-institute-nhlbiWorld Thrombosis Day (WTD): https://www.worldthrombosisday.org/about/wtd/Atrial fibrillation and cancer – An unexplored field in cardiovascular oncology: https://www.sciencedirect.com/science/article/abs/pii/S0268960X18301012?via%3DihubSee Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

This week, please join author Kory Lavine and Associate Editor Thomas Eschenhagen as they discuss the article "Donor Macrophages Modulate Rejection After Heart Transplantation." Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we are going to the world of preclinical science and we are going to learn about a very important new finding pertaining to heart transplant rejection, and macrophages may modulate this, but before we get to that feature, how about we grab a cup of coffee and go through some of the other articles in the issue? Dr. Carolyn Lam:             I got mine. Would you like to go first, Greg? Dr. Greg Hundley:           You bet, Carolyn. Well, my first study comes to us from Dr. Michael Pencino from Duke University. Carolyn, this study was performed to understand the predictive utility of a previously derived polygenic risk score for long-term risk of coronary heart disease and its additive value beyond traditional risk factors and how that might be able to inform prevention strategies. To accomplish this, data from adults aged 20 to 59 free of cardiovascular health disease from the Framingham Offspring Study and the Atherosclerosis Risk in Communities, or ARIC Study, were analyzed. Now, since the polygenic risk score was derived from people of predominantly European ancestry, individuals who self-reported white race were those that were included. Dr. Carolyn Lam:             Oh, interesting, so what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. Somewhat surprisingly, they found that, among 9,757 participants, both the traditional risk factor score and the polygenic risk score where significantly associated with incident cardiovascular heart disease in young, early midlife, and late midlife. Now, the delta C index, when the polygenic risk score was added to the traditional risk factor, score was 0.03, 0.02, and 0.002 in the young, the early midlife, and the late-midlife participants, respectively. Carolyn, despite a statistically significant association between the polygenic risk score and the 30-year risk of cardiovascular heart disease, the C index improved only marginally with the addition of the polygenic risk score to the traditional risk factor model among young adults and did not improve among midlife adults and, thus, Carolyn, the polygenic risk score, an immutable factor, has limited clinical utility for long-term cardiovascular heart disease prediction when added to a traditional risk factor model. Dr. Carolyn Lam:             I really like that, Greg, because I think it also tells us that the traditional risk factors, which we can do something about, are still very important. Isn't that great? Well, the next paper is about POTS. Remember what that is? Should I give you a quiz? All right. It's okay. POTS, or Postural Orthostatic Tachycardia Syndrome, is a disorder of orthostatic intolerance that primarily affects females of childbearing age. While the underlying pathophysiology of POTS is not fully understood, it has been suggested that autoimmunity may play a role. Now, the aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between 116 POTS patients and 81 healthy controls, and they were from Calgary, Canada, and Malmo, Sweden. Dr. Greg Hundley:           Carolyn, really interesting, so what did they find here? Dr. Carolyn Lam:             The investigators, led by Dr. Raj from University of Calgary in Canada, found that commercially available autoantibody concentrations to G protein-coupled receptors were not increased or altered in POTS patients relative to healthy controls as assessed using ELISA. Now, while this study suggests that these G protein-coupled receptor autoantibody concentrations alone cannot explain the pathophysiology of POTS, autoantibody activity and signals not picked up by ELISA should still be explored as these results may provide more insights into the pathophysiology of POTS. Dr. Greg Hundley:           Very nice, Carolyn. Well, my next study comes to us from the world of pulmonary arterial hypertension. Carolyn, clinical worsening is commonly used as an endpoint in pulmonary arterial hypertension trials. These authors, led by Dr. Steeve Provencher from the Institut Universitaire de Cardiologie Pneumologie de Quebec, aimed to assess the trial-level surrogacy of clinical worsening for mortality in pulmonary artery hypertension trials and whether the various clinical worsening components were similar in terms of frequency of occurrence, treatment-related relative risk reduction and importance to patients. Dr. Carolyn Lam:             Okay, so what did they find? Dr. Greg Hundley:           Right, Carolyn, so they searched MEDLINE, Embase and the Cochrane Library for trials evaluating the effects of pulmonary arterial hypertension on clinical worsening and, among 35 independent cohorts, so 9,450 patients, the effects of pulmonary arterial hypertension-specific therapies on clinical worsening modestly correlated with mortality. Additionally, study-level clinical worsening was not found to be a surrogate for mortality in pulmonary arterial-hypertension trials. Moreover, components of clinical worsening largely vary in frequency, response to therapy and importance to patients and, thus, are not necessarily interchangeable. Dr. Carolyn Lam:             Thank you, Greg. Can I tell you about some other papers in today's issue? There's a Research Letter from Dr. Cosentino on cardiorenal outcomes with ertugliflozin by baseline metformin use, and this is a post hoc analysis of the VERTIS CV trial. Dr. Greg Hundley:           Oh, very good, Carolyn. Well, I've got an exchange of letters from Professors Boriani and Steinberg regarding the article “Driving Restrictions and Early Arrhythmias in Patients Receiving a Secondary Prevention Implantable Cardioverter-Defibrillator, the DREAM-ICD-II Study.” There's also an ECG Challenge from Professor Gao entitled “Syncope in a 3-Year-Old Child During the Perioperative Period. What is the diagnosis? What Signs Point Toward Impending Life-threatening Event?” Then, finally, there's a nice, On My Mind piece from Professor Greenland entitled “Insurance Payers Should Cover Selective Coronary Artery Calcium Testing in Intermediate Risk Primary Prevention Patients.” Well, Carolyn, how about we get on to that feature discussion and dive into the world of rejection after heart transplantation? Dr. Carolyn Lam:             Yay. Here we go. Dr. Greg Hundley:           Welcome, listeners, to this feature discussion on August 23rd. We have a very interesting article today to discuss with our author and associate editor pertaining to preclinical science and cardiac transplant rejection. Our author today is Dr. Kory Lavine from Washington University in St. Louis and our associate editor today is Dr. Thomas Eschenhagen from Hamburg, Germany. Welcome gentlemen. Kory, we'll start with you. Can you describe for us some of the background information pertaining to the construct of your study and what was the hypothesis that you wanted to address? Dr. Kory Lavine:               Well, thank you for having me. Our study focused on heart transplant rejection, which remains a major clinical challenge that limits both the survival of heart transplant recipients as well as availability of donor hearts. Current clinical practice really focuses on suppressing the immune system in a global way, and that is somewhat effective, but carries important risks that include infection and life-threatening malignancies. Many studies have appropriately focused on immune cells that infiltrate the transplanted heart that come from the recipient to search for new ways to suppress the immune system safely. What we've understood and learned over the past several years is that the donor heart has its own immune system and its own immune cells, and the majority of those immune cells that come with the donor heart are macrophages that can be broadly divided into two distinct lineages with different functions, tissue-resident macrophages, which lack the cell surface receptors CCR2, and monocyte-derived macrophages with expressed cell surface receptors CCR2. We tested the hypothesis in this study that these macrophages that come with the donor heart remain active for a period of time after transplantation and play important roles in either suppressing or accelerating heart transplant rejection. Dr. Greg Hundley:           What was the hypothesis that you wanted to address with your study? Dr. Kory Lavine:               Yeah, so our prior work and others' work within this field had suggested that tissue-resident macrophages, CCR2-negative macrophages, are inflammatory, and CCR2-positive macrophages have the opposite functions being inflammatory and play roles in potentiating and initiating inflammation in the heart. In this study, we hypothesized that CCR2-negative macrophages would protect from rejection, while CCR2-positive macrophages may promote heart transplant rejection and could serve as a new therapeutic target to prevent rejection in transplant recipients. Dr. Greg Hundley:           Excellent. Kory, can you describe for us the study design that you used to test your hypothesis? Dr. Kory Lavine:               Yeah. The study design and approach we used involved a mouse model of heart transplantation where we transplant a donor heart into a recipient mouse that's fully mismatched at all the MHC loci, and this serves as a nice model for both cellular and antibody-mediated rejection. To facilitate tracking these donor macrophages, we used various genetic lineage tracing systems and, to study their phenotypes, we used single-cell RNA sequencing and, to understand their function, we used mouse models that allow us to specifically deplete each of the donor macrophage populations as well as genetic models to manipulate their activation and signaling. Dr. Greg Hundley:           The outcome measures were going to be what? Dr. Kory Lavine:               Yeah. The outcome measures for transplant rejection in this mouse model are allograph survival, so the survival of the transplanted heart. We're able to directly look at how much rejection is present by histopathology, and then we're able to observe various mechanistic features using detailed phenotyping such as single-cell RNA sequencing and T-cell activation assays. Dr. Greg Hundley:           Very nice, Kory. Well, all, our listeners, we're very excited to hear what were your study results? Dr. Kory Lavine:               We learned that donor macrophages are dynamic and they survive for a period of time after transplantation or eventually lost due to transplant rejection. When we phenotyped the macrophages that came from the donor heart, we learned that they remained transcriptionally distinct from immune cells that enter the heart that were derived from the recipients, and they had important and distinct functions. If we depleted the tissue-resident macrophages that were CCR2-negative, we observed reduced allograph survival and increased rejection. If we depleted CCR2-positive macrophages that came from the donor heart, we observed improved allograph survival and reduced rejection. Mechanistically, we learned that CCR2-positive macrophages are activated through a MyD88-dependent pathway and, if we inhibited MyD88 cytokines which controls the expression of pro-inflammatory cytokines and chemokines, we could prolong the survival of the donor heart for a very significant period of time, reduce rejection and prevent the development of T-cells that would attack the donor heart. From a mechanistic aspect, what we uncovered is that this signaling pathway in CCR2-positive macrophages regulated the recruitment of an activation of antigen-presenting cells which played important roles in generating T-cells that would target the transplanted heart. Dr. Greg Hundley:           It sounds like a really informative and leap forward in the whole sphere of transplant rejection. Well, listeners, now we're going to turn to our associate editor, Dr. Thomas Eschenhagen. Thomas, you have many papers come across your desk. What attracted you to this particular paper and then, secondly, how do you put the results of this study really in the context of other research examining heart transplant rejection? Dr. Thomas Eschenhagen:           Yeah, thanks for having me. I mean, first, we got attracted by this paper because it's somewhat an out-of-the-box approach. It's not the standard approach to improve the systemic immunosuppression as many studies did and with actually a lot of success over the last 30 years, survivor got much better. There had been a lot of progress in the field of transplantation medicine as we all know, but as Kory said already, we still have 30% rejection, and these immunosuppressions come at a price. Having this study which turns around somehow the argumentation and looks at the donor organ was something which really attracted us. It uses advanced methods and it applies somewhat in a practical way a concept which emerged over the last, I don't know, maybe decade this concept that macrophages are really very different kind of cells. They're all called macrophages, but they're quite different and even maybe in certain respects having opposing effect. I think many people know about this M1/M2 concept. It's CCR2 receptor positive and negative. It's criticized by some people, but here we see that it really seems to be really important and, of course, then the third argument why we really like the story is that it has a specific, clear translation impact. I mean, looking at the heart, the donor heart, and potentially even treating the donor heart before transplanting it is something which comes immediately out of the story, and that's something which we found super attractive. Dr. Greg Hundley:           Really interesting, so really understanding the mechanism and focusing on donor hearts. Well, listeners, let's circle back with Kory. Kory, given that, what do you think is the next study that really needs to be performed in this sphere of research? Dr. Kory Lavine:               I think Thomas said it exactly as we're thinking about it, so the next area that we're really excited to attack and we're hopeful that the field will focus on is ways to build methods and technologies to treat the donor heart between the time of procurement and the time of transplant, when it's being transported and potentially even being perfused for a period of time. We're really interested in finding approaches to identify small molecules and other potential biologic therapies that could be used to prevent the activation of donor CCR2-positive macrophages. It's a really attractive approach because treating the donor heart ex vivo decreases the risk of adversely affecting other organs that may be transplanted if you're treating the donor, for instance, and it may decrease the risk of immunosuppression and infection by not having to treat the recipient and we're catching the heart in this window where the risks are much lower. The other area that we're really excited to focus on is trying to identify the exact mediators that are generated from donor CCR2-positive macrophages that mediate the recruitment and activation of antigen-presenting cells because that would represent another potential therapeutic target. Dr. Greg Hundley:           Very nice. Thomas, what are your thoughts about what might be the next study to be performed really in this sphere of research? Dr. Thomas Eschenhagen: It's obviously something rather a question to Kory than to me, but I agree to what he said. I think it is pretty obvious what are the next steps mechanistically on the one hand, but practically on the other hand. I mean, at this point, we are at the mouse level, so the question is to which extent can this concept be translated into larger animals and then finally in humans? I was wondering, given these newer methods to keep donor hearts alive for long, extended periods, I was wondering which extent you are already collaborating with the respective groups who develop this approach because that obviously would increase the window of opportunity here for drugs. I think it's really an exciting and pretty visible next steps which we see here, and I can just hope that you're going this path and that it will be successful. Dr. Greg Hundley:           Kory, any thoughts on those collaborations that Thomas just spoke of? Dr. Kory Lavine:               We're definitely establishing collaborations to focus on ex vivo profusion of donor hearts because that's, as Thomas mentioned, is a perfect window to manipulate the immune populations that are within the donor heart. Those studies have to be team science, they have to be collaborative and they have to have a focus on large animals and then moving into clinic. We're definitely forming those collaborations and excited to work as a group. Dr. Greg Hundley:           Very nice. Well, listeners, what an exciting paper to discuss here as part of this feature discussion from the world of preclinical science. We want to thank Dr. Kory Lavine from Washington University in St. Louis, Missouri, and also our own associate editor, Dr. Thomas Eschenhagen from Hamburg Germany, for really bringing us this research study highlighting that distinct populations of donor and recipient macrophages coexist within the transplanted heart, and donor CCR2-positive macrophages are key mediators of allograph rejection and deletion of MyD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograph survival. 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 opinions expressed by the 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.

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Welcome to this episode of Physician's Weekly podcast. I am your host, Dr. Rachel Giles, from Medicom Medical Publishers in collaboration with Physician's Weekly. And yes, this week I am grateful to have my voice at all, after 3 days of viral laryngitis. This week, women's health has been all over the news, and that will be the topic of this week's InDEPTH episode. May 8th through 14 was also the National Women's Health Week, during which the U.S. Department of Health and Human Services' Office on Women's Health is encouraging women and girls to reflect on their individual health needs and take steps to improve their overall health.  The lenses of this InDEPTH dive are access to care and practice setting.Women's health remains a major problem in the US. In this episode we first take a look at maternal mortality in the US; the rate in the United States is roughly 20 maternal deaths per 100,000 births (about 700 deaths among the approximately 4 million people who give birth each year). Those statistics are not going down, but up for the last 15 years. American women today are 50% percent more likely to die because of pregnancy-related health issues than their mothers were. We interview Dr. Charles Jaynes, Vice President, Clinical Operations, Ob Hospitalist Group to understand the many factors that cause pregnancy and childbirth to remain unusually risky in the U.S. Based on recent CDC data, the leading causes of pregnancy-related deaths are cardiovascular conditions, infection, and hemorrhage.With hypertension and heart disease being major contributors to maternal morbidity, our second interview takes a deeper dive into the factors that can facilitate timely detection of cardiovascular disease, particularly in women. Physician's Weekly senior editor Martta Kelly interviews Dr. Carlos Iribarren, of the Kaiser Permanente Division of research in Oakland CA about his recent study, from the MINERVA  cohort study of over 5000 women.They talk about how over the past decade, total and premature CVD deaths among women in the United States increased by 20,000 between 2009 and 2019. In addition to mortality, morbidity related to CVD has also increased, particularly among younger women. In the Atherosclerosis Risk in Communities Study between 1995 and 2014, the proportion of hospitalizations for acute myocardial infarction in young adults aged 35 to 54 years increased for women in contrast with a decline for men.  To curb the growing burden of CVD morbidity and mortality among women, innovative approaches to improve risk prediction and prevention of CVD are needed. Breast arterial calcification (BAC), a form of medial artery calcification that can be detected on routine mammography, has been proposed as a sex-specific marker for CVD risk among women. However, in contrast to coronary artery calcium, the biologic basis and clinical utility of BAC remains unclear given nearly two-thirds of United States women over the age of 40 undergo routine screening mammography every 1 to 2 years, the potential value of BAC for CVD risk estimation could impact millions of women without incurring extra cost or radiation exposure. The interview with Dr. Iribarren talks about their recently published data One note about Dr. Jaynes interview: he refers to ACOG a few times, which is an abbreviation for The American College of Obstetricians and Gynecologists, and also to the monthly journal published by that professional society as the “Green Journal”.Enjoy listening!More reading:https://www.womenshealth.gov/nwhw/aboutIribarren C, Chandra M, Lee C, Sanchez G, Sam DL, Azamian FF, Cho HM, Ding H, Wong ND, Molloi S. Breast Arterial Calcification: a Novel Cardiovascular Risk Enhancer Among Postmenopausal Women. Circ Cardiovasc Imaging. 2022 Mar;15(3):e013526. 

Omega-3 and cancer recovery: How supplementation helps reduce hospital stays after operations Capital Medical University (China) Omega-3 supplementation boosts immunity and helps reduce inflammation among gastrointestinal cancer patients after surgery, new meta-analysis reports. Recent studies have indicated that nutritional intervention can reduce these problems, with omega-3 polyunsaturated fatty acids (n-3 PUFAs) particularly promising because of their inflammation benefits. Results showed that patients on an n-3 PUFAs regime had lower levels of inflammation markers. The academics, from China's Capital Medical University, stated: “The results of our study showed that n-3 PUFAs significantly decreased the level of inflammation and increased immune function. “Thus modulation of immune responses and reduction of inflammatory responses together lessens postoperative hospital stay for GI cancer patients.”     Vitamin D levels higher in exercisers   Johns Hopkins University The Journal of Clinical Endocrinology & Metabolism published the finding of researchers at Johns Hopkins University of a correlation between increased physical activity and higher levels of vitamin D. Higher levels of vitamin D and exercise was also associated with a lower risk of cardiovascular disease. The study included 10,342 men and women who were free of coronary heart disease and heart failure upon enrollment in the Atherosclerosis Risk in Communities study between 1987 to 1989. Physical activity levels were assessed during follow-up visits that took place over a 19.3-year period. Stored serum samples obtained at the second visit were analyzed for 25-hydroxyvitamin D3. Following adjustment for lifestyle and other factors, those who met the recommended levels had a 31% lower risk of being deficient in vitamin D than those with poor activity levels. Subjects in the recommended activity group with levels of vitamin D of 30 ng/mL or more had a 24% lower risk of cardiovascular disease.   Gingko biloba helps protect against the toxic cognitive effects of aluminium chloride Atomic Energy Authority (Egypt) Ginkgo biloba extract helped protect the brain from the toxic effects of aluminium chloride, exposure to which has been linked to diseases such as Alzheimer's. Researchers found its antioxidant properties were key in protecting the brain neurons of rats from oxidative stress caused by aluminium chloride (AlClʒ) intake. “The toxic effect of AlClʒ caused significant histologic changes in brain and testis tissues which is in agreement with other data that found accumulation of Al metal in neurons which cause ultra-structural changes,” wrote researchers from the Atomic Energy Authority in Egypt wrote in Nutrition Journal. “Administration of Ginkgo biloba extract (GbE) with aluminium chloride improved some biochemical and histologic changes observed in the brain and testis of male rats.” Overexposure to aluminium, a potent neurotoxin, could be a possible factor in several neurodegenerative disorders including Alzheimer's disease, say researchers. GbE on the other hand, has antioxidant and free radical scavenging properties. It has been used to help treating cerebral disorders that result from ageing and hypoxia. Previous studies also highlighted its ability to regulate neurotransmitters and exert neuprotective effects.   New data shows avocado consumers have improved nutrient intakes USDA and Haas Avocado Board A new analysis of the National Health and Nutrition Examination Survey (NHANES) data, compared avocado consumers to non-consumers and found that consuming avocados may be associated with an overall better diet, higher intake of essential nutrients, lower body weight, lower Body Mass Index (BMI) and smaller waist circumference. Insulin and homocysteine levels were lower in the avocado group, as well as a significantly reduced incidence of metabolic syndrome. Homocysteine, when elevated, has been associated with an increased risk of cardiovascular disease.i Metabolic syndrome is the name for a group of risk factors that raises the risk for heart disease and other health problems, such as diabetes and stroke.ii The analysis, "Avocado consumption by adults is associated with better nutrient Intake, diet quality, and some measures of adipositywas published in the journal Internal Medicine Review. SUMMARY OF KEY FINDINGS: * Compared to non-consumers, avocado consumers have:   Higher intakes of dietary fiber, total fat, good fats (monounsaturated fatty acids and polyunsaturated fatty acids), vitamins E and C, folate, magnesium, copper and potassium.   Lower intakes of total carbohydrates, added sugars and sodium. * Improved physiologic measures include:   On average, avocado consumers weighed 7.5 lbs less, had a mean BMI of 1 unit less and 1.2 in. smaller waist circumference compared to non-consumers.   Avocado consumers were 33% less likely to be overweight or obese and 32% less likely to have an elevated waist circumference compared to non-consumers.   Incidence of metabolic syndrome was significantly reduced for avocado consumers.       Better quality relationships associated with reduced dementia risk University of East Anglia (UK) Positive social support from adult children is associated with reduced risk of developing dementia, according to a new research published today. Conversely, negative social support is linked with increased risk, according to the 10-year follow-up study carried out by a team of researchers from the University of East Anglia (UEA), University College London (UCL), London Metropolitan University and the University of Nottingham. The researchers analysed a decade of data that followed 10,055 core participants from ELSA who were dementia-free at the start of the study. Participants were interviewed every two years and incidence of dementia was identified from self-reports by participants or information given by nominated informants. Positive support was characterised by having a reliable, approachable and understanding relationship with spouses or partners, children and other immediate family. But negative support scores showed stronger effects - an increase of one point in the negative support score led to up to 31 per cent rise in the risk. Negative support was characterised by experiences of critical, unreliable and annoying behaviours from spouses or partners, children and other immediate family.   After spouse passes, death risk from ‘broken heart' rises Rice University In the three-month period following a spouse's death, widows and widowers are more likely to exhibit risk factors linked to cardiovascular illness and death, according to a new study This could make a bereaved spouse more likely to “die of a broken heart,” the researchers say. The study, which appears in Psychoneuroendocrinology, found that individuals who have lost a spouse within the last three months have higher levels of pro-inflammatory cytokines (immune markers that indicate inflammation in the bloodstream) and lower heart rate variability (HRV) compared with non-bereaved individuals who share the sex, age, body mass index, and educational level. Both are factors that increase an individual's risk for cardiac events, including death. The study is the first to demonstrate that bereavement is associated with elevated levels of ex vivo cytokines and lower HRV. “In the first six months after the loss of a spouse, widows/widowers are at a 41 percent increased risk of mortality,” says lead author Chris Fagundes, an assistant professor of psychology in Rice University's School of Social Sciences. “Importantly, 53 percent of this increased risk is due to cardiovascular disease. This study is an important step toward understanding why this is the case by identifying how bereavement gets under the skin to promote morbidity and mortality.” Finally, the bereaved spouses reported 20 percent higher levels of depressive symptoms than the control group. Participants ranged in age from 51 to 80 (average 67.87) and included 22 percent men and 78 percent women. The sex and age of the control group was comparable, and the results were the same when accounting for slight differences in weight and health behaviors.

Commentary by Dr. Valentin Fuster

Treatment with Rhodiola mimics exercise to resist high-fat diet-induced muscle dysfunction Central South University (China), April 30, 2021   According to news reporting out of Changsha, People’s Republic of China, research stated, “Muscle dysfunction is a complication of high-fat diet (HFD)-induced obesity that could be prevented by exercise, but patients did not get enough therapeutic efficacy from exercise due to multiple reasons.” The news reporters obtained a quote from the research from Xiangya Hospital of Central South University: “To explore alternative or supplementary approaches to prevent or treat muscle dysfunction in individuals with obesity, we investigated the effects of Rhodiola on muscle dysfunction as exercise pills. SIRT1 might suppress atrogenes expression and improve mitochondrial quality control, which could be a therapeutic target stimulated by exercise and Rhodiola, but further mechanisms remain unclear. We verified the lipid metabolism disorders and skeletal muscle dysfunction in HFD feeding mice. Moreover, exercise and Rhodiola were used to intervene mice with a HFD. Our results showed that exercise and Rhodiola prevented muscle atrophy and dysfunction in obese mice and activating the SIRT1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved. EX-527, SIRT1 inhibitor, was used to validate the essential role of SIRT1 in salidroside benefit.” According to the news editors, the research concluded: “Results of cell culture experiment showed that salidroside alleviated high palmitate-induced atrophy and mitochondrial quality control impairments, but these improvements of salidroside were inhibited by EX-527 in C2C12 myotubes. Overall, Rhodiola mimics exercise that activates SIRT1 signaling leading to improvement of HFD-induced muscle dysfunction.”     Prenatal exposure to pesticides increases the risk of obesity in adolescence First study to analyse the long-term effects of persistent organic pollutants on cardiometabolic risk in adolescents Barcelona Institute for Global Health (Spain), May 3, 2021 Exposure before birth to persistent organic pollutants (POPs)-- organochlorine pesticides, industrial chemicals, etc.--may increase the risk in adolescence of metabolic disorders, such as obesity and high blood pressure. This was the main conclusion of a study by the Barcelona Institute for Global Health (ISGlobal), a research centre supported by the "la Caixa" Foundation. The study was based on data from nearly 400 children living in Menorca, who were followed from before birth until they reached 18 years of age.  POPs are toxic, degradation-resistant chemicals that persist in the environment. Examples of such compounds are pesticides and organochlorine insecticides (DDT, etc.). POPs have adverse effects on both human health and the environment and their use is regulated globally. Prenatal exposure to these substances has been associated with cardiometabolic risk factors in childhood, but there were previously no studies assessing whether such associations continue into adolescence, a developmental stage characterised by significant changes in the endocrine system and rapid increases in body mass. The aim of this investigation, carried out within the framework of the INMA Project-Environment and Childhood, was to study the associations between prenatal exposure to POPs and body mass index (BMI) as well as other markers of cardiovascular risk in adolescence. Data from 379 children in Menorca was analysed. POP levels were measured in umbilical cord blood samples and the children were then seen periodically between the ages of 4 and 18 years. At these visits, BMI, body fat percentage and blood pressure were recorded as they grew. When the child reached 14 years of age, the scientists measured blood biomarkers of cardiometabolic risk (cholesterol, triglycerides, glucose, etc.). The results of this study, published in the journal Environment International, suggest an association between prenatal POP exposure and a higher BMI in adolescence, particularly in the case of the fungicide hexachlorobenzene (HCB) and the insecticide compound dichloro-diphenyl-trichloroethane (DDT).  Exposure to these two organochlorides--HCB and DDT¬--was also associated with higher blood pressure in childhood and adolescence and increased cardiometabolic risk at 14 years of age.  ISGlobal researcher Núria Güil-Oumrait, the first author of the study, explains that "this is the first longitudinal study to analyse the relationship between persistent organic pollutants and cardiometabolic risk throughout childhood and adolescence. Our findings show that the association between these substances and infant BMI does persist into adolescence and that prenatal exposures are associated with the main risk factors for metabolic syndrome in adults, a condition that today affects one in four people worldwide. With respect to the mechanisms that might explain this association, Güil-Oumrait points out that "it is thought that POPs may interact with hormone receptors or with the generation of free radicals, and the chief problem is that these pollutants accumulate in the fatty tissues of living organisms, where they can persist for years, even decades".  Martine Vrijheid, study coordinator and head of the Childhood and Environment Programme at ISGlobal, highlights the fact that "some of these substances could be considered endocrine disruptors, that is, chemicals that interfere with hormonal regulation". In her view "more studies are needed in this field, especially focussing on childhood and adolescence, which are critical developmental stages characterised by particular vulnerability".     One cup of leafy green vegetables a day lowers risk of heart disease Research has found that by eating just one cup of nitrate-rich vegetables each day people can significantly reduce their risk of heart disease. Edith Cowan University (Australia), May 4, 2021 New Edith Cowan University (ECU) research has found that by eating just one cup of nitrate-rich vegetables each day people can significantly reduce their risk of heart disease. The study investigated whether people who regularly ate higher quantities of nitrate-rich vegetables, such as leafy greens and beetroot, had lower blood pressure, and it also examined whether these same people were less likely to be diagnosed with heart disease many years later. Cardiovascular diseases are the number one cause of death globally, taking around 17.9 million lives each year. Researchers examined data from over 50,000 people residing in Denmark taking part in the Danish Diet, Cancer, and Health Study over a 23-year period. They found that people who consumed the most nitrate-rich vegetables had about a 2.5 mmHg lower systolic blood pressure and between 12 to 26 percent lower risk of heart disease. Lead researcher Dr Catherine Bondonno from ECU's Institute for Nutrition Research said identifying diets to prevent heart disease was a priority. "Our results have shown that by simply eating one cup of raw (or half a cup of cooked) nitrate-rich vegetables each day, people may be able to significantly reduce their risk of cardiovascular disease," Dr Bondonno said. "The greatest reduction in risk was for peripheral artery disease (26 percent), a type of heart disease characterised by the narrowing of blood vessels of the legs, however we also found people had a lower risk of heart attacks, strokes and heart failure."  Forget the supplements The study found that the optimum amount of nitrate-rich vegetables was one cup a day and eating more than that didn't seem to give any additional benefits. "People don't need to be taking supplements to boost their nitrate levels because the study showed that one cup of leafy green vegetables each day is enough to reap the benefits for heart disease," Dr Bondonno said. "We did not see further benefits in people who ate higher levels of nitrate rich vegetables." Smoothies are ok Dr Bondonno said hacks such as including a cup of spinach in a banana or berry smoothie might be an easy way to top up our daily leafy greens. "Blending leafy greens is fine, but don't juice them. Juicing vegetables removes the pulp and fibre," Dr Bondonno said. The paper "Vegetable nitrate intake, blood pressure and incident cardiovascular disease: Danish Diet, Cancer, and Health Study" is published in the European Journal of Epidemiology. It is a collaboration between Edith Cowan University, the Danish Cancer Society and The University of Western Australia. The research adds to growing evidence linking vegetables generally and leafy greens specifically with improved cardiovascular health and muscle strength. This evidence includes two recent ECU studies exploring cruciferous vegetables and blood vessel health and green leafy vegetables and muscle strength.     Mindfulness programs can boost children's mental health   University of Derby (UK), May 4, 2021 Mindfulness programs can improve the mental health of school-age children and help them to feel more optimistic, according to new research from the University of Derby and Derbyshire Educational Psychology Service. More than 1,000 pupils aged between 9-12 years old across 25 schools in Derbyshire, received one 45-minute mindfulness session per week for nine weeks during the year-long project, which involved a collaboration between Dr. William Van Gordon, Associate Professor in Contemplative Psychology at the University, and Derbyshire Educational Psychology Service. Mindfulness is an ancient meditation technique that involves focussing awareness on the present moment, as a means of fostering calm, wellbeing and insight. The weekly sessions involved activities such as practicing mindful breathing and paying attention to bodily sensations, as well as exercises intended to help cultivate attention skills and a greater awareness of emotions. The impact of the sessions, which were delivered by teachers in a traditional classroom environment, was evaluated by comparing psychological assessments that the children completed before the classes began, with assessments undertaken after the program had concluded. Part of the evaluation measured children's emotional resiliency using The Resiliency Scale for Children, while wellbeing was rated using the Stirling Children's Wellbeing Scale. Overall, the study found a significant improvement in positive emotional state, outlook and resiliency. There was also an increase in the different dimensions of resilience: optimism increased by 10%, tolerance was improved by 8% and self-efficacy, how a child feels they can cope with a situation based on the skills they have and the circumstances they face, improved by 11%. Professor Van Gordon said: "Findings from the study indicate that mindfulness delivered by school teachers can improve wellbeing and resiliency in children and young people. "This is consistent with wider evidence demonstrating the positive impact of mindfulness on school children's levels of emotional resiliency, emotional stability, wellbeing and stress. "These findings are also in line with the view that preventative interventions given at a young age can help to reduce the incidence of mental health problems in young people."   Vitamin D levels higher in exercisers Johns Hopkins University, May 01 2021  The issue of the Journal of Clinical Endocrinology & Metabolism published the finding of researchers at Johns Hopkins University of a correlation between increased physical activity and higher levels of vitamin D. Higher levels of vitamin D and exercise was also associated with a lower risk of cardiovascular disease. The study included 10,342 men and women who were free of coronary heart disease and heart failure upon enrollment in the Atherosclerosis Risk in Communities study. Physical activity levels were assessed during follow-up visits that took place over a 19.3-year period. Stored serum samples obtained at the second visit were analyzed for 25-hydroxyvitamin D3. Subjects who achieved American Heart Association recommended physical activity levels had average levels of vitamin D that were higher than those who had intermediate and poor levels of activity. Following adjustment for lifestyle and other factors, those who met the recommended levels had a 31% lower risk of being deficient in vitamin D than those with poor activity levels. Subjects in the recommended activity group with levels of vitamin D of 30 ng/mL or more had a 24% lower risk of cardiovascular disease. The association between exercise and vitamin D was stronger in subjects of European ethnicity than among African Americans. The authors noted that European-Americans as well as those who engage in exercise are likelier to be supplement users. “We did find that vitamin D supplement use was higher among those with increased physical activity,” they observed. "In our study, both failure to meet the recommended physical activity levels and having vitamin D deficiency were very common" stated coauthor Erin Michos, MD, MS, of Johns Hopkins University School of Medicine. "The bottom line is we need to encourage people to move more in the name of heart health."     One teaspoon daily of trehalose can help maintain glucose homeostasis: a double-blind, randomized controlled trial  Hayashibara Co. Ltd (Japan), April 24, 2021 Background Trehalose is a natural disaccharide that is widely distributed. A previous study has shown that daily consumption of 10 g of trehalose improves glucose tolerance in individuals with signs of metabolic syndrome. In the present study, we determined whether a lower dose (3.3 g/day) of trehalose improves glucose tolerance in healthy Japanese volunteers. Methods This was a randomized, double-blind, placebo-controlled study of healthy Japanese participants (n = 50). Each consumed 3.3 g of trehalose (n = 25) or sucrose (n = 25) daily for 78 days. Their body compositions were assessed following 0, 4, 8, and 12 weeks; and serum biochemical parameters were assayed and oral 75-g glucose tolerance tests were performed at baseline and after 12 weeks. Results There were similar changes in body composition and serum biochemistry consistent with established seasonal variations in both groups, but there were no differences in any of these parameters between the two groups. However, whereas after 12 weeks of sucrose consumption, the plasma glucose concentration 2 h after a 75-g glucose load was significantly higher than the fasting concentration, after 12 weeks of trehalose consumption the fasting and 2-h plasma glucose concentrations were similar. Furthermore, an analysis of the participants with relatively high postprandial blood glucose showed that the plasma glucose concentration 2 h after a 75-g glucose load was significantly lower in the trehalose group than in the sucrose group. Conclusions Our findings suggest that trehalose helps lower postprandial blood glucose in healthy humans with higher postprandial glucose levels within the normal range, and may therefore contribute to the prevention of pathologies that are predisposed to by postprandial hyperglycemia,, even if the daily intake of trehalose is only 3.3 g, an amount that is easily incorporated into a meal.     Coffee compound enhances autophagy to protect against cell injury Chengdu University of Traditional Chinese Medicine (China), April 30, 2021 According to news reporting originating from Sichuan, People’s Republic of China, research stated, “Autophagy serves an important role in amyloid-beta (A beta) metabolism and tau processing and clearance in Alzheimer’s disease. The progression of A beta plaque accumulation and hyperphosphorylation of tau proteins are enhanced by oxidative stress.” Our news editors obtained a quote from the research from the Chengdu University of Traditional Chinese Medicine, “A hydrogen peroxide (H2O2) injury cell model was established using SH-SY5Y cells. Cells were randomly divided into normal, H2O2 and chlorogenic acid (5-caffeoylquinic acid; CGA) groups. The influence of CGA on cell viability was evaluated using a Cell Counting Kit-8 assay and cell death was assessed using Hoechst 33342 nuclear staining. Autophagy induction and fusion of autophagic vacuoles assays were performed using monodansylcadaverine staining. Additionally, SH-SY5Y cells expressing Ad-mCherry-green fluorescent protein-LC3B were established to detect autophagic flow. LysoTracker Red staining was used to evaluate lysosome function and LysoSensor ™ Green staining assays were used to assess lysosomal acidification. The results demonstrated that CGA decreased the apoptosis rate, increased cell viability and improved cell morphology in H2O2-treated SH-SY5Y cells. Furthermore, CGA alleviated the accumulation of autophagic vacuoles, reduced the LC3BII/I ratio and decreased P62 levels, resulting in increased autophagic flux. Additionally, CGA upregulated lysosome acidity and increased the expression levels of cathepsin D. Importantly, these effects of CGA on H2O2-treated SH-SY5Y cells were mediated via the mTOR-transcription factor EB signaling pathway.” According to the news editors, the research concluded: “These results indicated that CGA protected cells against H2O2-induced oxidative damage via the upregulation of autophagosomes, which promoted autophagocytic degradation and increased autophagic flux.” This research has been peer-reviewed.

When a character in a movie has a heart attack, they typically clutch their chest, have trouble breathing and fall to the ground with sharp chest pains. This is a common reaction but there is a wide range of symptoms associated with a heart attack that do not always include distinct chest pain, especially in women. Can’t stress that point enough, ladies! Cardiovascular disease is the #1 killer of both men and women in the U.S. and it kills more women than all forms of cancer combined. Heart health is not just something to be concerned about when we're older. A recent study by Atherosclerosis Risk in Communities found that heart attack rates have risen among individuals ages 35-54, especially women. February is Heart Health Month. Your lifestyle dictates your chance of heart problems, including stroke and nearly all other types of illness. 80% of heart disease is preventable, which is good news. In this episode, I share lifestyle tips for a healthy heart, a healthier body and longevity as well as some surprising heart attack symptoms to be aware of that are also associated with other issues so they often go ignored. Links & Resources mentioned: Book a complimentary consultation call with Kelly Download your free toolkit: Clean Your Beauty Routine & Improve Your Metabolism LETSCOM Fitness Tracker with Heart Rate Monitor

Commentary by Dr. Valentin Fuster

Heart Rate Variability, or "HRV" as it's often referred to, is a simple yet powerful biological metric that we can use to determine our ability to perform, physically and psychologically, on a given day. Increasingly becoming a more popular data point in fitness trackers, this biomarker can provide real-time insight into how well we have recovered from previous stressors (whether physical or mental).Although HRV is heavily impacted by our daily activity, it's also dependent on many other factors like: diet, sleep, age, gender, genetics, etc. This is why your HRV is specific to YOU and should be viewed relative to your historic HRV. When you understand your personal HRV, it serves as a very useful indicator of your overall health, fitness, and recovery ability.This week, Andy and Aaron walk through the concept of Heart Rate Variability ("HRV"), why it's important, how we can use it, and what we can do to improve it. Some fitness trackers that measure HRV (along with many others):Oura RingWhoopGarmin Vivosmart 4Polar H10 Heart Rate SensorLearn more on InstagramWatch us on YouTubeVisit LabRatsPodcast.com Resources:Study: Heart rate variability and occupational stress—systematic reviewStudy: Affect of Heart Rate Variability Biofeedback on Sport Performance, a Systematic ReviewStudy: Stress and Heart Rate Variability: A Meta-Analysis and Review of the LiteratureStudy: Heart Rate Variability and Lifetime Risk of Cardiovascular Disease: the Atherosclerosis Risk in Communities StudyArticle: Ways to Trigger the Parasympathetic Nervous SystemArticle: Everything You Need to Know About Heart Rate Variability (HRV)Article: How I Track My Heart Rate Variability, Recovery Status, And Training Readiness (And Why These Metrics Are So Important).Article: Sympathetic vs. Parasympathetic State: How Stress Affects Your HealthDisclaimer: This podcast is not intended to provide medical advice, diagnosis or treatment. The products, information, services and other content provided on and through this podcast, including information that may be provided in the show notes (directly or via linking to third-party sites), are provided for informational purposes only. Please consult with your physician or other healthcare professional regarding any medical or health-related diagnosis or treatment options.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week features Circulation Global Rounds, a brand-new series of papers from all across the world that you are going to want to hear about, coming right up after these summaries. The first original paper this week tells us that community trends and acute decompensated heart failure may differ by race and sex. Dr Patricia Chang from University of North Carolina in Chapel Hill and colleagues examine the 10-year rates and trends of hospitalized acute decompensated heart failure in the Atherosclerosis Risk in Communities or ARIC study, which sampled heart failure–related hospitalizations in four US communities from 2005 to 2014, using ICD-9 codes. They found that acute heart failure with reduced ejection fraction was more common in black men and white men, whereas acute heart failure with preserved ejection fraction was most common in white women. Rates of hospitalized acute decompensated heart failure increased over time, with higher rates in blacks, and rising cases of preserved ejection fraction heart failure. Mortality rates were 30% at one year with a more pronounced decrease over time in blacks but generally did not differ by heart failure types. Whether racial differences may be related to age of onset comorbidities, or other community level and social economic factors, deserve further study. The next paper is a population-based study identifying long-term outcomes and risk factors and children with hypertrophic cardiomyopathy. Dr Alexander from Boston Children's Hospital and colleagues examine the National Australian Childhood Cardiomyopathy Study, a long-term national cohort study with a median follow-up duration of 15 years. They found that the greatest risk of death or transplantation for children with hypertrophic cardiomyopathy was in the first year after diagnosis, with 14% of patients achieving this combined end point compared to 0.4% per year thereafter. Risk factors for death or transplantation included symmetric left ventricular hypertrophy at diagnosis, Noonan syndrome, increasing left ventricular free wall thickness, and lower fractional shortening during follow up. The majority of surviving patients had no symptoms. Thus, children with hypertrophic cardiomyopathy who are alive one year after diagnosis have a low long-term rate of death or transplantation. Deaths from heart failure usually occur soon after diagnosis, whereas the risk of sudden cardiac death is ongoing. The next paper is the first demonstration of a peripheral clock in the perivascular adipose tissue that could contribute to the homeostatic regulation of circadian blood pressure variation. Co-corresponding authors Dr Chang and Chen from University of Michigan and their colleagues used a novel brown adipose specific aryl hydrocarbon receptor, nuclear translocator-like protein 1 or Bmal1 and angiotensinogen knockout mouse model to demonstrate that local Bmal1 in perivascular adipose tissue regulated angiotensinogen expression and the ensuing increase in angiotensin II, which acted on smooth muscle cells in the vessel walls to regulate basal activity and blood pressure in a circadian fashion during the resting phase. In fact, deletion of Bmal1 or angiotensinogen in the perivascular adipose tissue resulted in a superdipper phenotype with exacerbated hypotension during the resting phase. These findings imply that it is possible that obesity could alter the perivascular adipose tissue peripheral clock, thus promoting abnormal dipper phenotypes and increasing cardiovascular risk. The results therefore inform the design of novel therapeutic approaches for hypertension by targeting the perivascular adipose tissue peripheral clock. What is the net clinical benefit of oral anticoagulation for very elderly patients with atrial fibrillation? Well, the next paper by first author Dr Chao, cocorresponding authors, Dr Chen from Taipei Veterans General Hospital and Dr Lip from University of Birmingham, addresses this question. These authors use a nationwide cohorts study in Taiwan to compare the risks of ischemic stroke and intercerebral hemorrhage between patients with and without atrial fibrillation, all aged 90 years and above, from 1996 to 2011, and they also compared patients treated with warfarin and non-vitamin K antagonists oral anticoagulants, or NOX from 2012 to 2015 when NOX were available in Taiwan. They found that even among these very elderly patients aged 90 years and above, atrial fibrillation was associated with an increased risk of ischemic stroke compared to patients without atrial fibrillation. Warfarin use was associated with a lower risk of ischemic stroke, with no difference in intercerebral hemorrhage risk compared to nonwarfarin treatment. The use of warfarin was associated with a positive net clinical benefit compared to being untreated or to antiplatelet therapy. Compared to warfarin, NOX were associated with a lower risk of intracerebral hemorrhage, with no difference in the risk of ischemic stroke. Thus, oral anticoagulation may still be considered for thromboprophylaxis in very elderly patients with atrial fibrillation, with NOX being a favorable choice The final paper provides insights into the mechanisms linking obesity and cardiovascular diseases. Co-corresponding authors, Dr Kong and Wang from Peking University Health Science Center and colleagues use a combination of animal models and human adipose biopsies to characterize a new adipokine named family with sequence similarity 19, member A5 or FAM19A5. This novel adipokine was capable of inhibiting post injury neointoma information via sphingosine-1-phosphate receptor 2 and downstream G12/13-RhoA signaling. Thus, down regulation of FAM19A5 during obesity and loss of its vascular protective function may trigger cardiometabolic diseases. Well, that wraps it up for our summaries. Now for our feature discussion. I'm just so excited about today's feature discussion, because we're talking about Circulation going global. And I am just absolutely delighted to have with us, our Editor-in-Chief himself, Dr Joe Hill from UT Southwestern, as well as our Senior Advisory Editor, Dr Paul Armstrong from University of Alberta. So Joe, could you start by telling us a little bit more about your vision for the global outreach of Circulation? Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global journal with a global footprint. We have editors distributed around the world in 16 countries and 10 time zones. And importantly, those editors all have an equivalent role at the leadership table. Part of the reason for this is because cardiovascular disease is now, as we are all aware, a global scourge. There are no more final frontiers for cardiovascular disease. That said, the manifestations of cardiovascular disease differ in different parts of the world. In the developed world, and the developing world, for example, the way cardiovascular disease manifests itself can be very different. And at the same time, the way in which the disorders are tackled are different. The way we tackle heart disease in the West can be different than it is in the East, for example. And there are important initiatives that have emerged in different pockets of the world, best practices that we need to understand better. What can we all learn from the way in which cardiovascular disease manifests itself around the world and it's being addressed around the world? Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in - Chief and I heard you say this, I was just floored, because coming from Singapore and all our listeners out there in Japan and China, we just really appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit more about this new initiative then for the journal. Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from Canada, who is a household name in the cardiovascular world, he and I cooked up a scheme that Paul will describe, where we will reach out on a regular basis for insights from various different countries, ultimately, circling the globe progressively over time. And I will defer to Paul to tell us more about the specifics. Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but still believing that you can teach an old dog new tricks, I would point out that Circulation is almost 70 years old, and it has staying power. And one of the reasons that it has staying power is because it is capable of reinventing itself, and so I was attracted to help out again, from the editorial process, given Joe's vision and leadership and the excitement around the reinvention that you've described, to get involved with this initiative. And I was inspired, of course, by the fact that those of us who do clinical trials appreciate that a lot of different ideas, a lot of different cultures and perspectives are brought to a collaborative table. And I'm thinking back now, Carolyn to three years ago, when you and I first met enjoying courses as part of a trial in heart failure, which involves 43 countries, 800 sites, it will be 5000 patients centers, we've traveled separately and together around the world, convincing people that there are unmet needs in heart failure and other parts of cardiovascular disease, we learned that the approach to standard of care, the rigor which is applied, the exquisite sensitivities around differences that are meaningful, and the tricks that some investigators and countries use that we can all I think, learn from has been very revealing. So I think in this initiative, we want to have thought leaders. And we've already I think, commenced and have two outstanding leaders from Japan and India to come forward in the first two quarters of this initiative. Tell us about the regional epidemiologic features, cardiovascular disease in their regions, what the most important challenges are, what their best practices are, that you're alluded to, who provides cardiovascular care and what the impediments are to progressing because we think if we listen and learn as essentially knowledge brokers, because welcome to Circulation, we can facilitate raising the level of all of the boats in the water and potentially make new partnerships and do a better job. So I'm excited about this. I'm delighted that Joe was receptive and really look forward to working with him and some of these terrific people around the world, you included who brings such a unique and important perspective from which we can all learn. Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International knowledge brokers, that's what we hope to be. Isn't that fabulous, just an opportunity to learn from each other, everybody having stuff to bring to the table? Tell us a bit more though, what are you looking for in these papers? Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic. We're going to allow diversity of approaches. We're going to invite a thought leader and hope that that thought leader might invite one or two others, we want to limit it to three co-authors. We want obviously some insights into how cardiovascular health professionals are being trained, what research infrastructure exists, and how they access the literature, how do they read Circulation, how do they read other journals, and are there collaborative ideas that they've developed to their neighbors to the East and West that may be could be broadened? Are there unmet needs that they've indicated similar or different from those in Western Europe, South America? We've got about seven or eight points of light that we hope to illuminate in the course of this exercise. And the prospectus that's laid out in an editorial that Joe and I collaborated on that I believe, Joe, is going to come out in early July. Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just the opposite of a formulaic, cookie cutter approach. We want to leverage the beautiful diversity of our world. The different approaches that people take to attack this scourge that is keeping a humble approach to tackle instead of the visas that is humbling bar none. There is nothing that is more globally important than the continued growth and expansion of cardiovascular disease. And importantly, we can all learn from each other. There are exciting initiatives that I've learned about in South America and in pockets of Europe and in Asia, and in the Middle East that we can all benefit from, and we want to shine a bright light on that. These pieces will be relatively short. They will be in our Frame of Reference section, so 1200 words or so, so that they are accessible so that people, you know, feel that they can carve out, you know, four minutes in their busy day to read what cardiovascular disease looks like, as Paul said, our first ones will be from Japan and India, and we plan to reach out to South America and to the Middle East, and just continue on around until over the course of the next number of years, we've touched virtually every country in the world. Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that you might be looking to focus on? Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is that in the West, in the developed world, cardiovascular disease increasingly has become a chronic disorder where more and more people, over the course of the last six years are surviving their acute coronary syndrome, their tachyarrhythmia events, and they are developing chronic disorders like heart failure, whereas in the East, it is the atherothrombotic manifestations that have both MI and stroke that are expanding rapidly. So given that the face of cardiovascular disease is different in different parts of the world, different strategies have to be leveraged to address that, and we want to learn about that. Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these papers and just reflect on the things that we're learning. Paul, did you have anything else that you wanted to add? Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes and obesity and the expanding epidemic that seems to effect some regions such as India, in the Middle East, even more than other areas, but I think this is going to be great. We're gonna have some fun and learn and exciting and hopefully it will catalyze better care and better thinking around this enemy that we all face. Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited as I am about this. You have to read the editorial. It's a fantastic read. Thanks for joining us today. And don't forget to tune in again next week.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.                                                 Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.                                                 Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.                                                 They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.                                                 The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.                                                 From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.                                                 The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.                                                 The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.                                                 The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.                                                 RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.                                                 Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.                                                 The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.                                                 They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.                                                 That brings us to the end of our summaries. Now, for our featured discussion.                                                 Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.                                                 I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.                                                 Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find? Dr Robin Mathews:         The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?                                                 We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.                                                 ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.                                                 What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.                                                 We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.                                                                                                 What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.                                                 When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.                                                 We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant. Dr Carolyn Lam:                What a detailed summary. Thanks so much.                                                 Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful? Dr Jeptha Curtis:               It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.                                                 I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.                                                 What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.                                                 As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.                                                 All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.                                                 What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals. Dr Carolyn Lam:                Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that? Dr Sandeep Das:               Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.                                                 One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."                                                 I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems. Dr Carolyn Lam:                Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US? Dr Robin Mathews:         Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."                                                 Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.                                                 In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.                                                 At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts. Dr Sandeep Das:               One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?                                                 The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive. Dr Robin Mathews:         Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.                                                 I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.                                                 At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them. Dr Carolyn Lam:                Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.                                                 Thank you so much for listening today, and don't forget to tune in again next week.

Dr. Paul 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 for this month's issue. We'll also hear from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field.                                                 In our first article, Barry Maron associates report on the long term clinical course of hypertrophic cardiomyopathy patients following ICD therapy for ventricular arrhythmias. They studied a cohort of 486 high-risk hypertrophic cardiomyopathy patients with ICDs from eight international centers. Of these 486 patients over 6.4 years, 94 patients or 19% experienced appropriate ICD interventions, terminating VT or VF. Of the 94 patients receiving appropriate ICD therapy, 87 were asymptomatic or only mildly symptomatic at the time of appropriate ICD interventions. Of these 87 patients, 74 or 85% remained in classes one or two without significant change in clinical status of the subsequent 5.9 years up to 22 years. Among the 94 patients, there was one sudden death in three patients who died from non arrhythmic hypertrophic cardiomyopathy related processes. Post ICD intervention, freedom from hypertrophic cardiomyopathy, mortality was 100% at one year, 97% at five years, and 92% at 10 years, distinctly lower than the risk of ischemic or non ischemic cardiomyopathy in ICD trials.                                                 Hypertrophic cardiomyopathy patients with ICDs interventions reported the heightened anxiety and expectation of future shocks. However, they did not affect general psychological well-being or quality of life. The authors concluded that in hypertrophic cardiomyopathy, unlike ischemic heart disease, prevention of sudden death with ICD therapies unassociated with a significant increase in cardiovascular morbidity and mortality, nor transformation into heart failure deterioration, ICD therapy does not substantially impair overall psychological and physical well-being. In our next article, Abdulla Damluji and associates examined the cost of hospitalizations for cardiac arrest using the US nationwide inpatient sample from 2003 to 2012. Using the log transformation of inflation adjusted costs the authors examined 1,387,396 patients who were hospitalized after cardiac arrest. They had a mean age of 66 years. Inpatient procedures included coronary angiography in 15%, PCI in 7%, intra-aortic balloon pump in 4.4%, therapeutic hypothermia in 1.1%, and mechanical circulatory support in 0.1% of patients.                                                 Notably the rates of therapeutic hypothermia increased from 0 in 2003 to 2.7 in 2012, p less than 0.001. Both hospital charges inflation adjusted costs linear increased over time. In a multi-variant analysis predictors of inflation adjusted costs included large hospitals size, urban teaching hospital, and length of stay. Among co-morbidities, atrial fibrillation or fluid and electrolytes imbalance were the most common associated with cost. The authors found that during the period between 2003 and 2012 post cardiac arrest, hospitalizations had a steady rise and associated healthcare costs likely related to increase length of stay, medical procedures and systems of care.                                                 In our next paper, Peter Huntjens and associates examined intrinsic interventricular dyssynchrony as a predictor of human dynamic response to cardiac resynchronization. The authors use a cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular or intraventricular activation on resynchronization therapy response that is the change in LV dP/dt max. The simulated change in LV dP to dt max had a range of 1.3 to 26.5% increased considerably with increasing inter ventricular dyssynchrony. In contrast, the isolated effect of intra ventricular dyssynchrony was limited with the change in the LV dP/dt max range and the left ventricle from 12.3 to 18.3% in the right ventricle from 14 to 15.7%.                                                 Secondly, electrocardiographic imaging derived activation characteristics of 51 CRT candidates were used to create individual models of ventricular activation in CircAdapt. The model predicted change in LV dP/dt max was close to the actual value in left bundle branch block patients with 2.7% difference between measured and simulated when only intrinsic interventricular dyssynchrony was personalized. Among non left bundle branch block patients a change in LV dP/dt max was systematically over predicted by CircAdapt with a 9.2% difference between measured and simulated. Adding intra ventricular activation to the model did not improve the accuracy of response prediction. The authors found that computer revealed intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT.                                                 In the next paper Kenji Kuroki and associates examined the use of voltage limit adjustment of substrate mapping and fast Fourier transform analysis of local ventricular bipolar electrograms during sinus rhythm to predict VT isthmuses. They performed these studies and nine post infarction patients who underwent catheter ablation for total of 13 monomorphic ventricular tachycardias. Relatively higher voltage areas on electroanatomical map or defined as high voltage channels, which were further classified as full or partial if the entire or more than 30% of the high voltage channel was detectable. 12 full high voltage channels were identified in seven of nine patients. Relatively higher fast Fourier transform areas were defined as high frequency channels, which were located on seven of 12 full high voltage channels. Five VT isthmuses or 71% were included in the seven full high voltage channels positive in high frequency channel positive sites.                                                 While no VT isthmuses were found in five full high voltage channel positive but high frequency channel negative sites, high frequency channels were identical to 9 out of 16 partial high voltage channels. Eight VT isthmuses or 89% were included in nine partial high voltage channel positive in high frequency channel positive sites, whereas no VTs isthmuses were found in the seven partial high voltage channel positive and high frequency channel negative sites.                                                 All high voltage channel positive in high-frequency channel positive sites predicted VT isthmus with a sensitivity of 100% and specificity of 80%. The authors concluded that based on this small series that combined use of voltage, limited adjustment and fast Fourier transform analysis may be useful method to detect VT isthmuses.                                                 In the next study, John Whitaker and associates examined the use of lesion index, LSI index, a proprietary algorithm combining contact force, radio-frequency application duration, and RF current. Cardiac CT was used to assess atrial tissue thickness. Ablation lines two to three per animal were created in the right atrium in seven mini pigs with point lesions using 25 watts of energy. Two weeks after the ablation, serial sections of targeted atrial tissue or examine histologically to identify gaps and transmural ablation. LSI guidelines had a lower incidence of histological gaps. Four gaps in the 69 catheter moved or 5.8% compared to ablation using LSI plus two millimeter lines in which there is seven gaps in 33 catheter moves or 21.2% and using LSI plus four millimeter lines in which there are 15 gaps in 23 moves or 65.2% p less than 0.0. The change in LSI was calculated retrospectively is a distance between two adjacent lesions above the mean LSI of the two lesions. Changing LSI values of 1.5 or less were associated with no gaps in transmural ablation.                                                 The authors concluded that in this mod of chronic atrial ablation delivery of uninterrupted transmural linear lesions may be facilitated using LSI to guide catheter movement. When change in LSI between adjacent legions is 1.5 millimeters or lower, no gaps in atrial linear lesions should be expected.                                                 In our next paper, Matthew Bennett and associate examined whether their response to antitachycardia pacing in patients with ICD could further discriminate ventricular from super ventricular arrhythmias in patients receiving ATP in the RAFT trial. The RAFT trial randomized 1,798 patients with New York Heart Association class two or three heart failure, left ventricular ejection fraction less than or equal to 30%, in QRS duration 120 millisecond or greater, to an ICD plus or a minus cardiac resynchronization. Beginning with 10,916 ATP attempts for 8,150 tachycardia episodes in 924 patients, the author's excluded tachycardias where ATP terminated the episode or were the specific etiology tachycardia was uncertain. In this study, they analyzed 3,676 ATP attempts delivered to 2,046 tachycardia episodes in 541 patients. The authors found that a shorter difference between the post pacing interval is PPI minus TCL, was more likely to be associated with VT than SVT, mean of 138.1 milliseconds for VT and 277.4 milliseconds for SVT p, less than 0.001. A PPI minus TCL value of less than or equal to 300 milliseconds had a sensitivity in 97.4% and a specificity of 28.3% for VT.                                                 The authors concluded that specifically the PPI minus TCL following antitachycardia pacing may help distinguish ventricular from supraventricular arrhythmias.                                                 In the next study, Shailee Shah and Amr Barakat and associates examined the outcomes after repeat AF ablation. The authors examined 137 patients out of a total of 10,378 patients undergoing Afib ablation who had had initial long-term success defined from recurrent arrhythmias for greater than 36 months off anti-arrhythmic drugs in subsequent underwent repeat ablation for recurrent atrial fibrillation. The median arrhythmia free period that define long-term success was 52 months. In redo-ablations reconnection of at least one of the pulmonary veins was found in 111 or 81% of patients. Additional non PV ablations were performed in 127 or 92.7% of patients. After a mean follow-up of 17 months, 103 patients or 75% were arrhythmia-free, 79 off anti-arrhythmics, and 24 on arrhythmics. The authors found that repeat ablations with re-isolation to the point of veins and modifying the atrial substrate had a good success rate.                                                 In the next article Qiongling Wang and associates hypothesized that genetic inhibition of CaMKII oxidation in a mouse model of Duchenne muscular dystrophy can alleviate abnormal calcium homeostasis thus preventing ventricular arrhythmias. The authors tested whether the selective loss of oxidation of the CaMKII effects ventricular arrhythmias in the mouse model of Duchenne muscular dystrophy. Genetic inhibition of ox-CaM kinase II by knocking replacement of the regulatory domain methionines with valines, which we'll call MMVV, prevented ventricular tachycardia in the mdx mice. Confocal calcium imaging of ventricular myocytes, isolated from the mdx MMVV mice revealed normalization of intra-calcium release events compared to myocytes from the mdx mice. Abnormal action potentials as assessed by optical mapping mdx were also alleviated by genetic inhibition of ox-CaMK II. Knockout of the NADPH oxidase regulatory sub-unit P 47 Fox normalized elevated ox-CaMK II, repaired intracellular calcium hemostasis and rescued inducible ventricular arrhythmias in the mdx mice. The authors concluded that inhibition of ROS or ox-CaMK II protects against pro-arrhythmic intracellular calcium handling, preventing ventricular arrhythmias in a mouse model of Duchenne muscular dystrophy.                                                 In the next article, Kyohei Marume and Teruo Noguchi and associates examined whether the combination of QRS duration of 120 milliseconds or greater in late gadolinium enhancement is a precise prognostic indicator for the primary endpoint of all cause death and a composite of sudden cardiac death or aborted sudden cardiac death in 531 patients with dilated cardiomyopathy. They also analyzed the association between the combination of late gadolinium enhancement and increased QRS duration in these end points among patients with a class one indication for implantable defibrillator. The author's divided study patients in three groups according to late gadolinium enhancement in QRS duration. Two negative indices that is late gadolinium enhancement negative and narrow QRS, one positive index with either late gadolinium enhancement positive or wide QRS or two positive indices late gadolinium positive and wide QRS and followed them for 3.8 years. Multiple variable Cox regression analysis identified to positive indices as significant predictors of all cause death. A hazard ratio of 4.29 p equals 0.026. Among the 317 patients with a class one indication for ICD, the five year event rate of sudden cardiac death or aborted sudden cardiac death was lowest in the two negative indices groups, 1.4%. With propensity score matching cohorts the two negative indices group had a significant lower event rate of sudden cardiac death or aborted sudden cardiac death than to two other groups hazard ratio 0.2, p equals 0.046.                                                 The authors concluded that the combination of late gadolinium enhancement in wide QRS provides additional prognostic stratification compared to late gadolinium enhancement status alone.                                                 In the next study, Matthew Sulkin and associates examined whether a novel local impedance measurement on an ablation catheter identifies catheter tissue coupling and is predictive of lesion formation. The author's first studied explanted hearts, 10 swine, and then in vivo 10 swine, using an investigational electro anatomical mapping system that measures impedance from an ablation catheter with mini electrodes incorporated into the distal electrode. Rhythmia and Intellanav, Boston Scientific.                                                 Explanted tissue was placed in a warmed 37 degree celsius saline bath mounted on a scale, and the local impedance was measured 15 millimeters away from the tissue to five millimeters of catheter tissue compression at multiple catheter angles. Lesions were created for 31 and 50 watts from 5 to 45 seconds for an N of 70. During in vivo valuation of the local impedance measurements of the myocardium 90 and blood pool 30 were guided by intracardiac ultrasound while operators were blinded to the local impedance data. Lesions were created with 31 and 50 watts for 45 seconds in the ventricle with an n of 72. The local impedance of myocardium, which was 119.7 ohms, was significantly greater than in blood pool 67.6 ohms the p of less than 0.01. Models that incorporate local impedance drop to predict lesion size had better performance that models incorporate force time integral r squared of 0.75 versus r squared of 0.54 and generator impedance drop r squared of 0.2 versus r squared of 0.58. Steam pops displayed a significantly higher starting local impedance and a larger change in local impedance compared to successful RF applications, p less than 0.01.                                                 The authors concluded that local impedance recorded for miniature electrodes provides a valuable measure of catheter tissue coupling and the change in local impedance is predictive of lesion formation during RF ablation.                                                 In the next paper, Boaz Avitall and associates found that the rising impedance recorded from a ring electrode placed two millimeters from the cryoballoon signifies ice formation covering the balloon surface and indicates ice expansion. The authors studied 12 canines in a total of 57 pulmonary veins, which were targeted for isolation. Two cryoapplications were delivered per vein with a minimum of 90 and a maximum 180 second duration. Cryoapplications was terminated upon reaching a 500 ohm change from baseline. Animals recovered 38 plus or minus six days post procedure, and the veins were assessed electrically for isolation. Heart tissue was histological examined. Extra cardiac structures were examined for damage. Pulmonary vein isolation was achieved in 100% of veins if the impedance reached 500 ohms in 90 to 180 seconds. When the final impedance was between 200 and 500 ohms within 180 seconds of freeze time, pulmonary vein isolation was achieved in 86.8%. For impedance of less than 200 ohms pulmonary vein isolation was achieved in 14%. No extra cardiac damage was recorded. The authors found that impedance rise of 500 ohms at less than 90 seconds with a freeze time of 90 seconds resulted in 100% pulmonary vein isolation.                                                 In our final papers Sally-Ann Clur and associates examined left ventricular isovolumetric relaxation time as the potential diagnostic marker for fetal Long QT Syndrome. Left ventricular isovolumetric contraction time, ejection time, left ventricular isovolumetric relaxation time, cycle length, and fetal heart rate were measured using pulse doppler wave forms in fetuses. Time intervals were expressed as percentage of cycle length, and the left ventricular myocardium performance index was calculated. Single measurements were stratified and compared between Long QT Syndrome fetuses and controls. Receiver operator curves were reformed for fetal heart rate in normalized left ventricular isovolumetric relaxation time. A linear mixed effect model including multiple measurements was used to analyze fetal heart rate, the left ventricular iso volume metric relaxation time, and the left ventricular myocardial performance index. There were 33 Long QT fetuses in 469 controls. In Long QT fetuses the left ventricular isovolumetric relaxation time was prolonged in all groups, p less than 0.001, as was the left ventricular isovolumetric relaxation time.                                                 The best cutoff to diagnose Long QT syndrome was the normalized left ventricular isovolumetric relaxation time greater than equal to 11.3 at less than or equal to 20 weeks, giving a sensitivity in 92% and a specificity of 70%. Simultaneous analysis of the normalized left ventricular isovolumetric relaxation time and fetal heart rate improved the sensitivity and specificity of Long QT Syndrome, AUC of 0.96. The normalized left ventricular isovolumetric relaxation time, the left ventricular myocardial performance index, and fetal heart rate trends differed significantly between Long QT Syndrome fetuses and controls throughout gestation.                                                 The authors concluded that left ventricular volumetric relaxation time is Prolonged QT fetuses. Findings of a prolonged normalize left ventricular isovolumetric relaxation time, and sinus bradycardia can improve the prenatal detection of fetal Long QT Syndrome.                                                 That's it for this month, but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcasts On the Beat. Take it away Suraj. Suraj Kapa:                          Thank you, Paul and welcome back to On the Beat were we will be summarizing hard-hitting articles across the entire electrophysiologic literature. Today we'll be starting within the realm of atrial fibrillation where we're review an article within the realm of anticoagulation and stroke prevention. Quon et al. published in last month's issue of JACC cardiac electrophysiology on anticoagulant use and risk of ischemic stroke and bleeding in patients with secondary atrial fibrillation. It is well known that use of anticoagulation in atrial fibrillation can reduce overall thromboembolic outcomes. However, its role in secondary atrial fibrillation is unclear. Thus, the authors sought to evaluate the effects anticoagulant use on stroke and bleeding risk. Amongst those where atrial fibrillation occurred in the setting of acute coronary syndrome, pulmonary disease, or sepsis. Amongst around 2300 patients evaluated retrospectively there was no evidence of a lower incidence of ischemic stroke among those treated with anticoagulants compared to those who are not.                                                 However, anticoagulation was associated with a higher risk of bleeding in those with new onset AF associated with acute pulmonary disease. The authors suggest as a result that there is unclear overall benefit for long-term anticoagulation in patients with presumed secondary atrial fibrillation. The difficulty in assessing this is how to define secondary atrial fibrillation. However, in many studies patients who developed in the setting of acute illness still had a high risk of developing quote unquote clinically significant AF in long-term follow-up. However, this was not necessarily absolute as many patients not necessarily develop AF that could be considered clinically significant. Thus, the clinical question that arises is: how long should we treat a patient with anticoagulation when they have presumed secondary atrial fibrillation. These data seem to suggest that there may be no net overall benefits. In other words, all-comers with secondary atrial fibrillation should not necessarily be forever treated with anti-coagulation. However, this slightly requires clinical trials to evaluate further.                                                 Next we delve into the realm of cardiac mapping and ablation where we view an article by Gaita et al. entitled 'Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow-up?', published in Europace last month. While pulmonary vein isolation is a widely accepted approach for treatment of atrial fibrillation, most reported studies review outcomes in terms of freedom of AF over a relatively short time period, generally two to five years. However longer term follow up is inconsistently reported. Gaita et al. sought to review 10 year outcomes amongst 255 patients undergoing ablation in a single center. They noted 52% remainder arrhythmia-free amongst a mixed cohort of both paroxysmal and persistent patients while 10% progressed to permanent atrial fiBrillation. They found that absence of increases in blood pressure, BMI, and fasting glucose was protective against an arrhythmia recurrence.                                                 These findings suggest that in a relatively small cohort of patients limited to a single center that even long-term outcomes after pulmonary vein isolation are generally quite good, exceeding 50%. However, future freedom from atrial fibrillation is heavily tied to control of other risk factors. In other words, if a patient is going to have poor control of diabetes, blood pressure, or gain weight, the benefit of their pulmonary vein isolation over long-term follow-up is likely less. These data thus highlight both the potential long-term benefit of PVI, but also the importance of counseling patients regarding the need for continued management and control of future and existing risk factors.                                                 Staying within the realm of atrial fibrillation we next review an article by Weng et al. entitled 'Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation' published in last month's issue of circulation. The probability of detecting atrial fibrillation in patients based on clinical factors and genetic risk is unknown. Weng et al. sought to clarify whether a combination of clinical and polygenic risk scores could be used to predict risk of developing atrial fibrillation over long-term followup in the Framingham Heart Study. Amongst 4,600 individuals, 580 developed incident atrial fibrillation and had an overall lifetime risk of developing atrial fibrillation of 37%. Those are the lowest risk tertile based on clinical risk factor burden and genetic predisposition had a lifetime risk of 22% versus 48% in the highest. Furthermore, a lower clinical risk factor burden was associated with delayed atrial fibrillation onset. In order to identify patients with atrial fibrillation, before negative sequelae such as stroke occur, patient and physician understanding of risk and monitoring needs is necessary. The fact is that it will be great to identify every single patient who has atrial fibrillation before they have a negative sequela of that atrial fibrillation such as ischemic stroke.                                                 However, performing continuous monitoring of all patients with potential negative sequelae of atrial fibrillation is extraordinarily difficult. The reason is it's excessively costly. We cannot monitor the entire population irrespective of whatever the risk factors are. However, if we're able to identify the highest risk cohorts early on before the atrial fibrillation onsets, this may offer opportunities for use of newer cheaper monitors. The work by Weng et al. suggests one such possible approach combines clinical and polygenic risk scores. Actionability of these data, however, remains to be seen and further validation other cohorts is necessary to clarify generalized ability.                                                 The next article we review is published in last month's issue of the Journal of American College of Cardiology by Lopes at al. entitled 'Digoxin and Mortality in Patients With Atrial Fibrillation. Lopes et al. sought to evaluate the impact of the Digoxin on mortality in patients with atrial fibrillation and the association with the Digoxin serum concentration and heart failure status. They value this association in over 17,000 patients. At baseline 32% were receiving Digoxin. Baseline Digoxin use did not associate with risk of death, but even in these patients a serum concentration of greater than 1.2 nanograms per milliliter was associated with a 56% increase in mortality risk. For each .5 nanogram per milliliter increase in oxygen concentration the hazard ratio increased by 19% for overall mortality. This was irrespective of heart failure status. Furthermore, in patients who are newly started in Digoxin over the follow-up period, the risk and death and sudden death was higher. These data suggests a significant risk associated with Digoxin use for management of atrial fibrillation irrespective of heart failure status. Furthermore, serum valleys above 1.2 require close consideration of dose de-escalation. Whether there is any optimal dose, however, from the study is unclear. These data amongst a host of prior data strongly suggest again strategic use of Digoxin  principally for the management of atrial fibrillation.                                                 Moving on within the realm of atrial fibrillation, we review an article published in last month's issue of Circulation Research by Yan et al. entitled Stress Signaling JNK2 Crosstalk with CaMKII Underlies Enhanced Atrial Arrhythmogenesis. In this more acellular based study the mechanism underlying atrial arrhythmogenesis associated with aging was evaluated. Yan et al. sought to figure out whether the stress response JNK in calcium mediated arrhythmias might contribute to atrial arrhythmogenesis in aged transgenic mouse models. They demonstrated significant increased activity of JNK2 and aging atria, those furthermore associated with rhythmic remodeling. This association was mediated through CaMKII and ryanodine receptor channel function, with activation of the former leading to increased calcium leak mediated by the ladder. This in turn related to increase atrial fibrillation likelihood. Identifying novel targets for atrial fibrillation therapy is critical. Given atrial fibrillation is a complex disease process related to a multitude of risk factors it can be assumed that the contribution of any single factor may be mediated through distinct mechanisms.                                                 Aging in particular as well regarded, but considered to be non-modifiable risk factor for atrial fibrillation. Identifying genes or pathways, the immediate aging associated fibrillation, may take the risk of aging as no longer a non-modifiable thing. The finding of the significance of JNK2 and associate downstream effects with AF risks and aging hearts may hold potential in offering unique therapeutic targets.                                                 Finally, within the realm of atrial fibrillation, we're viewing article by Chen et al. in last month's issue of the Journal of the American Heart Association entitled Association of Atrial Fibrillation With Cognitive Decline and Dementia Over 20 Years: The ARIC-NCS Study. Multiple studies have suggested a significant association between atrial fibrillation risk of dementia. However, these studies have limited time follow-up and were often done and predominantly white patients. Thus, the authors sought to use the data from ARIC, the Atherosclerosis Risk in Communities Neurocognitive Study, to assess the risk of cognitive decline associated with atrial fibrillation. Amongst over 12,000 participants, a quarter of whom are black and half of whom are white, they noted 2100 patients developed atrial fibrillation and 1,150 develop dementia over a 20 year follow up period.                                                 There was a significantly greater risk of cognitive decline amongst those who developed atrial fibrillation. In turn incident atrial fibrillation for the follow-up period was associated with a higher risk of dementia even after adjusting for other clinical and cardiovascular risk factors such as incidents that ischemic stroke. These data further strengthened prior evidence of a direct link between atrial fibrillation and risk of cognitive decline and dementia. Understanding this long-term risk raises the need to additionally identify approaches to prevent this occurrence, which in turn is dependent on understanding the underlying mechanisms. The finding that the risk of cognitive decline dementias independent of ischemic stroke events raises concern that either subclinical micro-embolic events or other factors may be playing a role in this risk and in turn raises question as to how best to prevent them. Until better understood, however, the question of whether the association is causal remains to be seen.                                                 Changing gears yet again, we now delve into the realm of ICDs, pacemakers and CRT. Published in last month, issue of Heart Rhythm Tarakji et al. published a paper entitled 'Unrecognized venous injuries after cardiac implantable electronic device transvenous lead extraction.' Overall risk of transvenous lead extraction includes that of potentially fatal venous laceration. The authors sought to evaluate the incidence of venous injury that may be unrecognized based on microscopic study of extracted leads. Amongst 861 leads obtained from 461 patients they noted 80 leads or almost 9%. Amongst 15% of patients showed segments vein on the lead body, most of which were transmural including the tissue layer. However, in terms of clinical significance, only 1% had need for emergent surgical intervention for clinically significant venous laceration. Risk factors for having the entire vein on the lead included age of lead, ICD leads, and the use of the laser sheath.                                                 These findings suggest that there may be a high incidence of subclinical venous injury after lead extraction though rarely resulting clinically apparent sequelae. As would be expected, venous injury, including transmural removal of portions of the vein traversed by the lead, was more common amongst older leads, which generally more often require laser sheets and ICD leads. The question is however, whether this carries any direct clinical implications. One they may be considered is the potential additive risk of an advancing new lead through the same venous channel, particularly in the setting of potential transmural venous injury that already exists.                                                 Next in last month's issue of Heart Rhythm we review an article by Sharma at al. entitled 'Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience.' The use of resynchronization therapy for treatment of patients with heart failure and wide QRS has been shown to offer morbidity and mortality benefits. However, many patients maybe non-responders, and recent studies on His bundle pacing of suggested potential clinical benefits. His bundle pacing essentially only requires one pacing catheter attached within the region of the His bundle Sharma et al. sought to evaluate the safety and success rates of His bundle pacing for patients who have either failed standard resynchronization therapy or in whom most tried as a primary intervention. They noted His bundle pacing was successful in 90% of patients with reasonable myocardial and His bundle capture thresholds. Patients in both groups exhibits significant narrowing of QRS morphology and improvement in left ventricular ejection fraction from a mean of 30 to 43%. However, a total of seven patients had lead related complications.                                                 These database on a retrospective analysis of two types of patients, those failing standard biventricular therapy, and those on whom his bundle pacing was attempted as a primary modality suggest overall safety and efficacy in a handful of experienced centers. The promise of His bundle pacing is that a may allow for more effective resynchronization than standard approaches. The high rate of success suggests that His bundle pacing maybe both safe and reasonable to pursue. However randomized trials across more centers are needed to fully prove its benefit, particularly as a primary modality of treatments.                                                 Next we review ICDs and chronic kidney disease. In last month's issue of JAMA cardiology by Bansal at al. entitled 'Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease.' While the benefit of ICDs in patients with low EF is widely recognized, modifying factors that may increase risk of death are not as well defined. These include things like advanced age and chronic kidney disease. Bansal et al. sought to evaluate long-term outcomes and ICD therapy in patients with chronic kidney disease. In retrospective study of almost 5,900 ambulatory patients amongst whom 1550 had an ICD, they found no difference in all cause mortality. However, ICD placement was associated with an increased risk of subsequent hospitalization due to heart failure or any cause hospitalization.                                                 In light of recent studies such as DANISH the robust sense of ICD benefit is being questioned. One of the thoughts for the absence of similar benefit to prior studies lies in the improving care of ambulatory heart failure patients. In patients with chronic kidney disease several questions rises to the risk with ICD, including infectious risk in dialysis patients and the concomitant mortality risk with renal dysfunction. The author suggested in retrospective study, no incremental benefit of ICDs in patients with chronic kidney disease and perhaps some element of added risk is related to hospitalization. However, this study has several limitations. It is retrospective and many patients received ICDs may have been perceived to be sicker in some way. Thus care must be taken in interpretation, but consideration of randomized studies to adjudicate benefit are likely necessary.                                                 Finally, within the realm of devices, we reviewed an article by Tayal et al. entitled "Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS Complexes.' publishing the Journal of American College of Cardiology last month. Several parameters have been stressed to identify benefit of resynchronization therapy in patients with wide QRS include cross correlation analysis with tissue doppler imaging. However, many patients may have evidence in mechanical dyssynchrony even in the absence of an apparent wide QRS thus Tayal et al. sought to evaluate the benefit of resynchronization therapy amongst 807 patients with heart failure and a narrow QRS mean criteria in a randomized study. Of the 807 46% had delayed mechanical activation. Those without delay mechanical activation had underwent we standardization therapy and were associated with worse overall outcomes likely due to new delayed mechanical activation potentially related to CRT pacing. These data support the absence of a role for resynchronization therapy in patients with a narrow QRS. This is expected as resynchronization therapy likely offers the most benefit in patients with mechanical dyssynchrony that results from electrical dyssynchrony.                                                 Since by its very nature resynchronization therapy relies on non physiologic cardiac pacing thus compared to normal cardiac activation the nature of resynchronization pacing is desynchronization. These data support the absence of a role for resynchronization therapy in patients with heart failure and narrow QRS complexes.                                                 Moving on to cellular electrophysiology we review an article by Kozasa et al. published in last month's issue of Journal of Physiology entitled 'HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node.' Heart rate is controlled by an interplay between sympathetic and parasympathetic components. In turn HCN4 abnormalities have been implicated in congenital sick sinus syndrome. The authors sought to clarify the contribution of HCN4 to sinus node autonomic regulation. They created a novel gain-of-function mouse where the HCN4 activity could be modulating from zero to three times normal. They then evaluated ambulatory heart-rate variability and responsive heart rate to vagus nerve stimulation. They found HCN4 over-expression did not increase heart rate, but attenuated heart-rate variability. It also attenuated bradycardic response to vagus nerve stimulation. Knockdown of HCN4 in turn lead to sinus arrhythmia and enhanced parasympathetic response. These data suggest HCN4 attenuates sinus node response to vagal stimuli thus stabilizing spontaneous firing of the node. The clinical application of this remain to be seen but are maybe important in that they highlight a mechanism for a heretofore poorly understood mechanism for how exactly HCN4 abnormalities may lead to sick sinus syndrome.                                                 Within the realm of ventricular arrhythmias we highlighted a number of articles published this past month. The first article we review was published in last month's issue of JACC clinical electrophysiology, entitled characterization of the electrode atomic substrate and cardiac sarcoidosis: correlation with imaging findings of scarring inflammation published by [inaudible 00:41:40] et al. In patients with cardiac sarcoidosis one of the questions is how to define the electronic atomic substrate, particularly before we entered the electrophysiology laboratory. Both active inflammation and replacement fibrosis maybe be seen in patients. The authors evaluated in 42 patients with cardiac sarcoidosis, the association between an abnormal electrograms and cardiac imaging findings including PET and Computed Tomography, as well as Cardiac MRI. They noted that amongst these 40 patients, a total of 21,000 electrograms were obtained, and a total of 19% of these were classified as abnormal. Most of the abnormalities occurred in the basal paravalvular segments and intraventricular septum. They further noted that many of these abnormalities in terms of electrograms were located outside the low voltage areas, particularly as it relates to fractionation. In about 90% of patients they notice late gadolinium enhancements and they noted abnormal FDG uptakes suggesting active inflammation in about 48%.                                                 However, it should be noted that only 29 of the 42 patients underwent cardiac imaging. Segments with abnormal electrograms tended to have more late gadolinium enhancement evidence scar transmurality, and also they noted that the association of abnormal PET scan did not necessarily occur with abnormal electrograms. Thus, they concluded that in patients with cardiac sarcoidosis and ventricular tachycardia pre-procedural imaging with cardiac MRI could be useful in detecting electroanatomic map abnormalities that may in turn be potential targets for substrate ablation. However, they were more likely associated with more scar transmurality and lower degrees of inflammation on PET scanning. These data are important in that they highlight potential non-invasive means by which to understand where substrate might occur in patients with the cardiac sarcoidosis. It is well recognized that cardiac sarcoidosis is associated with increased risk of ventricular arrhythmias. These risks have increased ventricular arrhythmias, might be targetable with ablation. Newer therapies might even offer non invasive means by which to perform ablation in patients best. Thus if we could identify non based on mechanisms of identifying the substrate, this will be even more critical.                                                 The critical findings of this particular paper lie in noting that most of the abnormalities still is in intra ventricular sePtum in basal segments, and also that it is MRI in late gadolinium enhancement and associates more with the abnormal electrograms. Interestingly, the absence of inflammation correlating with the presence of more abnormal electrograms suggests that it is not so much the act of inflammation as being reflected in the endocardial map, but the existence of scar.                                                 Next, again within JACC clinical electrophysiology we review an article by Porta-Sánchez et al. entitled 'Multicenter Study of Ischemic Ventricular Tachycardia Ablation With Decrement Evoked Potential Mapping With Extra Stimulus.' The authors sought to conduct a multicenter study of decrement evoked potential base functional tech ventricular tachycardia substrate modification to see if such mechanistic and physiologic strategies could result in reduction in VT burden. It is noted that really only a fraction of the myocardium in what we presume to be substrate based on the presence of low voltage areas are actually involved in the initiation and perpetuation of VT. Thus if we can identify the critical areas within the presumed substrate for ablation, this would be even a better way of potentially honing in on our targets. They included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping fractionated late potentials were targeted and an extra stimulus was provided to determine which display decrements. All patients underwent DEEP focus ablation with elimination being correlated with VT non-inducibility after radio-frequency ablation. Patients were predominantly male, and they noted that the specificity of these decrement evoked potentials to detect the cardiac isthmus for VT was better than that of using late potentials alone. They noted 15 of 20 patients were free of any VT after ablation of these targets over six months of follow-up, and there was a strong reduction in VT burden compared to six months pre ablation.                                                 They concluded that detriment evoked potential based strategies towards ablation for ventricular tachycardia might identify the functional substrate and those areas most critical to ablation. They in turn regarded that by its physiologic nature it offers greater access to folks to ablation therapies.                                                 This publication is important in that it highlights another means by which we can better hone in on the most critical regions for substrate evaluation in patients with ventricular tachycardia. The fact is more extensive ablation is not necessarily better and might result in increased risk of harm if we think about the potential effects of longer ablations or more ablation lesions. Thus if we could identify ways of only targeting those areas that are most critical to the VT circuits, we could perhaps short and ablation procedural time, allow for novel ways of approaching targeted ablation with limited amounts of ablation performed, or perhaps even improve overall VT outcomes by knowing the areas that are most critical to ensure adequate ablation therapy provided. However, we need to understand that this is still a limited number of patients evaluated in a non randomized manner. Thus whether or not more extensive ablation performed might have been better is as of yet unclear                                                 Staying within the realm of ventricular tachycardia we review an article published in last month's issue of Heart Rhythm by Winterfield et al. entitled the 'Impact of ventricular tachycardia ablation on healthcare utilization.' Catheter ablation of atrial tachycardia has been well accepted to reduce recurrent shocks in patients with ICDs. However, this is a potentially costly procedure, and thus effect on overall long-term health care utilization remains to be seen. The authors sought to evaluate in a large scale real world retrospective study the effect of VT ablation on overall medical expenditures in healthcare utilization. A total 523 patients met study inclusion criteria from the market scan database. After VT ablation median annual cardiac rhythm related medical expenditures actually decreased by over $5,000. Moreover the percentage of patients with at least one cardiac rhythm related hospitalization an ER visit decreased from 53 and 41% before ablation respectively, to 28 and 26% after ablation. Similar changes we're seeing in number of all cause hospitalizations and ER visits. During the year before VT ablation interestingly there was an increasing rate of healthcare resource utilization, but a drastic slowing after ablation.                                                 These data suggests that catheter ablation may lead to reduced hospitalization in overall healthcare utilization. The importance of these findings lies in understanding why we do the things we do. We can provide a number of therapies to patients, but we seek two different effects. One is the individual effect of improving their particular health. The second thing is trying to avoid increasing healthcare expenditures on a population level and making sure resources are utilized. If we can reduce recurrent hospitalizations and overall healthcare expenditure in patients by providing a therapy in addition to provide individual benefit, this is the optimal situation. These data suggests that VT ablation might provide such a benefits, that in fact it reduces overall healthcare utilization while improving overall outcomes.                                                 Next and finally within the realm of ventricular arrhythmias, we review more on the basic side the role of Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias, published by Verdonschot et al. in last month's issue of European Heart Journal. It is known now that truncating Titin variants might be the most prevalent genetic cause of dilated cardiomyopathy. Thus, the authors sought to study clinical parameters and long term outcomes related to Titin abnormalities in dilated cardiomyopathy. They reviewed 303 consecutive and extensively phenotype dilated cardiomyopathy patients who underwent cardiac imaging, Holter monitoring, and endomyocardial biopsy and in turn also underwent DNA sequencing of 47 cardiomyopathy associated genes. 13% of these patients had Titin abnormalities. Over long-term followup they noted that these patients had increased ventricular arrhythmias compared to other types of dilated cardiomyopathy, but interestingly, they had similar survival rates. Arrhythmias in those Titin abnormal patients were most prominent in those who were subjected to an additional environmental trigger, including viral infection, cardiac inflammation, other systemic disease or toxic exposure. They also noted the cardiac mass was relatively reduced in titan admirable patients.                                                 They felt that all components of the mitochondrial electron transport chain we're simply up-regulated in Titin abnormal patients during RNA sequencing and interstitial fibrosis was also augmented. As a result, they concluded that Titin variant associated dilated cardiomyopathy was associated with an increased risk of ventricular arrhythmias, and also with more interstitial fibrosis. For a long time we have reviewed all non ischemic cardiomyopathy as essentially equal. However, more recent data has suggested that we can actually hone in on the cause. In turn, if we hone in on the cause, we might be able to understand the effects of specific therapies for ventricular arrhythmias based on that underlying cause. Patchy fibrosis might not be as amenable, for example, to ablation as discreet substrate that we might see in infarct related VT. Understanding the relative benefit in very specific types of myopathies might hold benefit in understanding how to, one, risk stratify these patients, and two, understand what type of therapy, whether pharmacologic or ablative, might result in greatest benefit to the patients.                                                 Changing gears entirely now to the role of genetics, we review multiple articles in various genetic syndromes published this past month. First, we reviewed an article by Providência et al. published in the last month's issue of heart entitled 'Impact of QTc formulae in the prevalence of short corrected QT interval and impact on probability and diagnosis of short QT syndrome.' The authors sought to assess the overall prevalence of short corrected QT intervals and the impact on diagnosis of short QT syndrome using different methods for correcting the QT interval. In this observational study they reviewed the sudden cardiac death screening of risk factors cohorts. They then applied multiple different correction formulae to the ECGs. They noted that the prevalence of individuals with the QTc less than 330 and 320 was extremely low, namely less than .07 and .02% respectively. They were also more frequently identified using the Framingham correction. The different QTc correction formulae could lead to a shift of anywhere from 5 to 10% of individuals in the cohort overall.                                                 They further noted, that based on consensus criteria, instead of 12 individuals diagnosed with short gut syndrome using the Bazett equation, a different number of individuals would have met diagnostic criteria with other formulae, 11 using Fridericia, 9 with Hodges, and 16 using the Framingham equation. Thus, they noted that overall the prevalence of short QT syndrome exceedingly low and an apparently healthy adult population. However, reclassification as meeting criteria might be heavily dependent on which QT correction formula is used. The importance of these findings is that not all QTs are created equal.                                                 Depending on how you compute the QT interval in which formula to use may affect how you actually risk characterize a patient. Unfortunately, these data do not necessarily tell us which is the right formula, but this highlights that it might be relevant to in the future evaluate the role of different formulae and identifying which is the most necessary to classify a patient.                                                 Moving on to an article published in last month's issue of the journal of clinical investigation by Chai et al. we review an article entitled 'Physiological genomics identifies genetic modifiers of Long QT Syndrome type 2 severity.' Congenital Long QT Syndrome is a very well recognized, inherited channelopathy associated life-threatening arrhythmias. LQTS type 2 is specifically caused by mutations in casein to encoding the potassium channel hERG. However, even with the mutation not all patients exhibit the same phenotype. Namely some patients are more at risk of life threatening arrhythmias in spite of having the same mutation as others who do not exhibit the same severity phenotype. The authors sought to evaluate whether specific modifiable factors within the remaining genetic code might be modifying the existing mutation. Thus, they sought to identify contributors to variable expressivity in an LQT 2 family by using induced pluripotent stem cell derived cardiomyocytes and whole exome sequencing in a synergistic manner.                                                 They found that patients with severely effected LQT 2 displayed prolonged action potentials compare to sales from mildly effected first-degree relatives. Furthermore, stem cells derived from patients were different in terms of how much L-type calcium current they exhibited. They noted that whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2 in those patients with more severe phenotypes in whom greater L-type calcium current was seen. This suggests that abnormalities or even polymorphisms in other genes might be modifying the risk attributed to by mutations in the primary gene. This showcases the power of combining complimentary physiological and genomic analysis to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. This is extraordinarily critical as we understand on one level that when we sequence a monogenic disorder that there might exist variants of uncertain significance, namely they have not been classified as disease causing, but could be. In turn, we also recognize that mutations in a family might effect different relatives differently. However, why this is has been relatively unclear.                                                 If we can understand and identify those patients who are most at risk of dangerous abnormal rhythms, this will be useful in how much to follow them, and what type of therapy to use in them. The fact that other genes might modify the risk even in the absence of specific mutations, suggests that novel approaches to characterizing the risk might help for the risk modified patients classification in general. Clinical use, however, remains to be seen.                                                 Moving on from long QT, we evaluate 'The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy' noted in last month's issue of the Journal of American College of Cardiology and published by Papadakis et al. It is well known, the negative autopsies are not uncommon in patients, however, families might be wondering how at risk they are. Thus, the authors sought to assess the impact of systematic ajmaline provocation testing using high right precordial leads on the diagnostic yield Brugada syndrome in a large cohort of Sudden Arrhythmic Death syndrome families. Amongst 303 families affected by Sudden Arrhythmic Death Syndrome evaluation was done to determine whether or not there was a genetic inherited channelopathy cause. An inherited cardiac disease was diagnosed in 42% of the families and 22% of relatives Brugada syndrome was the most prevalent diagnosis overall amongst 28% of families. Ajmaline testing was required, however, to unmask the Brugada Syndrome in 97% of diagnosed individuals. Furthermore, they use of high right precordial leads showed a 16% incremental diagnostic yield of ajmaline testing for diagnosing Brugada syndrome.                                                 They further noted that a spontaneous type 1 regard or pattern or a clinically significant rhythmic event developed in 17% of these concealed regardless syndrome patients. The authors concluded the systematic use of ajmaline testing with high right precordial leads increases the yield of Brugada Syndrome testing in Sudden Arrhythmic Death Syndrome families. Furthermore, they noted that assessments should be performed in expert centers or patients could also be counseled appropriately. These findings are important and one of the big questions always becomes how aggressively to test family members of patients or of deceased individuals who experienced sudden arrhythmic death. Many of these patients have negative autopsies, and genetic autopsy might not be possible due to lack of tissue or blood products that can be adequately tested.                                                 The data here suggest that amongst a group of 303 sudden arrhythmic death, families that Brugada Syndrome is by far the most frequent diagnosis. If an inherited cardiac disease was identified. In turn, it is not ECG alone or echo alone that helps identify them, but requires drug provocation testing in addition to different electrode placements. Whether or not this will consistently offer benefit in patients in general or my result in overcalling remains to be seen next within the realm of genetic predisposition.                                                 We view an area where we don't know if there's a genetic predisposition in article published by Tester et al. entitled Cardiac Genetic Predisposition in Sudden Infant Death Syndrome in last month's issue of the journal of american college of cardiology. Sudden Infant Death Syndrome is the leading cause of post-neonatal mortality and genetic heart diseases might underlie some cases of SIDS. Thus the authors sought to determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for Sudden Infant Death Syndrome. They study the largest cohort to date of unrelated SIDS cases, including a total of 419 individuals who underwent whole exome sequencing and targeted analysis for 90 genetic heart disease susceptibility genes. Overall, 12.6% of these cases had at least one potentially informative genetic heart disease associated variants. The yield was higher in those mixed European ancestry than those of European ancestry.                                                 Infants older than four months were more likely to host a potentially informative gene. Furthermore, they noted that only 18 of the 419 SIDS cases hold a [inaudible 01:01:26] or likely pathogenic variant. So in other words, only 4% of cases really had a variant that they could say was distinctly pathogenic or likely pathogenic. Thus, overall, the minority of SIDS cases have potentially informative variant in genetic heart disease susceptibility gene, and these individuals were mostly in the 4 to 12 month age group. Also, only 4% of cases had immediately clinically actionable variance, namely a variant, which is well recognized as pathogenic and where we could actually say that a specific therapy might have had some effect. These findings can have major implications for how best to investigate SIDS cases in families. It might suggest that SIDS cases where the individual was older, nearly 4 to 12 months of age might have a greater yield in terms of identifying variance.                                                 While this might not affect the deceased in fit, it might affect, families are planning on having another child in whom a variant can be identified.                                                 Finally, within the realm of genetics, we review an article published in last month's issue of Science Advances by Huang. et al. entitled 'Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations'. Mutations that induce loss of function of human KCNQ1 underlie the Long QT Syndrome type 1. While hundreds of mutations have been identified the molecular mechanism by which they result in impaired function are not as well understood. The authors sought to investigate impact of 51 specific variants located within the voltage sensor domain and emphasized effect on cell surface expression, protein folding, and structure. For each variant efficiency of trafficking of the plasma membrane, impact of proteasome inhibition, and protein stability were evaluated. They noted that more than half of the loss of function mutations were seen to destabilized structure of the voltage sensor domain, generally accompanied by mistrafficking and degradation by the proteasome.                                                 They also noted that five of the folding defective Long QT Syndrome mutant sites were located in the S0 helix, where they tend to interact with a number of other loss of function mutation sites in other segments of the voltage sensor domain. They suggested these observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilized KCNQ1 overall. They also note the importance of these findings is that mutation-induced destabilization of membrane proteins may be a more common cause of disease functioning in humans. The importance of these findings lies in better understanding why specific mutations lead to appa

Paul Wang:         Welcome to the monthly podcast “On The Beat”, for Circulation: Arrhythmia and Electrophysiology. I am 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.                                 In our first article, Adetola Ladejobi and associates studied 1,433 patients, between 2000 and 2012, who were discharged alive after sudden cardiac arrest. A reversible and correctable cause was identified in 792 patients, or 55%. A reversible cause for sudden cardiac arrest was defined as significant electrolyte or metabolic abnormality, evidence of acute myocardial infarction or ischemia, recent initiation of antiarrhythmic drug, or illicit drug use, or other reversible circumstances.                                 Of the 792 sudden cardiac arrest survivors, due to reversible or correctable cause, 207 or 26% of the patients received an ICD after their indexed sudden cardiac arrest. During a mean follow-up of 3.8 years, 319 or 40% of patients died. ICD implantation was highly associated with a lower all-cause mortality, p < 0.001, even after correcting for unbalanced baseline characteristics.                                 In subgroup analyses, only patients with sudden cardiac arrest, were not associated with myocardial infarction, extracted benefit from the ICD, p < 0.001.                                 The authors concluded that in survivors of sudden cardiac arrest, due to a reversible and correctable cause, ICD therapies associated with lower all-cause mortality, except if the sudden cardiac arrest was due to myocardial infarction.                                 Further prospect of multi-center randomized control trials will be needed to confirm this observation.                                 In our next study, Carlo Pappone and associates, studied 81 patients with persistent atrial fibrillation, randomized to undergo high density electrophysiological mapping, to identify repetitive regular activities, before modified circumferential pulmonary vein ablation, or modified circumferential pulmonary vein ablation alone. The primary endpoint was freedom from arrhythmia recurrence at one year.                                 In the 81 patients with persistent atrial fibrillation, there were 479 regions exhibiting repetitive regular activities in these patients, or 5.9 repetitive regular activities per patient. There were 232 regions in the mapping group, which consisted of 41 patients, and 247 regions in the control group, consisting of 40 patients. Overall, 39% of the repetitive regular activities were identified within pulmonary veins, whereas 61% were identified in non-pulmonary vein regions.                                 Mapping-guided ablation resulted in higher arrhythmia termination rate, as compared to conventional strategy, 61% vs. 30%, p < 0.007. Total RF duration, mapping, and fluoroscopy times were not significantly different between the groups. No major procedure related adverse events occurred.                                 After one year, 73% of the mapping group of patients were free of recurrences, compared to 50% of the control group, p = 0.03.                                 The authors concluded that targeted ablation of regions showing repetitive regular activities provided adjunctive benefit in terms of arrhythmia freedom at one year in treatment of patients with persistent atrial fibrillation. These findings should be confirmed by additional larger randomized multi-centered studies.                                 In the next article, Maciej Kubala and associates examine repolarization abnormalities in 40 patients with arrhythmogenic right ventricular cardiomyopathy, comparing extent and location of abnormal T-waves of one millimeter or greater in depth, downsloping elevated ST segment in two or more adjacent leads to the area and location of endocardial bipolar and unipolar, and epicardial bipolar voltage abnormalities. They found an abnormal unipolar right ventricular endocardial area of 33.4% with presence in eight patients without negative T-waves. Patients with negative T-waves extending beyond V3, seen in 20 patients, had larger low bipolar and unipolar endocardial areas, and larger epicardial low bipolar areas, compared to those with negative T-waves limited to leads V1 to V3.                                 ECG localization of negative T-waves regionalized to the location of substrate. Patients with downsloping elevated ST segment, all localized to leads V1, V2 had more unipolar endocardial abnormalities involving outflow in mid-right ventricle, compared to patients without downsloping elevated ST segment.                                 The authors concluded that in arrhythmogenic right ventricular cardiomyopathy, abnormal electric current areas were proportional to the extent of T-wave inversion on the 12 lead electrocardiogram. Marked voltage abnormalities can exist without repolarization changes. Downsloping elevated ST segment patterns in V1 and V2 occurs with more unipolar endocardial voltage abnormalities, consistent with more advanced trans neural disease.                                 In the next manuscript, Teresa Oloriz and associates examine the timing and value of program stimulation after catheter ablation for ventricular tachycardia. They performed 218 program ventricular stimulations six days after ablation in 210 consecutive patients, 48% with ischemic cardiomyopathy in the median left ventricular ejection fraction of 37%. After ablation, ICDs were programmed according to NIPS results. Class A were noninducible, Class B non documented inducible VT, and Class C documented inducible VT. Concordance between the programmed ventricular stimulation at the end of the procedure and at six days was 67%. The positive predictive value and negative predictive value were higher for the programmed ventricular stimulation at day six. Ischemic patients and those with preserved ejection fraction showed the highest negative predictive value.                                 Among noninducible patients at the end of the procedure, but inducible at day six, 59 patients had VT recurrence at one year follow-up. Recurrences were 9% when both studies were noninducible. There were no inappropriate shocks, incidents of syncope with 3%, none harmful. The rate of appropriate shocks per patient per month according to NIPS was significantly reduced, comparing the month before and after the ablation.                                 The authors concluded that programmed ventricular stimulation at day six predicts VT recurrence.                                 In the next study, Tor Biering-Sørensen and associates examined ECG global electrical heterogeneity, GEH, in its longitudinal changes, are associated with cardiac structure and function, in their Atherosclerosis Risk and Community study, ARIC, consisting of 5,114 patients, 58% which were female and 22% African Americans. Using the resting 12-lead ECGs, and echocardiographic assessments of left ventricular ejection fraction, global strain, left ventricular mass index, end diastolic volume index, end systolic volume index at visit five.                                 Longitudinal analysis included ARIC participants with measured GEH at visits one to four. GEH was quantified by spatial ventricular gradient, the QRST angle, and the sum of the absolute QRST integral. Cross sectional and longitudinal regressions were adjusted for manifest subclinical cardiovascular disease.                                 Having four abnormal GEH parameters was associated with a 6.4% left ventricular ejection fraction decline, a 24.2 gram/meter square increase in left ventricular mass index, a 10.3 milliliter/meter square increase in left ventricular end diastolic volume index, and a 7.8 milliliter/meter square increase in left ventricular end systolic index. All together, clinical and ECG parameters accounted for approximately one third of the left ventricular volume in 20% of the systolic function variability.                                 The associates were significantly stronger in patients with subclinical cardiovascular disease. The QRST integral increased by 20 millivolts/meter second for each three year period participants who demonstrated left ventricular dilatation at visit five. Sudden cardiac death victims demonstrated rapid GEH worsening, while those with left ventricular dysfunction demonstrated slow GEH worsening.                                 The authors concluded that GEH is a marker of subclinical abnormalities in cardiac structure and function.                                 In the next manuscript, Takumi Yamada and associates studied 19 patients with idiopathic ventricular arrhythmias, originating in the parietal band in 14 patients, in the septal band in 5 patients. Among 294 consecutive patients with right ventricular arrhythmia origins, parietal band and septal band ventricular arrhythmias exhibited a left bundle branch block, with left inferior in 12 patients', superior in 2 patients' axes, in left or right inferior axis pattern in four and one patients respectively.                                 In Lead 1, all parietal band ventricular arrhythmias exhibited R-waves, while septal band ventricular arrhythmias often exhibited S-waves. A QS pattern in lead AVR, in the presence of a knock in the mid QRS were common in all infundibular muscle ventricular arrhythmias. During infundibular muscle ventricular arrhythmias, a far-field ventricular electrogram, with an early activation, was always recorded in the His bundle region, regardless of the location of ventricular arrhythmia regions. With 9.2 radiofrequency applications in a duration of 972 seconds, catheter ablation was successful in 15 of the 19 patients. Ventricular arrhythmias recurred in four patients during a fallout period of 43 months.                                 In the next paper, Uma Mahesh Avula and associates examine the mechanisms underlying spontaneous atrial fibrillation, in an Ovine model of left atrial myocardial infarction. The left atrial myocardial infarction was created by ligating the atrial branch of the left anterior descending artery. ECG loop recorders were implanted to monitor atrial fibrillation episodes.                                 In seven sheep, Dantrolene, a Ryanodine receptor blocker, was administered in vivo, during the observation period. The left atrial myocardial infarction animals experienced numerous episodes of atrial fibrillation during the eight day monitoring period, that were suppressed by Dantrolene. Optical mapping showed spontaneous focal discharges originating through the ischemic/normal-zone border. These spontaneous focal discharges were calcium driven, rate dependent, and enhanced by isoproterenol, but suppressed by Dantrolene.                                 In addition, these spontaneous focal discharges initiated atrial fibrillation-maintaining reentrant rotors anchored by marked conduction delays at the ischemic/normal-zone border. Nitric oxide synthase one protein expression decreased in ischemic zone myocytes, or NADPA oxidase in xanthine oxidase enzyme activities in reactive oxygen species increased. Calmodulin aberrantly increased, Ryanodine binding to cardiac Ryanodine receptors in the ischemic zone. Dantrolene restored the physiologically binding of Calmodulin to the cardiac Ryanodine receptors.                                 The authors concluded that atrial ischemia causes spontaneous atrial fibrillation episodes in sheep, caused by spontaneous focal discharges that initiate re-entry. Nitroso redox imbalance in the ischemic zone is associated with intensive reactive oxygen species production, and altered the Ryanodine receptor responses to Calmodulin. Dantrolene administered normalize the Calmodulin response and prevents left atrial myocardial infarction, spontaneous focal discharges in atrial fibrillation initiation.                                 In the next study, Wouter van Everdingen and associates examine the use of QLV for achieving optimal acute hemodynamic response to CRT with a quadripolar left ventricular lead. 48 heart failure patients with left bundle branch block were studied. Mean ejection fraction 28%, mean QRS duration 176 milliseconds. Immediately after CRT implantation, invasive left ventricular pressure volume loops were recorded during biventricular pacing, with each separate electrode at four atrial ventricular delays.                                 Acute CRT response, measured as a change in stroke work compared to intrinsic conduction, was related to the intrinsic interval between the Q on the electrocardiogram and the left ventricular sensing delay, that is the QLV, normalized for the QRS duration, resulting in QLV over QRS duration in the electrode position.                                 QLV over QRS duration was 84% and variation between the four electrodes was 9%. The change in stroke work was 89% and varied by 39% between the electrodes. In univariate analysis, an anterolateral or lateral electrode position in a high QLV to QRS duration ratio had a significant association with a large change in stroke work, all P less than 0.01.                                 In a combined model, only QLV over QRS duration remained significantly associated with a change in stroke work, P less than 0.5. However, a direct relationship between QLV over QRS duration in stroke work was only seen in 24 patients, while 24 other patients had an inverse relation.                                 The authors concluded that a large variation in acute hemodynamic response indicates that the choice of stimulated electrode on the quadripolar electrode is important. Although QLV to QRS duration ratio was associated with acute hemodynamic response at a group level, it cannot be used to select the optimal electrode in the individual patient.                                 In the next study, Antonio Pani and associates conducted a multi-centered prospective study evaluating the determinance of zero-fluoroscopy ablation of supraventricular arrhythmias. They studied 430 patients with an indication for EP study and/or ablation of SVT. A procedure was defined as zero-fluoroscopy when no fluoroscopy was used. The total fluoroscopy time inversely was related to number of procedures previously performed by each operator since the study start. 289 procedures, or 67%, were zero-fluoro. Multi-variable analyses identified as predictors of zero-fluoro was the 30th procedure for each operator, as compared to procedures up to the ninth procedure, the type of arrhythmia, AVNRT having the highest probability of zero-fluoro, the operator, and the patient's age. Among operators, achievement of zero-fluoro varied from 0% to 100%, with 8 operators, or 23%, achieving zero-fluoro in 75% of their procedures. The probability of zero-fluoro increased by 2.8% as the patient's age decreased by one year. Acute procedural success was obtained in all cases.                                 The authors concluded that the use of 3D mapping completely avoided the use of fluoroscopy in most cases, with very low fluoro time in the remaining, and high safety and effectiveness profiles.                                 In the next paper, Demosthenes Katritsis and associates examine the role of slow pathway ablation from the septum as an alternative to right-sided ablation. Retrospectively, 1,342 undergoing right septal slow pathway ablation for AV nodal reentry were studied. Of these, 15 patients, 11 with typical and 4 with atypical AVNRT, had a left septal approach following unsuccessful right sided ablation, that is, the righted left group. In addition, 11 patients were subjected prospectively to a left septal only approach for slow pathway ablation, without previous right septal ablation, that is, left group. Fluoroscopy times in the right and left group, and the left groups were 30.5 minutes and 20 minutes respectively, P equals 0.6. The rate of [inaudible 00:18:24] current delivery time for comparable, 11.3 minutes and 10.0 minutes respectively.                                 There are no additional ablation lesions at other anatomical sites in either group, and no cases of AV block were encountered. Recurrence rate for arrhythmias in the right and left group was 6.7% and 0% in the left group, in the three months following ablation.                                 The authors concluded that the left septal anatomical ablation of the left inferior nodal extension is an alternative to ablation of both typical and atypical AV nodal reentry when ablation at the right posterior septum is ineffective.                                 In our next study, Mark Belkin and associates reported prior reports of new-onset device-detected atrial tachyarrhythmias. Despite the clear association between atrial fibrillation and the risk of thromboembolism, the clinical significance of new-onset device-detected atrial tachyarrhythmias and thromboembolism remains disputed.                                 The authors aim to determine the risk of thromboembolic events in these patients. Using the Ovid Medline, Cochrane, SCOPUS databases to identify 4,893 reports of randomized control trials, perspective or retrospective studies of pacemaker and defibrillator patients reporting the incidence of device detected atrial tachyarrhythmias.                                 The authors examine 28 studies, following a total of 24,984 patients. They had an average age of 69.9 years and a mean study duration of 21.8 months. New-onset device-detected atrial tachyarrhythmias was observed in 23% of patients. Among nine studies, consisting of 8,181 patients, reporting thromboembolism, the absolute incidence was 2.1%. Thromboembolic events were significantly greater among patients with new-onset device-detected arrhythmias, with a relative risk of 2.88, compared to those who had less than one minute of tachyarrhythmias, 1.77 risk ratio.                                 The authors concluded that new-onset device-detected atrial tachyarrhythmias is common, affecting close to one quarter of all patients with implanted pacemakers and defibrillators.                                 In our last paper, Sanghamitra Mohanty and associates performed a meta-analysis systematically evaluating the outcome of pulmonary vein isolation with and without thermoablation in patients with atrial fibrillation. For pulmonary vein ablation alone, only randomized trials conducted in the last three years reporting single procedure success rates, off antiarrhythmic drugs at 12 months or greater follow-up were included. In the PVI plus FIRM group, all public studies reporting a single procedure off antiarrhythmic drug success rate with at least one year follow-up were identified.                                 Meta-analytic estimates were derived, using the DerSimonian and Laird Random-effects Models, and pooled estimates of success rates. Statistical heterogeneity was assessed using the Cochran Q test and I-square. Study quality was assessed with the Newcastle-Ottawa Scale.                                 15 trials were included, 10 with PVI plus FIRM, with 511 patients, non-randomized perspective design, and 5 pulmonary vein isolation-only trials, consisting of 295 patients, all randomized.                                 All patients in the pulmonary vein only trials had 100% non paroxysmal atrial fibrillation, except for one study, and no prior ablations. About 24% of the PVI plus FIRM patients had paroxysmal atrial fibrillation.                                 After 15.9 months of follow-up, the off antiarrhythmic drug pooled success was 50% with FIRM plus PVI, compared to 58% in the PVI alone. The difference in the effect size between the groups was not statistically significant. No significant heterogeneity was observed in this meta-analysis.                                 The authors concluded that the overall pooled estimate did not show any therapeutic benefit of PVI FIRM over PVI alone.                                 That's it for this month, but keep listening. Suraj Kapa will be surfing all journals for the latest topics of interest in our field. Remember to download the podcast On The Beat. Take it away, Suraj. Suraj Kapa:          Thank you, Paul, and welcome back to “On The Beat”. Again, my name is Suraj Kapa and I'm here to review with you articles across the cardiac electrophysiology literature that were particularly hard hitting in the month of February.                                 To start, we review the area of atrial fibrillation, focusing on anticoagulation. Reviewing an article published in this past month's issue of the Journal of the American Heart Association, by Steinberg et al., entitled Frequency and Outcomes of Reduced Dose Non-Vitamin K Antagonist Anticoagulants, results from ORBIT AF II. The ORBIT AF II registry, also called the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, is a prospective national observational registry of AF patients.                                 The author sought to describe the frequency, appropriateness, and outcomes of patients prescribed reduced doses of NOACs in the community practice. They reviewed the records of almost 8,000 patients receiving NOACs and noted that the vast majority, nearly 84%, received a standard dose of NOACs, consistent with the U.S. FDA labeling. While only 16% received a reduced dose, only 43% of these were consistent with labeling instructions. Those who received reduced dose NOACs inappropriately more often tended to be younger and have, interestingly, lower overall bleeding risks scores.                                 Furthermore, compared with those appropriately receiving dosing, patients receiving inappropriately reduced dose NOACs had a higher unadjusted rates of thromboembolic events and death.                                 These data are important to understand, in that, discussion with patients, that inappropriate reduction of NOACs does not necessarily offer appropriate protection against long-term risk of thromboembolic events. Thus, close attention must be paid to consideration of the use cases and instructions for use.                                 While the registry cannot get into the details of why the dose was reduced in the spectrum of patients, it does highlight the fact that this continues to be a problem in general practice.                                 Further data is needed to understand what leads to inappropriate dose reduction, which could include factors such as patient preference, or physician education.                                 Staying within the realm of anticoagulation and understanding individual needs, we next review an article published in this past month's issue of Circulation, by Nielsen et al., entitled Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation. Should we use a CHA2DS2-VA score rather than CHA2DS2-VASc? In this review, the authors sought to evaluate whether female sex is truly an overall risk factor, as opposed to a risk modifier.                                 Using three nationwide registries, they identified patients with nonvalvular atrial fibrillation between 1997 and 2015, and they calculated two sets of scores. The first score, they termed a CHA2DS2-VA score, calculated for men and women with follow-up of one year in the Danish National Patient Registry. They wanted to calculate the risk based on this pseudo-value method. They then reviewed female sex as a prognostic factor by inclusion as an interaction term on the CHA2DS2-VA score, to calculate overall thromboembolic risk.                                 Amongst over 200,000 patients with atrial fibrillation, almost half of whom are women, they noted that the mean CHA2DS2-VA score, where sex is excluded, was a tad higher in women than men, namely 2.7 vs. 2.3. However, women had an overall higher one year thromboembolic rate of 7.3 vs. 5.7 per 100 person-years. Interestingly, with a CHA2DS2-VA score of zero, the absolute risk of thromboembolism was equal amongst men and women, around .5%. Once overall points increased above one, however, women exhibited a higher stroke risk. This interaction was statistically significant.                                 Thus, the authors indicated that female sex is a risk modifier for stroke in patients with atrial fibrillation, rather than a risk factor. The terminology is important to consider. Essentially, what they are noting is that at the lower risk level, female sex, in and of itself, is not something that necessarily puts somebody in the higher risk cohorts. Instead, at higher risk levels, because of other factors, a woman may have a higher overall risk of stroke than men. Thus, stroke risk is accentuated in women, who would have been eligible for oral anticoagulating treatment anyway, on the basis of a CHADS score above one.                                 These data highlight the importance of thinking about the fact that at the lower risk score level, female sex alone might not be sufficient to say that a patient has reached the CHA2DS2-VASc score of one and above. But, really, you need an overall CHA2DS2-VA score, or a risk score, inclusive of at least two other risk factors to indicate that now, being a female is going to modify the risk and further accentuate it.                                 Now, one thing to note is, these data are very consistent with the guidelines. The European guidelines indicates that female sex alone, which in the CHA2DS2-VASc score would confer a risk score of one, should not, by itself, construe the need to put somebody on anticoagulation.                                 However, it's important to highlight that these data show that at a CHA2DS2-VASc score of one in females, they should really be construed as equivalent to a CHA2DS2-VASc score of zero in men.                                 Using the CHA2DS2-VA score, where sex is excluded, but considering that women overall have a higher incidence of stroke at any given CHA2DS2-VA level above one, will help better counsel women about the importance of being on anticoagulants.                                 The next article we review relates to long-term risk related to atrial fibrillation, published in February's issue of Heart Rhythm, by Nishtala et al., entitled Atrial Fibrillation and Cognitive Decline in the Framingham Heart Study. While there's much out there about the potential long-term role of cognitive decline in atrial fibrillation patients, longitudinal research investigating the relationship is relatively sparse. Thus, the authors sought to investigate the association between atrial fibrillation and cognitive performance, cross-sectionally and longitudinally.                                 They chose patients within the Framingham study who are dementia and stroke-free at the time of baseline neuropsychological assessments. They evaluated atrial fibrillation status as a two level variable, namely prevalent atrial fibrillation vs. no atrial fibrillation in cross-sectional analyses. And they also separated into prevalent atrial fibrillation at baseline, interim development of atrial fibrillation, and those who didn't develop any atrial fibrillation in longitudinal analysis.                                 They studied 2,682 participants in the Framingham Heart study, including original and offspring cohorts. They noted that a baseline of about 4% had diagnosed atrial fibrillation. Prevalent AF was noted to be significantly associated with poorer attention. Interestingly, sex differences were noted, with men performing worse on test of abstract reasoning and executive function than women.                                 They noted that prevalent atrial fibrillation was significantly associated with the longitudinal decline in executive function, in both the original cohorts, as well as interim atrial fibrillation being significantly associated with longitudinal decline in executive function of the offspring cohorts. Thus, they noted that atrial fibrillation is associated with a profile of long-term change in cognitive function.                                 The importance of these data are to further highlight the potential contribution of atrial fibrillation to cognitive decline. While the exact mechanisms remain to be fully elucidated, the question of how to get ahead of the cognitive decline associated with atrial fibrillation is further put out by these data.                                 Whether the relationship between atrial fibrillation and cognitive decline is due to recurrent thromboembolic events vs. the therapies used vs. other factors such as humid anatomic factors resulting in poor brain perfusion, are relatively unclear.                                 Certainly it is also possible that atrial fibrillation simply reflects a process associated with other factors that might lead to cognitive decline. However, again, further mechanistic studies and potential treatment interventions to mitigate the risk of cognitive decline are still needed.                                 Speaking of this, we next review a paper published in the European Heart Journal this past month, by Friberg and Rosenqvist, entitled Less Dementia with Oral Anticoagulation in Atrial Fibrillation.                                 Speaking of treatments to avoid long-term cognitive decline, the authors sought to evaluate if oral anticoagulant treatment might offer protection against long-term dementia risk in atrial fibrillation.                                 These retrospective registry studies of patients with the hospital diagnoses of atrial fibrillation and no prior diagnosis of dementia in Sweden, including patients between 2006 and 2014. The study included a total of 444,106 patients over 1.5 million years. They noted that patients who were on anticoagulant treatment at baseline were associated with a 29% lower risk of dementia than patients without anticoagulant treatments. Thus, there is an overall 48% lower risk on treatments with the appropriate anticoagulation. There is no difference on whether Warfarin or the newer oral anticoagulants were used.                                 Thus, the authors concluded that the risk of dementia is higher without oral anticoagulant treatment in patients with atrial fibrillation, suggesting that early initiation of anticoagulant treatment in patients with atrial fibrillation could be of value to preserve long-term cognitive function.                                 This relates directly back to the previous paper, which focused more on the epidemiologic risk, while this paper focuses on elements that might construe mechanism or treatment options.                                 Many authors have concluded the incredible importance of early recognition of the need for anticoagulant initiation in patients with atrial fibrillation. While the exact mechanism of cognitive decline and dementia in atrial fibrillation remains to be completely elucidated, certainly recurrent thromboembolic events that might be relatively silent as they occur, but result in a long-term cumulative risk might be helped by placing patients on anticoagulants.                                 This becomes another reason to counsel patients on the importance of long-term anticoagulant therapy. Certainly, the limitations of these studies, however, are the retrospective nature and the fact that there might be some subtle differences that may not be otherwise able to be construed from retrospective registry data regarding the relative role of anticoagulants in truly protecting against long-term cognitive decline. However, the data are certainly provocative.                                 Continuing within realm and discussing outcomes associated atrial fibrillation, we next review an article by Leung et al., entitled The Impact of Atrial Fibrillation Clinical Subtype on Mortality, published in JACC: Clinical Electrophysiology this past month.                                 The author sought to investigate the prognostic implications of a subtype of atrial fibrillation, paroxysmal or persistent, on long-term prognosis. They sought to evaluate differences in mortality between paroxysmal or persistent atrial fibrillation amongst 1,773 patients. They adjusted for comorbid diseases associated with atrial fibrillation, as well as CHA2DS2-VASc score. In the study, a total of about 1,005 patients or about 57% had persistent atrial fibrillation. Over the follow-up period, about 10% of those with paroxysmal atrial fibrillation and 17% of those with persistent atrial fibrillation died.                                 They noted that persistent atrial fibrillation, after correcting for other comorbidities, was independently associated with worse survival. Thus, they concluded that persistent atrial fibrillation is independently associated with increased mortality in the long term.                                 These data are relevant in that they highlight that persistent atrial fibrillation in its nature might construe an overall higher risk cohort. It remains to be fully understood what are the true mechanistic differences between persistent and paroxysmal atrial fibrillation. Overall, however, the community grossly agrees that persistent atrial fibrillation likely suggests a higher degree of atrial myopathy. If we believe this, then it is reasonable to believe that the risk associated with this specific form of atrial fibrillation might result in higher long-term harm.                                 Of course, these data are subject to the same limitations of all retrospective data. Namely, these persistent atrial fibrillation patients might have received different therapies or been more sick to start with that cannot be construed by comorbidities alone.                                 Furthermore, these data do not necessarily get to the point of whether treating atrial fibrillation in the persistent patient more aggressively necessarily reduces the risk equivalent to that of paroxysmal patients. Thus, further understanding is needed to understand how to use these data to reduce this mortality difference.                                 Continuing within the realm of epidemiology of atrial fibrillation, we next review an article published in this past month's issue of Circulation, by Mandalenakis et al., entitled Atrial Fibrillation Burden in Young Patients with Congenital Heart Disease. It is assumed that patients with congenital heart disease are vulnerable to atrial fibrillation because of multiple factors. These include residual shunts, hemodynamic issues, atrial scars from previous heart surgery, valvulopathy and other factors.                                 However, there's limited data on the overall risk of developing atrial fibrillation and complications associated with it, especially in children and young adults with congenital heart disease. Furthermore, these children and young adults with congenital heart disease have never been compared with overall risk and control subjects.                                 The authors use the Swedish Patient and Cause of Death Registries to identify all patients with diagnoses of congenital heart disease born from 1970 to 1993. They then matched these patients with control subjects from the Total Population Register in Sweden. They noted amongst almost 22,000 patients with congenital heart disease and almost 220,000 matched control subjects that 654 patients amongst the congenital heart disease cohort developed atrial fibrillation, while only 328 amongst the larger control group developed atrial fibrillation. The mean follow-up overall was 27 years.                                 They noted the risk of developing atrial fibrillation was almost 22 times higher amongst patients with congenital heart disease than control subjects. They noted the highest risk with a hazard ratio of over 84 was noted in patients with conotruncal defects. Furthermore, at the age of 42 years, over 8% of patients with congenital heart disease had a recorded diagnosis of atrial fibrillation.                                 Interestingly, heart failure was a particularly important complication in patients with congenital heart disease and atrial fibrillation, with over 10% of patients developing atrial fibrillation and [inaudible 00:38:20] congenital heart disease developing a diagnosis of heart failure as well.                                 These data are important in that they help in counseling the importance of close follow-up of patients with congenital heart disease and their long-term risk of other complications. Even if patients might be perceivably well managed, incident atrial fibrillation might increase risk of stroke in these patients. It is further important to note that many of these patients cannot be evaluated according to traditional risk or evaluations. Thus, it is important to consider whether or not a patient should be treated with anticoagulation once they develop atrial fibrillation.                                 The high risk of overall atrial fibrillation incidents, particularly in patients with more complex congenital defects, needs to be taken into consideration when advising on the frequency of follow-up.                                 It is important to further note that we must think of this overall risk as the minimum possible risk, namely, counseling a congenital heart disease patient that up to one in ten of them may develop atrial fibrillation by the age of 42 years, is likely the minimum amount. The reason for this is many patients, due to either lack of follow-up or lack of sufficient monitoring, and the asymptomatic nature of atrial fibrillation in many patients might have not been diagnosed.                                 Implications or treatments remain to be seen, and whether or not there are methods to reduce the overall risk of atrial fibrillation is unclear. However, engaging congenital heart disease experts and advising patients, especially at younger ages, on the importance of close electrocardiographic monitoring for a potential atrial fibrillation risk is critical.                                 Next within the realm of atrial fibrillation, we switch to the topic of ablation. And review an article by Pallisgaard et al., published in this last month's issue of European Heart Journal, entitled Temporal Trends in Atrial Fibrillation Recurrence Rates After Ablation, between 2005 and 2014: a nationwide Danish cohort study.                                 Ablation has been increasingly used as a rhythm control strategy for patients with atrial fibrillation. Over this time, we have all noted evolution in both the experience and the techniques used. Thus, the authors sought to evaluate whether recurrence rate of atrial fibrillation has changed over the last decade. They included all patients with first-time AF ablation done between 2005 and 2014 in Denmark. They then evaluated recurrent atrial fibrillation based on a one year follow-up. They included a total of 5,425 patients undergoing first-time ablation.                                 They noted, interestingly, that the patient median age increased over time, and the median AF duration prior to ablation decreased over time. However, the rates of recurrent atrial fibrillation decreased from 45% in 2005 to 31% in the more recent years of 2013, 2014. With the relative risk of recurrent atrial fibrillation almost being cut in half.                                 They noted that female gender, hypertension, atrial fibrillation duration more than two years, and cardioversion with one year prior to ablation were all associated with an increased risk of recurrent atrial fibrillation, regardless of year.                                 These data, again, are retrospective and thus must be taken in the context of that consideration. However, they highlight that it is possible either our selection of appropriate patients for atrial fibrillation ablation or our techniques have improved overall success.                                 The fact that atrial fibrillation ablation is still a relatively young field, with evolving approaches and evolving techniques, needs to be taken into consideration when advising patients on success rates. Using data from many years prior to informed discussion today is fraught with potential error, especially as our catheter design and mapping system use and understanding of appropriate lesion set changes.                                 Of course, some criticism is required as well. While the patients included were relatively older in more recent years, the total AF duration prior to ablation decreased over the years. This suggests that patients are being ablated earlier than they were in the early days of atrial fibrillation ablation.                                 There is some data out there to suggest that earlier ablation for atrial fibrillation might result in a lower long-term recurrence rate. Thus, this might account for some of the difference. However, it is unlikely that it accounts for all of it, given the degree of reduction in overall risk of occurrence.                                 Staying within the trend of talking about changes in techniques for atrial fibrillation ablation, we next review an article published in this past month's issue of Heart Rhythm, by Conti et al., entitled Contact Force Sensing for Ablation of Persistent Atrial Fibrillation: A Randomized, Multicenter Trial. Contact force sensing is one of the newer techniques being used to optimize the success rates for atrial fibrillation ablation. It is generally felt that understanding when one is in contact will optimize atrial fibrillation ablation outcomes by ensuring the physician knows each time they are in contact, and also potentially reducing complications by avoiding excessive contact.                                 Thus, the authors designed the TOUCH AF trial to compare contact force sensing-guided ablation vs. contact force sensing-blinded ablation. They included a total of 128 patients undergoing first-time ablation for persistent atrial fibrillation, and thus randomized them to a situation where the operator was aware of the contact force vs. blinded to the contact force. While the force data was hidden in the blinded cohort, it was still recorded on the backend.                                 In all patients, wide antral pulmonary vein isolation plus a roof line was performed, and patients were followed at 3, 6, 9, and 12 months, with clinical visits, ECGs, and 48-hour Holter monitoring.                                 The primary endpoint was cumulative radio frequency time for procedures, and atrial arrhythmia is greater than 30 seconds after three months is considered a recurrence.                                 They noted that average force was higher in the contact force-guided arm than contact force-blinded arm, though not statistically significant, with an average of 12 grams in the latter and 14 grams in the former.                                 Interestingly, the total time of ablation did not differ between the two groups. Furthermore, there was no difference in the single procedure freedom from atrial arrhythmia, computing to about 60% in the contact force-guided arm vs. the 63% in the contact force-blinded arm. They did notice, however, that lesions with associated gaps were associated with significantly less force and less force-time integral.                                 The authors concluded from this, the contact force-guided ablation did not result in significant decrease in total radio frequency time or 12-month outcomes in terms of freedom from atrial arrhythmias.                                 These data are important to help guide us in terms of thinking about how the tools we use, as they change, actually alter outcomes. Sometimes we may perceive benefits based on logical thinking that's knowing more about what is happening when we are performing a procedure should optimize that procedure. However, this is not necessarily always the case, and thus highlights the importance of randomized trials to directly compare different situations, such as awareness of contact force vs. lack of awareness of contact force.                                 The relevance of these particular articles is that when we compare catheters with different designs, it does not necessarily highlight the importance of the force number itself. Namely, comparing a contact force catheter vs. non-contact force catheter implicates use of essentially two completely different catheters. To understand the incremental utility of force in making decisions, it is important to consider the same catheter, but simply with awareness or lack of awareness of the actual force number.                                 One of the limitations, however, is that individuals who might have been trained on using the same force sensing catheter might have some degree of tactile feedback and understanding of the amount of force being applied to the tip of the catheter, based on having been repeatedly exposed to contact force numbers during use of said catheter. Thus, there might be a difference in being blinded to contact force in early stage operators than in later stage operators who might have been trained based on repeated feedback.                                 Thus, it's difficult to conclude, necessarily, that contact force is not offering mental benefit. In fact, there's a fair chance that it does. However, offering a skeptical viewpoint to help guide the importance of continually evolving technology in actually improving outcomes is important.                                 Finally, within the realm of atrial fibrillation, we review an article published by Pathik et al., in this past month's issue of Heart Rhythm, entitled Absence of Rotational Activity Detected Using 2-Dimensional Phase Mapping and the Corresponding 3-Dimensional Phase Maps in Human Persistent Atrial Fibrillation.                                 Current clinically used phase mapping systems involve 2-dimensional maps. However, this process may affect accurate detection of rotors. The authors sought to develop 3-dimensional phase mapping technique that uses a 3D location of the same basket electrodes that are used to create the currently available 2-dimensional maps. Specifically, they wanted to determine whether the rotors detected in 2D phase maps were present in the corresponding time segments and anatomical locations in 3D phase maps.                                 They used one minute left atrial atrial fibrillation recordings obtained in 14 patients, using the basket catheter, and analyzed them offline, using the same phase values, based on 2-dimensional vs. 3-dimensional representations.                                 They noted rotors in 3.3% using 2D phase mapping, 9 to 14 patients demonstrated about 10 transient rotors, with a mean rotor duration of about 1.1 seconds. They noted none of the 10 rotors, however, were seen at the corresponding time segments and anatomical locations in 3D phase maps. When looking at 3D phases maps, 4 of the 10 corresponded with single wavefronts, 2 of 10 corresponded with simultaneous wavefronts, 1 of 10 corresponded with disorganized activity, and 3 of 10 had no coverage by the basket catheter at the corresponding 3D anatomical locations.                                 These data are important, in that they highlight the importance of when we consider reflecting 2-dimensional systems in a 3-dimensional world of atrial fibrillation. The role of ablating rotors is still in question. However, it is still an important question, and it requires continued study. The best way of identifying a rotor, knowing a rotor is a rotor, and understanding where the rotor is, are going to be critical to further evaluating whether actual ablation of these rotors has any relevance to long-term atrial fibrillation ablation.                                 The truth is, that we need to be sure that we are properly identifying all the rotors in order to help guide whether or not we are actually being successful in ablating atrial fibrillation. The importance of the study is in reflecting whether 2-dimensional representations of the 3-dimensional geometry is sufficient to reflect what is actually happening in that 3-dimensional geometry. These authors suggest that it is not.                                 One of the limitations, however, might be that when we wrap a 2-dimensional framework into 3 dimensions and perform additional post-processing, this might result in some degree of attenuation of the data. However, it does highlight the importance for continued rigorous evaluation of current approaches to phase mapping.                                 Several articles have been published in recent months as well, about different single processing techniques to evaluate whether or not a rotor is, in fact, a rotor and to help optimize identification of them.                                 The jury is still out on whether or not targeted ablation of rotors will, in fact, improve overall long-term atrial fibrillation ablation outcomes. The limitations might not necessarily be that rotors are not an appropriate target, but that we just don't understand entirely where rotors are, based on limited single processing options, or based on limitations of anatomical localization.                                 Next, delving into the realm of ablation at large, we review an article by Iwasawa et al., published in this past month's issue of Europace, entitled Trans Cranial Measurement of Cerebral Microembolic Signals During Left-Sided Catheter Ablation with the Use of Different Approaches - the Potential Microembolic Risk of a Transseptal Approach.                                 The authors note the importance of considering microemolization in subclinical brain damage during catheter ablation procedures. They evaluated microembolic signals detected by transcranial Doppler during ablation of supraventricular or ventricular arrhythmias with the use of either a transseptal or a retrograde approach.                                 The study set was small, only including 36 patients who underwent catheter ablation. They noted in about 11 patients left-sided ablation was done with transaortic approach, and in 9 patients a transseptal approach was used. The other 16 patients were not included, as they only had right-sided ablation.                                 The total amount of microembolic signature, based on transcranial Doppler were counted throughout the procedure and then analyzed offline. There is no significant difference in number of radio frequency applications, total energy delivery time, total application of energy, or total procedure time between the different groups. However, they did note that the mean total number of microembolic signals was highest in those undergoing transseptal approach to left-sided ablation. It was significantly lower in those having retrograde aortic approach, and lowest in those having right-sided only ablation.                                 Interestingly, many of the microembolic signals were detected during the transseptal puncture period, and then during the remainder of the procedure there was relatively even distribution of emboli formation. A frequency analysis suggested that the vast majority of microembolic signals are gaseous, in particularly Group 1 and Group 3, though only 91% in Group 2. No neurological impairment was observed in any of the patients after the procedure.                                 Recently, there's been a lot of focus on the potential long-term risk of cognitive impairments due to microembolic events in the setting of ablation. At least one recent paper in ventricular arrhythmias and several recent papers in atrial fibrillation ablation have suggested a fairly high risk of incidence cerebral emboli noted on MRI post ablation. While these results do not necessarily get at MRI lesions, they do suggest microembolic events. And what is most interesting, they look at microembolic events that occur throughout the entire ablation period with different approaches.                                 Interestingly, there is a massive spike in overall microembolic signals during the transseptal puncture period, and relatively even distribution throughout ablation, irrespective of application of radio frequency or not. Furthermore, while nearly all microembolic signals are gaseous, based on frequency analysis, with retroaortic approach or in those having right-sided only ablation, significantly less seem to be due to gaseous events in those having a transseptal approach.                                 It is known that there's possible damage to the internal dilation system when exposing it to transseptal needles or wires. Thus, one has to wonder whether some of the embolization could be from material associated with the actual transseptal puncture, either from portions of the punctured septum itself, or perhaps from the plastic material that which is being pushed transseptally.                                 These data still need to be considered and we have yet to see what the long-term applications of these kinds of findings are. It may be possible that while transseptal approach seems to offer more instant microembolic signals, if the long-term risk is no different, does it really matter?                                 However, these findings are provocative in the sense that they highlight potential significant differences and the risk of silent cerebral damage, based on the approach we use to ablation.                                 Changing gears, we next focus on the role of devices. And the first paper review is in the last month issue of JACC: Heart Failure, by Gierula et al., entitled Rate Response Programming Tailored to the Force Frequency Relationship Improves Exercise Tolerance in Chronic Heart Failure.                                 The authors sought to examine whether the heart rate at which the force frequency relationship slope peaks can be used to tailor heart rate response in chronic heart failure patients with cardiac pacemakers, and to see whether this favorably influences exercise capacity.                                 They performed an observational study in both congestive heart failure and healthy subjects with pacemaker devices. They then evaluated in a double-blind, randomized, controlled crossover study, the effects of tailored pacemaker rate response programming on the basis of a calculation of force frequency relationship based on critical heart rate, peak contractility, and the FFR slope.                                 They enrolled a total of 90 patients with congestive heart failure into the observational study cohorts, and 15 control subjects with normal LLV function. A total of 52 patients took part in the crossover study. They noted that those who had rate response settings limiting heart rate rise to below the critical heart rate were associated with greater exercise time and higher peak oxygen consumption, suggesting the tailored rate response program can offer significant benefit, particularly in congestive heart failure patients.                                 The importance of this trial is in that it highlights the importance of thoughtful decision-making in programming devices, and that group decision-making involving exercise physiologists, alongside pacemaker programming, and involving our congestive heart failure specialists might be the most critical in optimizing the approach to programming.                                 It might be that more aggressive measures are needed in congestive heart failure patients to decide on what optimal programming is, than it is in otherwise normal patients.                                 Staying within the realm of devices, we next focus on a publication by Sanders et al., published in this past month's issue of JACC: Clinical Electrophysiology, entitled Increased Hospitalizations and Overall Healthcare Utilization in Patients Receiving Implantable Cardioverter-Defibrillator Shocks Compared With Antitachycardia Pacing.                                 The authors sought to evaluate the effect of different therapies and healthcare utilization in a large patient cohorts. Specifically comparing antitachycardia pacing with high voltage shocks. They used the PROVIDE registry, which is a prospective study of patients receiving ICDs for primary prevention in 97 U.S. centers. They categorized these patients by type of therapy delivered, namely no therapy, ATP only, or at least one shock. They then adjudicated all ICD therapies, hospitalizations, and deaths.                                 Of the 1,670 patients included, there was a total follow-up of over 18 months. The vast majority, 1,316 received no therapy, 152 had ATP only, and 202 received at least one shock.                                 They noted that patients receiving no therapy and those receiving only ATP had a lower cumulative hospitalization rate and had a lower risk of death or hospitalization. The cost of hospitalization was known to be significantly higher for those receiving at least one shock than for those receiving only ATP therapy.                                 They noted no difference in outcomes or cost between patients receiving only ATP and those without therapy. Thus, the authors concluded that those receiving no therapy or those receiving only ATP therapy had similar outcomes, and had significantly reduced hospitalizations, mortality, and costs compared to those who received at least one high voltage shock.                                 The relevant findings from this study is similar to prior studies that suggest that any shock over follow-up is associated with potential increase in long-term mortality. The difficulty in assessing this, however, is the fact that it might be that those who have VT that can be appropriately ATP terminated, might be at a somewhat lower risk than those who need to be shocked to get out of their VT. Thus, the presumption of needing a shock to restore normal rhythm might suggest a higher risk cohort, it cannot be gleaned from traditional evaluation of morbid risk factors.                                 This is why the importance of considering how devices are programmed and whether or not a patient who has received shocks can be reprogrammed to offer ATP only therapy to terminate those same VTs, needs to be taken into consideration. How to best tailor this therapy, however, is still remaining to be determined, though more and more clinical trials are coming out to suggest in terms of optimal overall population-wide programming for devices.                                 Staying with the realm of devices, we next review an article by Koyak et al., in this past month's issue of Europace, entitled Cardiac Resynchronization Therapy in Adults with Congenital Heart Disease.                                 Heart failure is one of the leading causes of morbidity and mortality amongst patients with congenital heart disease. But there's limited experience in the role of cardiac resynchronization therapy amongst these patients. Thus, the authors sought to evaluate the efficacy of CRT in adults with congenital heart disease.                                 They performed a retrospective study on a limited number of 48 adults with congenital heart disease who received CRT, amongst four tertiary referral centers. They have defined responders as those who showed improvement in NYHA functional class or improvement in systemic ventricular ejection fraction. The median age at CRT implant was 47 years, with 77% being male. There was a variety of syndromes included.                                 They noted that the majority of patients, nearly 77%, responded to CRT, either by definition of improvement of NYHA functional class, or systemic ventricular function, with a total of 11 non-responders.                                 They noted that CRT was accomplished with a success rate comparable to those with acquired heart disease. However, the anatomy is much more complex and those technical challenges in achieving success o

Paul 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 journals in the field.                                 In our first article, Elyar Ghafoori and associates examined the ability of late gadolinium enhancement MRI done immediately after ablation to predict edema and chronically even size. In a canine model, the authors created ventricular radiofrequency ablation lesions. All animals underwent MRI immediately after ablation. After one, two, four and eight weeks, edema and microvascular obstruction MVO, in enhanced volumes were identified in MRI. Immediately after contrast administration, the microvascular obstruction region was 3.2 times larger than the chronic lesion volume size in acute MRI. The authors found that microvascular obstruction region on acute late gadolinium enhancement images acquired 26 minutes after contrast administration most accurately predicts chronic lesion volume.                                 In the next article, Elad Anter and associates characterized the atrial substrate in patients with paroxysmal atrial fibrillation and obstructive sleep apnea. The authors examined 86 patients with paroxysmal atrial fibrillation, 43 with moderate obstructive sleep apnea and 43 without obstructive sleep apnea. The right atrial and left atrial voltage distribution conduction velocities in electrogram characteristics were examined. The authors found that patients with obstructive sleep apnea had lower atrial voltage amplitude, slower conduction velocities, and higher prevalence of electrogram fractionation. Most commonly, the left atrial septum was an area of atrial abnormality while at baseline the pulmonary veins with the most frequent triggers for atrial fibrillation in both groups after pulmonary vein isolation in patients with obstructive sleep apnea had an increased incidence of extrapulmonary vein triggers, 41.8% versus 11.6%, p=0.003. The one year arrhythmia-free survival are similar between patients with and without obstructive sleep apnea, 83.7% and 81.4%, respectively.                                 In comparison, control patients with paroxysmal atrial fibrillation and obstructive sleep apnea who underwent pulmonary vein isolation alone without ablation of extrapulmonary vein triggers had an increased risk of arrhythmia recurrence, 83.7% versus 64.0%, p=0.03, suggesting that ablation of these triggers resulted in improved arrhythmia-free survival. A randomized trial would be needed to prove this relationship.                                 In the next article, Iolanda Feola and associates demonstrated that optogenetics may be used to induce and locally target a rotor in atrial monolayers. The authors used neonatal rat atrial cardiomyocyte monolayers expressing a depolarizing light-gated ion channel, calcium-translocating channelrhodopsin. These monolayers were subjected to patterned illumination to induce the single, stable, and centralized rotor by optical S1-S2 cross-field stimulation. Next, the core region of these rotors was specifically and precisely targeted by light to induce local conduction blocks of circular or linear shapes. Conduction blocks crossing the core region, but not reaching an unexcitable boundary, did not lead to termination. Instead, electrical waves started to propagate along the circumference of block. If, however, core-spanning lines of block reached at least one unexcitable boundary, reentrant activity was consistently terminated by wave collision, suggesting that this may be a key mechanism for rotor elimination.                                 In our next study, Adam Barnett and associates used data from the outcomes registry for better informed treatment of atrial fibrillation ORBIT-AF to determine how frequently patients receive care that was concordant with 11 recommendations of the 2014 AHA, ACC, HRS A-fib guidelines pertaining to antithrombotic therapy rate control in anti-arrhythmic medications. The authors also analyzed the association between guideline concordant care and clinical outcomes at both the patient's level and center level. The authors study 9,570 patients with the median A 275, median CHA2DS2-VASc score of 4. A total of 62.5% or 5,5977 patients received care that was concordant with all guideline recommendations for which they were eligible. Rates of guideline concordant care was higher in patients treated with providers, with greater specialization in arrhythmias; 60.0%, 62.4%, 67.0% for primary care physicians, cardiologists and electrophysiologist, respectively; p less than 0.001. During a median of 30 months of follow up, patients treated with guideline concordant care had a higher risk of bleeding hospitalization; hazard ratio, 1.21. Similar risk of death, stroke, major bleeding can all cause hospitalization.                                 In our next article, Hui-Chen Han and associates conducted electronic search of PubMed and Embase for English scientific literature articles to characterize the clinical presentation, procedural characteristics, diagnostic investigations and treatment outcomes of all reported cases of atrioesophageal fistula. Out of 588 references, 120 cases of atrioesophageal fistula were identified. Clinical presentation occurred between 0 and 60 days postablation with a median of 21 days. The most common presentations were fever 73%, neurological 72%, gastrointestinal 41%, and cardiac 40% symptoms. Computed tomography of the chest was the commonest mode of diagnosis, 68% although six cases required repeat testing. Overall mortality was 55%. In conclusion, the authors reported that atrioesophageal fistula complicating atrial fibrillation is associated with a very high mortality 55% with significantly reduced mortality in patients undergoing surgical repair 33% compared to endoscopic treatment 65%, and conservative management 97%. Odds ratio adjusted 24.9; p less than 0.01 compared to surgery. Neurological symptoms adjusted odd ratio 16.0. In GI bleed, adjusted odds ratio 4.2, were the best predictors of mortality.                                 In the next article, Wei Ma and associates reported that the site origin of left posterior fascicular ventricular tachycardia may be predicted using 12-lead EC morphology in the HIS-ventricular or H-V interval. The authors studied 41 patients who underwent successful catheter ablation of left posterior fascicular ventricular tachycardia. The location of the site of origin was separated into proximal, middle, and distal groups with H-V being greater than zero milliseconds in the proximal group, H-V zero to minus 15 milliseconds in the middle group, and H-V less than negative 15 milliseconds in the distal group. The earliest presystolic potential ratio that is PP-QRS interval during VT divided by the H-V interval during sinus rhythm was statistically significantly different between the three groups, 0.59, 0.45 and 0.31, respectively. In addition, the QRS ratio in the proximal group 114 milliseconds was significant nearer compared to the middle group 128 milliseconds and the distal group 140 milliseconds. The QRS duration in the ratio R to S in leads V6 and lead-1 could predict a proximal or distal origin of left posterior fascicular ventricular tachycardia with high sensitivity and specificity.                                 In our next article, Niv Ad and associates examined the safety and success of on-pump minimally invasive stand-alone Cox-Maze 3/4 procedure via right mini-thoracotomy in 133 patients with nonparoxysmal atrial fibrillation five years after surgery. The mean follow-up was 65 months in a patient population with a mean age of 57.3 years, mean left atrial size of 4.9 centimeters, mean AF duration of 51 months and 78% with longstanding persistent atrial fibrillation. All procedures were performed with no conversion to mid-sternotomy. No renal failure, strokes or operative mortality in less than 30 days. They reported a TIA in one patient, re-operation for bleeding in two patients, and median length of stay in four days. At five years, 73% of patients were in sinus rhythm off anti-arrhythmic drugs following a single intervention.                                 In the next article, Richard Soto-Becerra and associates reported that unipolar endocardial electro-anatomic mapping may be used to identify scar epicardially in chagasic cardiomyopathy. In 19 sick patients, a total of 8,494 epicardial and 6,331 endocardial voltage signals in 314 epicardial and endocardial match pairs of points were analyzed. Basolateral left ventricular scar involvement was observed in 18 out of 19 patients. Bipolar epicardial and endocardial voltages within scar were low, 0.4 and 0.54 millivolts, respectively in confluent indicating a dense transmural scarring process. The endocardial unipolar voltage value with the newly proposed less than of equal to four-millivolt cutoff predicted the presence and extent of epicardial bipolar scar, p less than 0.001.                                 In our next article, Bing Yang and associates reported the results of the stable SR study, which is a multicenter clinical trial of 229 symptomatic nonparoxysmal atrial fibrillation patients random-eyed one-to-one to two ablation strategies. In the stable SR group following pulmonary vein isolation, cavotricuspid isthmus ablation in conversion to sinus rhythm left atrial high density mapping was performed. Areas of low voltage and complex electrogram were further homogenized and eliminated, respectively. Dechanneling was done if necessary. In the step-wise group, additional linear lesions and defragmentation were performed. The primary endpoint was freedom of documented atrial tachyarrhythmias lasting 30 seconds or more after a single ablation procedure without anti-arrhythmic medications at 18 months. At 18 months, success according to intention-to-treat analysis was similar in the two arms with 74.0 success in the stable SR group and 71.5% success in the step-wise group; p=0.3. However, shorter procedure time reduced fluoroscopic time after pulmonary vein isolation and shorter energy delivery time were observed in the stable SR group compared to the step-wise group.                                 In the final paper, Alan Sugrue and associates studied the performance of a morphological T-wave analysis program in defining breakthrough long QT syndrome arrhythmic risk beyond the QTc value. The author studied 246 genetically confirmed LQT1 patients and 161 LQT2 patients with a mean follow-up of 6.4 years. A total of 23 patients experienced more than one breakthrough cardiac arrhythmic event with 5 and 10-year event rates of 4% and 7%. Two independent predictors of future long Qt syndrome-associated cardiac events were identified from the surface ECG using a proprietary novel T-wave analysis program. The authors found that the most predictive features included the left slope of T-wave in V6, hazard ratio of 0.40, and T-wave center of gravity X-axis in lead-1, hazard ratio 1.9, C statistic of 0.77. When added to QTc, discrimination improved from 0.68 for QTc alone to 0.78. Genotype analysis showed weaker association between these T-wave variables in LQT1 triggered events while these features were stronger in patients with LQT2 and significantly outperformed the QTc interval.                                 That's it for this month, but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcast On the Beat. Take it away, Suraj. Suraj Kapa:          Thank you, Paul. This month, we will again focus on hard-hitting articles from across the electrophysiological literature. I am Suraj Kapa and we're particularly focusing on articles published in October 2017.                                 The first article we will focus on is within the realm of atrial fibrillation specifically related to anticoagulation. In Journal of the American Heart Association in Volume 6, Issue 10, Lin, et al. sought to develop a prediction model for time in therapeutic range in older adults taking vitamin K antagonists. As we know, time in therapeutic range is critical for management of patients on vitamin K antagonists. As poor time in therapeutic range either due to subtherapeutic or supratherapeutic INRs, can lead to increased bleeding or thromboembolic risk. While novel oral anticoagulants have improved care of patients requiring anticoagulation, many patients either due to cost or due to other factors are unable to take the novel oral anticoagulants and thus must be maintained on vitamin K antagonists. In this study, Lin, et al. Used well-over 2,500 patients to create training and validation sets and thereby create two models for estimating time in therapeutic range. Through this, they created a simple model term PROSPER consisting of seven variables including pneumonia, renal dysfunction, prior bleeding, hospital stay more than seven days, pain medication use, lack of access to structured anticoagulation services, and treatment with antibiotics.                                 Using this, they showed that they can predict time in therapeutic range greater than 70% as well as thromboembolic and bleeding outcomes better than other existing time in therapeutic range scoring systems, such as the same TT2R2 score. The reason these scores are important are both to help patients understand when they may be at risk for not maintaining a time in therapeutic range and to assist them in identification of the right anticoagulant methodology or strategy. Also, perhaps to prospectively consider if we can identify patients who may require more intensive monitoring or structured therapy strategies. However, one must also consider that for scores like this, utilization is always critical. In other words, continuous validation of the scoring system must be done in order to make sure it's applicable across populations and across different groups of people in different communities.                                 Next, within the realm of anticoagulation and atrial fibrillation, we'll review the article by Chang, et al. published in JAMA in Volume 318, Issue 13 entitled Association Between Use of Non-Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding Non-Valvular Atrial Fibrillation. With any new drug that comes out, there's always the possibility of various medication interactions. The source of these medication interactions might be variable. They might include direct effects of other medications on systems by which the primary drug is metabolized. Also, might be due to synergistic effects of medications that might be unpredictable or effects on different aspects of systems the drugs are trying to treat. Thus oftentimes, larger population studies are required before one can appreciate drug interactions that might exist. This is particularly true with novel oral anticoagulant drugs. Part of the promise of the novel oral anticoagulants was that because of the extensive medication interactions associating vitamin K antagonists, the availability of the drug perhaps with fewer medication interactions resulting in alteration and bleeding or thromboembolic tendency will be very important.                                 In this important paper, Chang, et al. reviewed the effect of other medications on major bleeding events in patients on non-vitamin K oral anticoagulants such as dabigatran, apixaban, and rivaroxaban. Amongst over 91,000 patients, they noted that the concurrent use of amiodarone, fluconazole,  rifampin, and phenytoin compared with the novel oral anticoagulant alone was associated with a significant increase many times by odds ratio of 100 in risk of major bleeding. Several drugs including atorvastatin, digoxin, erythromycin or clarithromycin when used concurrently with NOACs interestingly were associated with the reduced risk of bleeding without elevating thromboembolic risk. The recent advent of NOACs in clinical use especially in patients who might be taking other medications always need to be considered in the context of how the other medications might affect the bleeding or thromboembolic risk. One of the key findings in this publication is the potential interaction with amiodarone and how concurrent use of amiodarone may increase the risk of major bleeding. Because of the general lack of tools to monitor the effects of NOACs on bleeding risk in patients, one needs to consider these population studies and whether or not there might be synergistic effects between medications going forward.                                 Unfortunately, we cannot adopt guidelines purely based on this data as to whether or not a dose adjustment should occur or whether or not the medication can be used at all. However, it does highlight the care that should be taken when using many of these drugs in conjunction with NOACs.                                 Finally within the realm of anticoagulation and atrial fibrillation, we'll review the article by Cannon, et al. in The New England Journal of Medicine entitled Dual Antithrombotic Therapy with the Dabigatran After PCI in Atrial Fibrillation. In this study, Cannon, et al. sought to systematically review the role of a warfarin strategy post-PCI versus dabigatran strategy post-PCI. They randomized patients to use of a combination of warfarin, aspirin, and a P2Y12 inhibitors such as clopidogrel post-PCI versus using dabigatran plus a P2Y12 inhibitor. They demonstrated that dual therapy approach with dabigatran resulted in significantly lower bleeding events than the triple antithrombotic/antiplatelet therapy group. There was no difference in adverse events including thromboembolism, unplanned revascularization or death between the groups. These findings were irrespective of whether patients were on 110 mg of dabigatran or 150 mg of dabigatran. These findings suggest that a dual therapy approach in the post-PCI setting with the NOACs as the dabigatran and the P2Y12 inhibitors such as clopidogrel lowers bleeding risk without increasing risk of major adverse events including thromboembolism or stent thrombosis after PCI.                                 However, it should be noted that one major criticisms of this trial is that the incremental bleeding risk conferred by aspirin could not be accounted for in the triple therapy cohort as aspirin was not used in the dual therapy cohorts. Thus, one cannot necessarily say whether the same finding would have been noted in a warfarin plus P2Y12 inhibitor versus dabigatran plus P2Y12 inhibitor especially given recent evidence suggesting no incremental benefit of aspirin particularly for thromboembolic risk associated with atrial fibrillation. However, the critical element of these findings is that a strategy excluding aspirin where dabigatran plus the P2Y12 inhibitor are used post-PCI might be actually safe.                                 Changing gears, we will next focus on an article within the realm of cardiac mapping and ablation in atrial fibrillation. This was published in the Journal of the American College of Cardiology in Volume 70, Issue 16 by Prabhu, et al. entitled Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. In this study, Prabhu, et al. studied in the multicenter randomized clinical trial the effect of catheter ablation for atrial fibrillation in the setting of left ventricular systolic dysfunction versus medical rate control. They looked at the change in ejection fraction over a follow-up of six months. A total of 68 patients were randomized in the study. They demonstrated an absolute improvement in EF by 18% in the ablation group versus 4% in the rate control group, with also a greater rate of EF normalization with ablation. In fact, over 50% of patients had EF normalization after ablation whereas only about 9% had a good medical rate control.                                 Furthermore, the improvements in EF correlated with the absence of late gadolinium enhancement on MRI and in the medical rate control group an average heart rate less than 90 beats per minute was achieved across the population randomized this approach. These findings are somewhat contrary to other studies that suggested that a rate versus a rhythm control approach were not really much different in patients with reduced left ventricular systolic function. These challenges are paradigm by suggesting that in fact successful restoration of normal rhythm in patients postablation can actually confer improvement in ejection fraction in some patients even when rate controlled. The success rates that should be noted in this study were similar to those published in most existing literature with about 56% of patients without further atrial fibrillation after a single ablation off medications and a success rate of 75% after a single ablation on medications. While the number of patients included are small and thus may be difficult to challenge the paradigm that was created, the rate versus rhythm control are equivalent in patients with reduced systolic function.                                 This finding should raise awareness that it is quite possible that there might actually be benefits in restoring normal rhythm by modern approaches in patients with reduced systolic function.                                 Moving on, still within the realm of atrial fibrillation, however, we'll next review the article by Aronsson, et al. in Europace Volume 19, Issue 10 entitled Designing an Optimal Screening Program for Unknown Atrial Fibrillation: A Cost-Effectiveness Analysis. More and more with an understanding that atrial fibrillation is essentially of epidemic proportions, but many patients tend to be asymptomatic and yet having an elevated stroke risk. People are focusing on how do we screen these populations in a manner that is both cost-effective as well as strategic. Aronsson, et al. tried to use computer simulation modeling to determine what the optimal age was to initiate screening for atrial fibrillation. They ran more than two billion different design screening programs that could be implemented at different age ranges and using data from published scientific literature. They tested these various screening programs. They demonstrated that the screening starting at the age of 75 was associated with the relatively low cost per gained quality adjusted life year. The overall cost at this level was 4,800 euros across the population for quality adjusted life year gained across that population.                                 The relevance of this publication while simulation model lies in highlighting the importance of considering what programs can we actually achieve in the modern day to better identify patients with atrial fibrillation who are not yet identified. Across the literature and in recent clinical meetings, there's a number of articles that are being published regarding the role of different strategies in identifying the asymptomatic, not yet diagnosed atrial fibrillation patients. This study presents an initial foray into systematizing programs that might be applied to recognition of these patients.                                 Along a similar course, we'll also review an article by Reiffel, et al. in JAMA Cardiology Volume 2, Issue 10 entitled Incidence of Previously Undiagnosed Atrial Fibrillation using Insertable Cardiac Monitors in a High-Risk Population: The REVEAL AF Study. In this study, Reiffel, et al. Reviewed the incidence of atrial fibrillation identified using implantable loop recorders in those with a high risk of stroke nearly a CHADS2 score of 3 or greater, but had not been previously diagnosed. It should be noted that while these patients have never been diagnosed with atrial fibrillation, 90% had nonspecific symptoms such as fatigue, dyspnea or palpitations, then theory could be attributed to atrial fibrillation. A total of 385 patients received monitors. They noted that by 30 months of monitoring, about 40% of patients have been identified as having atrial fibrillation that had not been diagnosed. If patients were only monitored for the first 30 days, however, the incident rate of atrial fibrillation in terms of new diagnosis was only 6%. In fact, the median time from device insertion to first episode of atrial fibrillation was almost four months at about 123 days.                                 In line with the previous discussed study by Arosson, et al., this study notes the importance of consideration of how we monitor patients at risk for stroke. The issue at hand is when we do screening, what is enough. The strategies used to identify atrial fibrillation of patients raised from advising on twice daily poll checks, which when done by the patient regularly might allow for identification of atrial fibrillation if they do it well to doing a single ECG, to doing a 24-hour Holter, to doing a 30-day monitor, to doing things like implantable loop recorders. However, this study by Reiffel, et al. suggests the a 30-day continuous monitor is truly insufficient if there is a high concern for atrial fibrillation. Thus with the goals to identify atrial fibrillation on high-risk patients or whether a significant clinical suspicion, one should always consider longer term monitoring by this study.                                 Finally, within the realm of atrial fibrillation, we'll review the article by Tilz, et al. published in Europace Volume 19, Issue 10 on left atrial appendage occluder implantation in Europe, indications anticoagulation post-implantation, results of the European Heart Rhythm Association survey. Currently, there's a high level of utilization of left atrial appendage occlusion for patients with atrial fibrillation who cannot otherwise be on a novel oral anticoagulants in Europe. Tilz, et al. performed a survey of providers performing these procedures. They found that about 52% of those centers performing left atrial appendage occlusion had electrophysiologist performing it as opposed to the remainder using interventional cardiologists. The most common indication for implantation was in those with high risk for stroke and with absolute contraindication to oral anticoagulation or history of bleeding. However, was most interesting from their study was that there was a very wide ranging practice in management after implantation in terms of use of antiplatelets for anticoagulants with 41% prescribing no therapy after implantation. There is even greater variability in therapies for patients who are found to have a thrombus after left atrial appendage occlusion ranging from no therapy to surgery.                                 These findings highlight the difficulty in managing practice patterns with novel technologist and in particular with left atrial appendage occlusion. The highly heterogeneous practice pattern found here suggests that large-scale population outcomes will be difficult to understand unless we understand the individual practice variation that is occurring such as considering what medications patients were prescribed on in the post-implant period or how patients were included in terms of whether or not they met the standard criteria. Furthermore, when a complication occurs such a thrombus septal left atrial appendage occlusion one might suspect that the implications of different strategies such as not doing any therapy all the way to routinely doing surgery tumor to clot should be considered.                                 Next, we will move on to the realm of ICDs, pacemakers, and CRT. First, reviewing the article by Pokorney, et al. published in Circulation in Volume 136, Issue 15 entitled Outcomes Associated With Extraction Versus Capping and Abandoning Pacing and Defibrillator Leads. In this study, Pokorney, et al. reviewed these two different approaches in abandoned leads amongst 6,859 patients. They found that extraction was associated with the lower risk of device infection, but there was no association between difference in mortality, need for future lead revision, or need for future extraction. This involved patients in the Medicare age group, but extraction patients of note, tended to be younger with fewer comorbidities, more often female and had a shorter lead dwell time. While they're statistically different, however, the actual number of years by which patients tended to be younger or to have a shorter lead dwell time was only a year.                                 The fact is that it is always hard to know what to do with an abandoned lead. Having more leads in the vascular system might lead to venous stenosis or might lead to patients having future problems when they need an extraction because of infection, or might make it harder to manipulate this in the vascular space. Thus whether extracting abandoned leads as opposed to just capping them and leaving there needs to be considered when taking any patient in for a lead revision or a lead addition for other reasons. These findings suggest that extraction confer similar mortality risk but lower long-term infection risk than capping them. However, it should be noted this is retrospective data set and given the extraction patients already were younger and had their leads for relatively shorter durations with your comorbidities, they might have reflected to healthier population anyway. However, these data are suggestive and highly the need for further study into whether a more aggressive approach with abandoned lead should be considered. Without randomized data, it will not be for certain.                                 Next, also within the realm of lead extraction, we'll review the article by Bongiorni, et al. published in the European Heart Journal in Volume 38, Issue 40 entitled The European Lead Extraction Controlled Study: A European Heart Rhythm Association Registry of Transvenous Lead Extraction Outcomes. This prospect of registry on lead extraction the largest to dates, Bongiorni, et al. reviewed safety and complications in addition to relationship to the type of center. They noted that the overall hospital major complication rate was 1.7% with mortality rate of 0.5% associated with lead extraction. The most common complication was actually pericardial synthesis, need for a chest tube or need for surgical repair. Overall, success rates for lead extraction in terms of complete removal of all lead components was 97%. However, it should be noted the overall complication rate and success rates were better in high-volume centers than low-volume centers. These findings are consistent with prior data published by [Desmott 35:22] and others, suggesting that more experience associates with better outcomes in lead extraction. However, these data represent the largest prospective registry on lead extraction and confirm the safety and efficacy of overall current practices.                                 These better data on modern lead extraction may help facilitate discussions with patients regarding actual outcomes and also decisions on whether or not extraction should be engaged in individual practices.                                 Next, we'll review the article by Aro, et al. in the realm of sudden death cardiac arrest entitled Electrical Risk Score Beyond Left Ventricular Ejection Fraction: Prediction of Sudden Cardiac Death in the Oregon Sudden Unexpected Death Study in the Atherosclerosis Risk and Communities Study, published in the European Heart Journal in Volume 38, Issue 40. In this study, Aro, et al. reviewed what features beyond ejection fraction could predict sudden death in community cohorts. They specifically focus on the electrocardiogram and demonstrated an electrocardiogram risk score based on the presence or absence of a number of features related to heart rate, left ventricular hypertrophy, QRS transition zone, QTc, and others. They found that amongst those patients with a left ventricular ejection fraction greater than 35%, the presence of four more of these ECG abnormalities confer an odd ratio of sudden death of 26.1. The importance of this article is highlighting how more complex considerations of clinical risk might help in further adjudication of sudden death in poorly characterized cohorts.                                 While most studies have concluded that addition of a variety of additional features such a T-wave alternans do not really confer incremental benefit beyond the ejection fraction in adjudicating sudden death risk and in helping decision making regarding ICD implantation. The fact is that more complex analyses that might exist in more nonlinear approaches or consider more advanced features, the ECG and combination, might confer some benefit in poorly characterized populations such as those with moderately reduced ejection fraction between 35 and 50. We know that while those with an ejection fraction less than 35% is a population have a higher risk within that population, the majority of patients who suddenly die do not have an EF less than 35%. Thus, identifying patients without an EF less than 35% who might be at risk is important. This study by Aro, et al. indicates one potential option to help discriminate patients who might not fit within normal categories for sudden death adjudication and did not fit neatly within the trials. However, prospect of evaluation of application of scoring systems either this one or others that may come in the future will be critical.                                 Changing realms yet again, we'll focus on cellular electrophysiology on an article by Kofron, et al. entitled Gq-Activated Fibroblasts Induce Cardiomyocyte Action Potential Prolongation and Automaticity in a Three-Dimensional Microtissue Environment, published in The American Journal of Physiology, Heart and Circulatory Physiology in Volume 313, Issue 4. In this publication, Kofron, et al. demonstrated that in this three-dimensional microtissue model, fibroblasts cause effects on the normal action potential in the surrounding environment leading to proarrhythmogenic automaticity. This model effectively demonstrated the activation of this fibroblast alone taken out of context by other triggers such as abnormalities of innervation, et cetera, could probably contribute to arrhythmogenicity into these hearts. It is well recognized in other studies that fibroblasts don't just cause proarrhythmic effects because of myocardial disarray. In fact, they can have paracrine effects on surrounding cells. This study by Kofron, et al. further highlights those potential effects. The presence of fibroblast amidst cardiomyocytes do not cause proarrhythmic tendency purely by shift in myocardial conduction direction, but also results from the effects of fibroblast once activated on these running cardiomyocytes action potentials of cells.                                 This study is suggesting specifically proarrhythmogenic arrhythmogenicity related to automaticity in those cardiomyocytes that are adjacent to fibroblast, highlights potential future targets for therapies and also highlights potential mechanisms by which arrhythmias might occurrence population.                                 Changing gears, we next look at genetic channelopathies in one article within the realm of Brugada syndrome and the second article within the realm of predicting QT interval. First, Hernandez-Ojeda, et al. published an article in The Journal of the American College of Cardiology Volume 70, Issue 16 entitled Patients With Brugada Syndrome and Implanted Cardioverter-Defibrillators: Long-Term Follow-Up. Amongst the 104 patients with long-term follow-up nearly greater than nine years on average, they noted a rate of appropriate therapy was very common especially in secondary prevention patients, however, was as much as 9% in otherwise asymptomatic patients. Appropriate ICD therapies, however, especially amongst asymptomatic patients were exclusively in those spontaneous type I Brugada ECG patterns and inducible ventricular arrhythmias, or those obviously the secondary prevention devices who have prior spontaneous ventricular arrhythmias. However, what is more interesting is that more than 20% of patients had some ICD-related complication. Furthermore, the overall incidence of inappropriate shocks was 8.7%, nearly the same rate as appropriate ICD therapies in the primary prevention population. These findings highlight that there is in fact a reasonable incidence of ventricular arrhythmic events needing ICD therapy even in asymptomatic Brugada patients.                                 However, I think the most striking finding is the high incidence of device-related complications of a follow-up, which highlights the need for considered selection and adequate device programming to avoid inappropriate ICD shocks and finally the need for regular follow-up of these relatively young patients receiving ICDs who might be more prone to complication with the long-term.                                 Changing gears, we'll next review an article by Rosenberg, et al. published in Circulation Genetics in Volume 10, Issue 5 entitled Validation of Polygenic Scores for QT Interval in Clinical Populations. Using more extensive genomic analyses, Rosenberg, et al. used populations and real-world cohorts including 2,915 individuals of European ancestry and 366 individuals of African ancestry. They demonstrated that clinical variables could account for about 9 to 10% of variation in QTc in Europeans and 12 to 18% in African ancestry individuals. However, interestingly, polygenic scores provided incremental explanation of a QTc variation but only in individuals of European ancestry. The reason we find this article interesting is the importance of understanding how much genetics can actually tell us and how what it can tell us might vary between difference, individuals of different backgrounds thus how we apply findings from one study to any other study. In the area of genetic testing, the Holy Grail is fully identifying overall risk scores to tell the patient what they may have without having to rely on clinical studies or other clinical variables. However, we do know that there is both an environmental component as well as the genetic components.                                 This study by Rosenberg highlights the importance of potentially considering both. The issue with the article, however, is the fact that while there was clear benefit of the polygenic score in patients of European ancestry, the African ancestry patients reflect the much smaller population almost one-eighth that of the patients included of European ancestry. Also, European versus African ancestry tend to be very broad-based terms. Whether or not there is greater polygenic variation within those of African ancestry as compared to those Europeans ancestry is relatively unclear. Thus while this study should be taken with grain of salt, it should also be considered in the context of providing a foray into seeing how polygenic scores could augment or understanding of how question intervals might vary in a population of people and might be identified immigrant patients.                                 Moving to the realm of ventricular arrhythmias, we'll first review the article by Siontis, et al. published in Heart Rhythm Volume 14, Issue 10 entitled Association of Preprocedural Cardiac Magnetic Resonance Imaging with Outcomes of Ventricular Tachycardia Ablation in Patients with Idiopathic Dilated Cardiomyopathy. In this study, Siontis, et al. tried to identify whether or not use of preprocedural MRI had any impact on overall procedural outcomes. They compared in a more modern practice where they are routinely obtaining cardiac MRI versus prior practice where they do not routinely obtain preprocedural MRI for ablation in patients with idiopathic dilated cardiomyopathy. They demonstrated that moderate use of preprocedural MRIs was associated with significantly greater procedural success mainly 63% in the modern approach versus 24% previously. The importance of the study why is in trying to understand what the actual value of preprocedural cardiac MRI is when patients are undergoing VT ablation particularly with non-ischemic cardiomyopathy. VT ablation outcomes are notoriously even harder to predict in non-ischemic cardiomyopathy cohorts than ischemic cardiomyopathy cohorts. Improved procedural experience, however, or different technologies may also alter long-term outcomes.                                 Thus, because the populations were not randomized and rather retrospective with a discrete change in practice that occurred temporally and just did not vary in terms of utilization over the course of periods of time when success rates might not have been affected just by incremental procedural success is difficult. However, these data suggest that future studies into the incremental role of MRI for VT ablation are needed to determine its utility.                                 Next, we'll review an article by Ho, et al. published in The Journal of Cardiovascular Electrophysiology in Volume 28, Issue 10 entitled ECG Variation During Ventricular Fibrillation Than Focal Sources Due to Wavebreak, Secondary Rotors, and Meander. Ho, et al. in this publication reviewed the role of rotors and focal sources in ventricular fibrillation. They attempted VF induction of 31 patients and use the combination of surface ECG and biventricular basket catheters to create face mask. They showed there's three differences between those with ventricular fibrillation that was mediate by rotors and those with ventricular fibrillation mediated by focal sources. Specifically those with rotor-based VF had greater voltage variation, which they demonstrated zero wavebreak, secondary rotor formation and rotor meander. One of the most critical findings of this study is the fact that a one-size-fits-all approach to consideration of the mechanism of fibrillation is likely unreasonable in most patients. They discriminate between rotor-based ventricular fibrillation and focal source-based ventricular fibrillation and highlighted there are discrete features that differentiate the two populations.                                 While this should be considered an initial foray into understanding these patients, clinical and computational size will be important into understand how we can discriminate mechanisms of complex arrhythmias between patients to help understand, which patients might most benefit from a specific ablation approach or therapeutic decision. This might also apply to atrial fibrillation where multiple mechanisms may coexist in the same patient for the pathogenesis of the arrhythmia.                                 Finally, we'll review an animal model by Patterson, et al. published in The Journal of Cardiovascular Electrophysiology in Volume 28, Issue 10 entitled Slow Conduction Through an Arc of Block: A Basis for Arrhythmia Formation Postmyocardial Infarction. In this study performed in the University of Oklahoma, Patterson, et al. reviewed a novel basis for arrhythmia formation after MI in an animal model. Amongst 108 anesthetized dogs, they demonstrated the delay potentials may decrement over shorter pacing cycle lengths leading to potential premature ventricular beat initiation after sufficient delay of the second potential. Thus, they demonstrated that there is a Wenckebach-like patterns of delayed activation specifically within this arc of conduction block associated with the region infarcted. These findings suggest that even across line of apparent conduction block there may be a potential for premature beat formation due to very slow conduction and thus a novel mechanism of PVC formation following myocardial infarction. Furthermore, it might highlight the mechanism by which to induce PVCs in this patient population                                 Just because there is conduction block the region of baseline mapping further provocative maneuvers to initiate or to discriminate where there might be very slow conduction might be critical to elicit arrhythmia in some patients.                                 Next, within the realm of syncope. We focus on article by Baron-Esquivias, et al. published in The Journal of American College of Cardiology Volume 70, Issue 14 entitled Dual-Chamber Pacing With Closed Loop Stimulation in Recurrent Reflex Vasovagal Syncope: The SPAIN Study. In this randomized double blind control study, Baron-Esquivias, et al. study the value of closed loop stimulation in the specific cohort of patients with cardio-inhibitory vasovagal syncope above 40 years of age. They demonstrated amongst 46 patients the closed loops stimulation was associated with the more than 50% reduction in syncopal spells in nearly three quarters of patients. However, it should be noted that up to 9% of patients continue to have syncope in your consistent frequency to prior. However, it should also be noted that sham cohort 46% of patients continue to have syncope while only a quarter were relieved. Syncope is one of the most challenging diagnosis to manage in electrophysiologic practice. This is both due to the heterogeneity of manifestation of syncope in terms of cause as well as the lack of many therapies that affect some of the autonomic features that mediate syncope. Largely, vasovagal syncope can be strategized into cardio-inhibitory and vasodilatory groups.                                 Generally, pacing will be more effective in theory for those more of a cardio-inhibitory than a vasodilatory component thus certainly patients can have both and thus that might be only partial attenuation of syncopal events by fixing the cardio-inhibitory by pacing but not the vasodilatory, which often requires medications. In this study, the use of closed loops stimulation seems to offer significant benefit in the specific population with cardio-inhibitory vasovagal syncope in age greater than 40 years. However, care should be taken not to necessarily apply these findings to patients not within this age group or within this diagnosis group.                                 Next within the realm of electrocardiography, we'll review an article by Yasin, et al. published in The Journal of Electrocardiology Volume 50, Issue 5 entitled Noninvasive Blood Potassium Measurement Using Signal-Processed, Single-Lead ECG Acquired from a Handheld Smartphone. Yasin, et al. reviewed the ability to determine changes in potassium level using the ECG. They demonstrated amongst 22 patients undergoing hemodialysis in whom estimation models could then be trained. The mean absolute error of ambulatory follow-up between the potassium estimated off of a single lead handheld smartphone-enabled ECG in the actual blood potassium was 0.38 milliequivalents per liter or a difference of 9% of the average potassium level. These findings suggest that in terms of clinical robustness a single lead smartphone-enabled handheld base ECG might be sufficient to estimate ambulatory potassium levels in patients who might be at high risk especially of hyperkalemia. The fact is that electrolytes and other abnormalities of a body homeostasis may be reflected in the ECG. However, whether the ECG may in turn be used to finally determine changes in characteristics such as electrolytes levels has not been very well described.                                 Previous work by the same group has suggested that the 12-lead ECG may be utilized to determine find potassium changes in patients undergoing hemodialysis. These findings while in small number of patients in this particular article highlights that ambulatory technologies such as the one they used here might in fact be utilized to discriminate potassium levels in patients who might be at risk of variations of potassium levels that can sometimes be life-threatening. Further validation will be required in larger populations, but this initial foray might create a paradigm for use of the ECG in ways beyond just looking for arrhythmias.                                 The final article we'll review is by Calzolari, et al. published in The Journal of American College of Cardiology, Clinical Electrophysiology in Volume 3, Issue 10 entitled In Vitro Validation of the Lesion Size Index to Predict Lesion Width and Depth After Irrigated Radiofrequency Ablation in a Porcine Model. In this paper published in the special of JACCEP focused on biophysics of ablation, Calzolari, et al. reviewed in vitro validation of lesion size indexing using radiofrequency ablation. Specifically, they reviewed the novel measure that incorporates not just contact force, power and time, but also impedance into predicting lesion quality. They noted that while lesion with in depth did not correlate with power or contact force alone, it did with either the lesion size indexing tool that they created and also with the force-time integral. However, the lesion size indexing where impedance was included was incrementally better than force-time integral. The truth is that improved prediction model lesion size inadequacy are critical during radiofrequency ablation.                                 Predicting lesion formation might help physicians know whether or not they have done adequate intervention at the time of application. They demonstrated incorporating impedance along with contact force, power, and time. The predictive value of their lesion indexing approach was quite good. However, further validation in association with an outcome is necessary to look at the incremental value. It also should be noted that this lesion size indexing tool did not necessarily predict steam pop formation, which is more often associated with power.                                 I appreciate everyone's attention to this key and hard-hitting articles that we have just focused on from this past month of cardiac electrophysiology across the literature. Thanks for listening. Now back to Paul. Paul Wang:         Thanks Suraj. You did a terrific job surveying all journals for the latest articles on topics of interest in our field. There's none an easier way to stay in touch with the latest advances. These summaries and a list of major articles in our field each month could be downloaded from Circulation, Arrhythmia, Electrophysiology website. We hope you'll find the journal to be the go-to place for everyone interested in the field. See you next month.    

Dr. Paul 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.                                                 In our first manuscript this month, Cho and Associates investigate the need for readmission for Dofetilide reloading. The FDA labeling for Dofetilide loading states that Dofetilide must be initiated or reinitiated in hospital with continuous electrocardiographic monitoring.                                                 In this article, the authors retrospectively examine the hospital records for 138 patients admitted for Dofetilide reloading for atrial arrhythmias. Of these 138 patients, 102 were reloaded at a previously-tolerated dose, 30 with a dose higher than a previously tolerated dose, and 2 at a lower dose, with the prior dosage unknown in 4 patients.                                                 In 44 patients, or 31.9%, dose adjustment or discontinuation of Dofetilide was performed, although, torsades de pointes occurred in two patients admitted to increased Dofetilide dosage, no torsades de pointes was observed in patients loaded with the same dose of Dofetilide.                                                 This is 0 versus 6.7% or P = 0.05. In 30 out of 102 patients, 29.4% reloaded at a previously tolerated dose. Dofetilide dose adjustment was required. In 11 out of 30 patients or 36.7% admitted for an increase in dose, a dose adjustment or discontinuation was required.                                                 The authors therefore concluded that dosage adjustments or discontinuation were frequent, and that their observations support the need for hospitalization for Dofetilide reloading. In the next manuscript Tilman Maurer and Associates report a novel superolateral approach to creating a mitral isthmus ablation line.                                                 Because the creation of an endocardial mitral isthmus line with the end point of bidirectional block maybe challenging, the authors examine 114 patients with perimitral annular flutter without a prior mitral isthmus ablation line.                                                 The authors compared the initial group of 57 patients, group A, who underwent catheter ablation using a novel superolateral mitral isthmus ablation line connecting the left sided pulmonary veins with the mitral annulus along the base of the left atrial appendage visualized by selective angiography to another group of patients, 57 patients in groups B undergoing ablation using a conventional mitral isthmus ablation line connecting the left inferior pulmonary vein to the mitral annulus.                                                 The authors found that bidirectional block was achieved in 56 out 57 patients in group A, or 98.2%, and 50 patients in group B, or 87.7%, P=0.06. Ablation from within the coronary sinus was required significantly less for creation of a superolateral mitral isthmus ablation line compared to a conventional mitral isthmus ablation line, 7.0% versus 71.9%, P is less than 0.01.                                                 The need for epicardial ablation from within the coronary sinus in the total length of the mitral isthmus line, 29.3 versus 40.8 millimeters were predictors for unsuccessful bidirectional mitral isthmus blockade. Pericardial tamponade was observed in group A, but not in group B, 5.2% versus 0%, P=0.24.                                                 The authors, therefore, concluded that superolateral mitral isthmus ablation line has a higher acute success rate compared with conventional mitral isthmus ablation line with a low likelihood of needing ablation from within the coronary sinus.                                                 In our next paper, Cronin and Associates examine the relationship between right ventricular pacing frequency, and the incidence of ventricular arrhythmias leading to ICD shock.                                                 Using the altitude database, the authors examined 389 appropriate shocks, and 425,625 transmissions received from 8,435 patients over a mean follow-up of 15.0 months.                                                 Transmissions with 80 to 98% right ventricular pacing were associated with a hazard ratio of 1.56 for an appropriate shock in the subsequent week compared to less than 1% right ventricular pacing, P=0.04 using a time dependent Cox proportional hazard model, however, the authors found that greater than or equal to 98% right ventricular pacing trended towards a lower risk of appropriate shock. Hazard ratio 0.61.                                                 Lifetime cumulative percentage right ventricular pacing was similarly associated with an increased risk of appropriate shocks at 80 to 98% right ventricular pacing, but not greater than or equal to 98% right ventricular pacing.                                                 The authors, therefore, concluded that an increased frequency of right ventricular pacing is associated with an increased risk of appropriate ICD shocks until the right ventricular pacing is greater than or equal to 98%.                                                 In the next manuscript, Wesley O'Neal and Associates examined 12,241 patients from The Atherosclerosis Risk in Communities Study, ARIC study, the association of individual QT components, that is R-wave onset to R-wave peak, R-peak to R-wave end, ST-segment, T-wave onset to T-wave peak, and T-peak to T-wave end with the occurrence of sudden cardiac death.                                                 The authors identified a total of 346 cases of sudden cardiac death identified over a median followup of 23.6 years. The prolongation of the QT interval was associated with a 49% risk of sudden cardiac death. Of the components of the QT interval only the T-wave onset to T-peak component was associated with sudden cardiac death with each standard deviation increase, hazard ratio of 1.19.                                                 The authors found similar results when the QT interval components were included in the same model, thus the authors conclude that the risk of a sudden cardiac death is driven by prolongation of the T-wave onset to T-peak component.                                                 In the next article by Kalliopi Pilichou and Associates, the authors examined copy number variations or CNVs in arrhythmogenic cardiomyopathy patients. The author studied 160 arrhythmogenic cardiomyopathy proband genotype negative for 5 arrhythmogenic cardiomyopathy desmosome genes using conventional mutation screening.                                                 Using multiplex ligation dependent probe amplification, MLPA, 9 heterozygous copy number variations were identified in 11 or 6.9% of the 160 probands. Of these, the authors found that 5 had the least of the entire plakophilin-2 gene to a deletion of only the PRP2 [exon 00:08:45], 1 a deletion of the PRP2 exon 6211, and 1 a PRP2 duplication of the 5 UTR to exon 1. One the desmocollin 2 duplication of exon 7 to 9, and one large lesion of chromosome 18 comprising both DSC2 and desmoglein 2 genes.                                                 All probands were affected by moderate severe forms of disease and 10 or 32% of the 31 family members carrying one of these deletions met the diagnostic criteria for arrhythmogenic cardiomyopathy.                                                 The authors concluded that identifying the copy number variations may increase the yield of genetic testing. In family members carrying the copy number variations, but not displaying the phenotype other factors are likely involved.                                                 In the article by Rahul Samanta and Associates, the authors examined in 7 sheep a mean of 84 weeks post MI, the influence of intramyocardial adipose tissue on scar tissue identification during endocardial contact mapping, the authors found that endocardial electrogram amplitude correlated significantly with intramyocardial adipose tissue.                                                 Unipolar, Right = negative 0.48, bipolar R = negative 0.45, but not correlated with collagen. Unipolar, R = negative 0.36, bipolar, R = negative 0.43. Intramyocardial adipose tissue, dense regions of myocardium were reliably identified using endocardial mapping with thresholds of less than 3.7 millivolts and less than 0.6 millivolts respectively for unipolar, bipolar, and combined modalities.                                                 Unipolar mapping using optimal thresholding remained significantly reliable, an AUC of 0.76. During mapping of intramyocardial adipose tissue confined to punitive scar border zone regions. Bipolar amplitude range of 0.5 to 1.5 millivolts.                                                 The authors concluded that combined bipolar and unipolar voltage mapping with optimal thresholds may permit delineation of intramyocardial adipose dense regions of myocardium following infarction.                                                 In the next article by Kevin Leong and Associates, the authors examined the substraight in electrophysiologic mechanisms that contribute to the characteristic ECG of Brugada syndrome. The authors studied 11 patients with concealed type 1 Brugada syndrome and 2 healthy controls by performing noninvasive electrocardiographic imaging, or ECGI, and ECG recordings during an Ajmaline infusion.                                                 Following Ajmaline infusion the right ventricular outflow tract had the greatest increase in conduction delay and activation recovery interval prolongation compared to the right ventricle or the left ventricle. In controls there was minimal change in the JST point elevation, the conduction delay, or activation recovery intervals at all sites with Ajmaline.                                                 In Brugada syndrome patients, conduction delay in right ventricular outflow tract, but right ventricle or left ventricle correlated with a degree of JST point elevation. Pearson R 0.81.                                                 No correlation was found between the JST point elevation and activation recovery interval prolongation in the right ventricular outflow tract the right ventricle or the left ventricle.                                                  The authors, therefore, concluded that the degree of conduction delay in the right ventricular outflow tract and not prolongation or re-polarization time accounts for the ST or J-point elevation seen in type 1 Brugada syndrome pattern.                                                 In the next article by Jonas Diness and Associates, the authors investigate the role of inhibition with small conductance calcium activated potassium channels in atrial fibrillation termination.                                                 Since these channels are predominately expressed in the atria compared to ventricles, they are a particularly attractive drug target. With a total of 43 pigs atrial tachy pacing was performed until they developed sustained atrial fibrillation that could not be reverted by vernakalant administration.                                                 After the SK channel inhibitor AP14145 was administered, vernakalant resistant AF reverted to sinus rhythm and could not be re-induced by burst pacing. In open chest pigs both vernakalant and AP14145 significantly prolonged atrial refractory of this and reduced AF duration without affecting the ventricular refractory in this or blood pressure.                                                 The authors concluded that SK currents played a role in porcine atrial repolarization and their inhibition by AP14145 demonstrates an arrhythmic affects in a vernakalant resistant porcine model of atrial fibrillation.                                                 In our final article by Padmini Sirish and Associates, the authors examined the role of several ion transporters in action potential duration in cardiac function. The solute carrier SIC26A6, which is highly expressed in cardiomyocytes plays an important role in cardiac intracellular pH regulation.                                                 Using the SIC26A6 knockout mice, the authors found that ablation of SIC26A6 results in action potential shortening, reduced calcium transients, reduced sarcoplasmic reticulum calcium load, and decreased sarcomere shortening in the SIC26A6 knockout cardiomyocytes.                                                 Ablation of the SIC26A6 reduced fractual shortening and cardiac contractility in vivo. Intracelluar pH regulation is elevated in the SIC26A6 knockout cardiomyocytes consistent with the chloride bicarbonate exchange activities of SIC26A6.                                                 The SIC26A6 knockout mice exhibited bradycardia and fragmented QRS complexes supporting the role of SIC26A6 in the cardiac conduction system, therefore, the authors provided evidence that the role of SIC26A6 cardiac electrogenic chloride bicarbonate transporter in ventricular myocytes as well as intracellular pH regulation, excitability, and contractility.                                                 That's it for this month, but keep listening.  Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcast "On The Beat." Take it away Suraj. Suraj Kapa:                          Thank you very much Paul and welcome everybody back to "On The Beat," where we'll review hard hitting articles across the electrophysiologic literature. It is my pleasure to introduce you to 15 different articles published in the past month of September across all the journals in cardiovascular medicine.                                                 The first area that we will be focusing on is atrial fibrillation with a specific focus within the realm of anticoagulation, and we refer you to a paper published by [Kurshida Doll 00:16:55], entitled "Factors Associated With Anticoagulation Delay Following New-Onset Atrial Fibrillation," published in The American Journal Of Cardiology on October 15, 2017.                                                 In this publication Kurshida Doll, reviewed the frequency with which there is a delay in introduction of oral anticoagulation after a new diagnosis of atrial fibrillation, and the impact on overall outcomes. In a large electronic medical record they identify incident episodes of atrial fibrillation between 2006 and 2014.                                                 They used the CHADS2 score rather than the CHADS-VASc score to estimate overall risk, and then after this they reviewekud the outcomes of the patients. They found for those patients in whom oral anticoagulation would have been recommended, the median time to initiation was around five days, with an interquartile range of 1 to 43, with by far most patients receiving Warfarin with about 86%.                                                 Interestingly, about 98 strokes occurred between the time of new atrial fibrillation diagnosis, and the actual initiation of oral anticoagulation. Several factors led to this delay in oral anticoagulation including female gender, absence of hypertension, prior falls, and the presence of chronic kidney disease.                                                 However, ultimately, by 6 months over 90% of patients were on oral anticoagulants appropriately, though still a slightly higher proportion appropriately in men than woman.                                                 They noted that most patients with new diagnosis of atrial fibrillation and noted to have an elevated stroke risk started on oral anticoagulation within 1 week. Given these findings it is important to consider how we wait to introduce oral anticoagulation into patients after initial diagnosis given many initial diagnoses may be made by internists, or even in some cases by the patient themselves on a remote monitor or an ambulatory monitor it is important to consider how they are tied into the individual, who would feel most comfortable and who's most apt to prescribe oral anticoagulation.                                                 Changing gears within atrial fibrillation we next move on to cardiac mapping and ablation, and specifically focus on a paper published by Black-Maier et al, in the September edition of "Heart Rhythm" entitled "Risk Of Atrioesophageal Fistula Formation With Contact Force-Sensing Catheters."                                                 While atrioesophageal fistula formation is a relatively rare complication of atrial fibrillation ablation it can be life threatening, contact force catheters for ablation of atrial fibrillation have come into vogue as they are felt to improve procedural effectiveness and potentially reduce complications by improving individual understanding of contact with the myocardium and when contact is excessive.                                                 However, there's been little exploration of the actual risk of atrioesophageal fistula. An [inaudible 00:19:50] from the association they refused the mod database or the manufacturer and user facility device experience database for adverse event reports.                                                 Amongst almost 27,000 device reports they identified a total of 78 atrioesophageal fistula cases. About 1,200 of the reports were related to contact force-sensing catheters and about almost 1,500 were related to non contact force sensing catheters.                                                 Of the 78 atrioesophageal fistula cases reported the vast majority were the contact force-sensing catheters with a total number of 65, or about 5 times more than with non contact force-sensing catheters.                                                 Unfortunately, esophageal temperature increases were only mentioned in about 2.5% of cases in contact force and power settings were not consistently reported in order to come to any conclusions. They noted the overall mortality with atrioesophageal fistula in this population was around 56%, with really the vast majority surviving as a result of surgical repair as apposed to stenting or no intervention.                                                 While this data is somewhat skewed because it's based on self reported data by proceduralists, who are reporting back to the mod database, it is important to consider whether or not there is actually an increase complication rate associated with contact force-sensing catheters as these catheters do reflect a fundamentally different catheter than the non contact force-sensing catheters routinely used due to changes in the stiffness, and the mechanics of the catheter itself.                                                 It is important to consider when using any new catheter with any new options for monitoring, or that might alter the stiffness, or other mechanical properties of the catheter, whether or not application of similar power settings are relevant.                                                 While the data is potentially skewed in the status set it will be important to consider it going forward as to whether or not there are implications of some increased risk of complications, and how to mitigate these by altering our contact force and power setting decision making.                                                 Further study will be required in order to better understand these data and the implications. I would refer the readers also to an article published by [inaudible 00:22:02] in circulation where they reviewed the mechanism of atrioesophageal injury and also to another publication published in The Journal Of Cardiovascular Electrophysiology this past month by [inaudible 00:22:11], where they did a meta analysis of the overall benefit of contact force related catheters over non contact force related catheters.                                                 In that paper they demonstrated that based on this meta analysis there seems to be an overall benefit in terms of outcomes in contact force-sensing catheters without a difference in procedural complications. However, I would refer the reader to the fact that there are very limited randomized studies comparing contact force versus non contact force catheters.                                                 Next, also within the realm of cardiac mapping and ablation we reviewed a publication by Haldar, et al., entitled Resolving Bipolar Electrogram Voltages During Atrial Fibrillation Using Omnipolar Mapping, published in the last edition of Circulation Arrhythmia Electrophysiology. Also, reviewed by Dr. Wang in last months podcast.                                                 The importance of this article lays in an improved understanding of what we mean when we talk about voltage or substraight mapping. In his paper, Haldar, et al., tried to understand better what the bipolar electrogram might actually refer to when comparing traditional bipolar mapping versus omnipolar mapping.                                                 This becomes important as we consider a low voltage guided substraight modification for not just atrial fibrillation ablation, but also potentially for ventricular arrhythmia ablation. They sought to compare the use of peak-to-peak voltage for assessment of bipolar voltage with omnipolar peak-to-peak voltages in both sinus rhythm and atrial fibrillation.                                                 They demonstrated that in canines vertical orientation of a catheter relative to the underlying tissue consistently resulted in a higher bipolar voltage in both sinus rhythm and atrial fibrillation. Furthermore, they show that the max obtained ominipolar voltage were consistently larger than multi-horizontal and vertical voltages in both rhythms.                                                 Vector field analysis of these wave fronts during atrial fibrillation in particular, demonstrated the omnipolar electrograms can account for a collision in fractionation, and required an electrogram of voltages independent of these effects. Thus, they suggested that the omnipolar electrograms can use maximum voltages, and can separate the influence from directional factors, collision, or fractionation especially when compared with contemporary bipolar techniques.                                                 The implications of the study are several. First off, when performing substraight mapping we traditionally use what we can in terms of trying to get appropriate bipolar signal analysis. However, catheters have significantly evolved since the early studies of bipolar voltage mapping in terms of establishing voltage cutoffs.                                                 There are many different multipolar catheters with varying interelectrode spacing, but sometimes prefer parallel orientation to the underlying myocardium as opposed to vertical orientation. The fact that bipolar voltage can significantly vary based on both orientation of the catheter as well as the rhythm is important when considering whether a substraight actually exists in a specific location or not, and what "Normal voltage cutoffs," where specific patients should be."                                                 When we consider novel catheters with increasing complex design including introduction of mini electrodes as well as omnipolar electrodes, it is important to consider whether an assessment of "Normal voltage," should be the same. Further study will be required to better understand how to best analyze these results.                                                 Moving to a different form of management in atrial fibrillation we will next refer you to a paper by Borris [Madal 00:25:44] published in this last month's edition of Heart Rhythm, entitled Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation, 1-Year follow-up outcome data of the EWOLUTION  trial.                                                 The EWOLUTION trial was a prospective multi center registry looking at the outcomes of WATCHMAN patients, who had indication for closure based on European society of cardiology guidelines. They sought to evaluate a 1 year followup of these patients.                                                 The baseline CHADS-VASc score was on average about 4-1/2 with a mean age of over 73 years. Almost a third of the patients had prior transient ischemic attach or ischemic stroke. They noted that the vast majority of the patients had a successful WATCHMAN implantation with a 1,005 out of 1,025 patients having successful implantation, with only 3 of these 1,005 patients having any leak greater than 5 millimeters.                                                 The majority up to 87% had T-followup at least once after initial implantation. Interestingly, the vast majority only used antiplatelet therapy with only 8% having vitamin K antagonist used in the post WATCHMAN implantation period.                                                 There was a reasonably high mortality of 10% in the first year after implantation, though this was felt to typically reflect advanced age and other comorbidities. Also, interestingly almost 4% of patients had thrombus on their device, which was independent of the drug regimen used. In other words whether antiplatelet therapy or vitamin K antagonists.                                                 Overall, the ischemic stroke rate was relatively low at 1.1%, with a relative risk of 84% versus estimated historical data, and also with a relatively low major bleeding rate of only 2.6% and this predominately being non-procedure of device related.                                                 Thus, they concluded that LA closure with the WATCHMAN device had a high implant and sealing success, and it appeared to be safe and affective in reducing ischemic stroke risk given that the relative incidence was only 1.1%, despite the fact that the vast majority were not actually even using oral anticoagulation.                                                 There are trial ongoing in the United States to evaluate whether or not patients can be safely kept off of oral anticoagulation in the peri-implant period as in some countries standard of care is to place them on anticoagulants in the immediate post implantation period.                                                 However, two other things need to be noted in this real world analysis of outcomes with WATCHMAN. Almost 10% or 1 out of 10 patients died within 1 year of followup, thus whether or not better patient selection is required to understand those patients will receive maximal benefit from this invasive procedure might be considered.                                                 Further, more almost 4% had device related thrombus. What this means in terms of stroke risk especially over longterm followup needs to also be considered. I think overtime we'll get better understanding of what those risks might be for an endocardial system for a left atrial appendage occlusion.                                                 But, staying within the realm of stroke risk in atrial fibrillation, we next review the article by King, et al., published in The Journal Of American College Of Cardiology, in the September 2017 edition entitled, Left Atrial Fibrosis and Risk of Cerebrovascular and Cardiovascular Events in Patients With Atrial Fibrillation.                                                 Cardiac MRI to evaluate late gadolinium enhancements suggesting regional cardiac fibrosis and atrial fibrillation is slowly taking steam, but primarily as a method of assessing potential efficacy of atrial fibrillation ablation with greater amounts of delayed enhancement potentially suggesting an overall lower risk, or a lower likelihood of success of atrial fibrillation ablation.                                                 King, et al., sought to evaluate in a retrospective cohort study regarding the risk of cerebrovascular and cardiovascular major events associated with a degree of delayed enhancement in MRI. They reviewed 1,228 patients undergoing cardiac MRI to assess left atrial fibrosis between 2007 and 2015.                                                 They then staged these patients and stratified them according their [Utah 00:29:45] stage, which had been previously recorded for the degree of fibrosis seen. They demonstrated on followup that there was a significantly higher incidence of major cardiovascular and cerebrovascular events associated with higher degrees of late gadolinium enhancement with a relative risk ratio of about 1.67.                                                 However, the only individual component of these outcomes that remains significantly associated with advanced gadolinium enhancement was actually stroke or TIA, with a hazard ratio of 3.94, thus they concluded that severe LA late enhancement is associated with increased cerebrovascular events principally.                                                 This study is important in that it highlights another potential risk factor that may need to be considered when risk stratifying patients for their risk of stroke. We recognize that even some paroxysmal patients can have extensive left atrial fibrosis, and some persistent patients might not have a ton of atrial fibrosis.                                                 Whether this can further help risk stratified patients in terms of overall stroke risk, and might identify and help characterize low risk patients further needs to be considered.                                                 One of the key features of this evaluation needs to be also the mechanism. In theory patients with greater endocardial injury of the atrium might be more prone to clot formation, and thus it may seem reasonable to expect indeed when we have more left atrial fibrosis as suggested by delayed enhancement on MRI. There may in fact be a higher greater cerebrovascular event rate.                                                 Finally, changing gears a little bit within the realm of risk stratification and management for atrial fibrillation we focused on autonomics and specifically a publication by Stavrakis et al., in the last month edition of Jack Clinical Electrophysiology, entitled Low Level Vagus Nerve Stimulation Suppresses Postoperative Atrial fibrillation And Inflammation In A Randomized Study.                                                 The group, headed up by Sonny [Poe 00:31:42] have previously published on both tragus stimulation as well as low level of vagus nerve stimulation in patients undergoing atrial fibrillation ablation. In this particular study they sought to evaluate whether or not implantation of a low level of vagus nerve stimulator during cardiac surgery could reduce the risk of postoperative atrial fibrillation.                                                 They sutured a bipolar wire to the vagus nerve preganglionic fibers along the lateral aspect of the superior vena cava at the time of surgery. They then performed high frequency stimulation of 50% below the threshold for slowing the heart rate for 72 hours, and those randomized to the vagus nerve stimulation group.                                                 The secondary group was a sham cohort. They demonstrated amongst the 54 patients randomized to either group that the frequency of postoperative atrial fibrillation was almost a third in the low level of vagus stimulation group when compared with the control group.                                                 Interestingly, their frequency of atrial fibrillation was not only lower, but the level of inflammatory markers also decreased with both serum tumor necrose factor alpha and interleukin 6 levels being significantly lower in the low level vagus nerve stimulation cohorts.                                                 In line with prior data from atrial fibrillation ablation these data were suggesting that low level of vagus nerve stimulation can suppress postoperative atrial fibrillation and attenuate the inflammatory response.                                                 Also, in this past month there was a paper by [Yoo 00:33:09] et al., in The Journal Of The American Heart Association, specifically looking at the use of vagus nerve stimulation at the level of the tragus in patients with obstructive sleep apnea associated atrial fibrillation.                                                 Similar to prior work form the Oklahoma group, they demonstrated that in fact there is a beneficial effect on reduction of atrial fibrillation, and this is primarily mediated through attenuation of autonomic factors that mediate obstructive sleep apnea related atrial fibrillation.                                                 Moving away from atrial fibrillation, we next delve in cellular physiology first starting with an article published in Nature Scientific Report this past month, on very low density lipoprotein in metabolic syndrome, and how it modulates gap junctions and slows cardiac conduction.                                                 In the past year there have been multiple studies regarding specific cell types and how they might interplay with cardiac fibrosis, and risk of conduction slowing. In this publication we had all reviewed the effect of very low density lipoproteins, and their effect on cardiac conduction in, in vitro models.                                                 They demonstrated that primarily through down regulation of [conexion 00:34:21] 40 and conexion 43, very low density lipoproteins have significant impact on cardiac conduction with increased prolongation of the P-wave, PR-intervals, QR restoration, and QTC intervals.                                                 Thus, they concluded that very low density lipoproteins may contribute to the path of physiology of both atrial fibrillation and ventricular arrhythmias that can be seen in metabolic syndrome. This report is important because it highlights the fact that we can actually see other cell types including LDL causing a significant reduction in cardiac conduction and thus mediating arrhythmogenesis.                                                 In fact there was one other paper published just a couple weeks prior also in The Nature Of Scientific Reports by [Lee 00:35:04] et al., entitled Human Electronegative Low-Density Lipoprotein Modulates Cardiac Repolarization Via LOX-1-Mediated Alteration Of Sarcolemmal Ion Channels.                                                 They showed that LDL can actually result in QTC prolongation in patients with ischemic heart disease by specific mechanisms involving LOX-1. Recognition of the mechanisms behind which less traditional factors such as VLDL or LDL may mediate alterations in cardiac conduction are important when we consider our potential novel targets for treatment of arrhythmias in patients whether for prevention or for treatments.                                                 In light of this attempt to identify novel targets we next move on to another paper in the realm of cellular electrophysiology published by [Toib 00:35:52] et al., in The American Journal of Physiology, Heart and Circulatory Physiology, entitled Remodeling Of Repolarization And Arrhythmia Susceptibility In A Myosin-Binding Protein C Knockout Mouse Model.                                                 In hypertrophic cardiomyopathy there might be multiple mechanisms that might lead to increased risk of ventricular arrhythmias. These might be scar related due to the fact that patients can burn out from the hypertrophic cardiomyopathy overtime and get both endocardial, epicardial, and mid myocardial fibrosis, but what are the mechanisms that might mediate the development of ventricular arrhythmias and hypertrophic cardiomyopathy remain to be elucidated, and there's been very limited evaluation of the effect of repolarizing potassium currents on this risk.                                                 Thus, Toib, et al., studied myosin-binding protein C knockout mice to look at what happens with repolarizing potassium currents in his cohorts. They demonstrated that in these knockout mice there was a prolongation in the corrected QT interval when compared to the wild type mice with overt ventricular arrhythmias.                                                 They also demonstrated that there is action potential prolongation associated with a decrease for polarizing potassium currents, and a decreased MRNA levels of several key potassium channels subunits, thus, they concluded that in this specific subtype of hypertrophic cardiomyopathy needed by myocin combining protein C mutations that part of the ventricular arrhythmia risk might be due to a decrease in polarizing potassium currents in turn leading to increase in action potential and QT interval.                                                 The reason that this particular finding is important is in my highlight drug selection in specific types of hypertrophic cardiomyopathy. In my postulate for example the class 3 antiarrythmics drugs might actually increase risk in some subtypes of hypertrophic cardiomyopathy due to down regulation of potassium channel subunits.                                                 Consideration of this is critical when best evaluating how to mange and treat these patients. Changing gears to another method of channelopathy we focus within the realm of genetic channelopathies and specifically on Brugada syndrome.                                                 In this last month's edition of Heart Rhythm, Sierra, et al., published their series of longterm prognosis of drug induced Brugada syndrome. They reviewed a consecutive cord of 343 patients with drug induced Brugada syndrome, and compared their outcomes with 78 patients with a spontaneous type 1 pattern.                                                 The mean age of patients was around 41 years. Interestingly, about 4% of the patients had a clinical presentation of 7 cardiac deaths, and 25% had a clinical presentation of syncope. However, the majority of the patients were asymptomatic, around 71%.                                                 Most of the patients were female amongst the drug induced Brugada syndrome cohort. They demonstrated that there were less ventricular arrhythmias both induced string and electrophysiology study, and seen over followup of up to 62 months in the drug induced Brugada syndrome cohort as compared with the spontaneous type 1 cohort.                                                 Overall, the event rate in drug induced Brugada syndrome was 1.1% of [person year 00:38:54] versus 2.3% of person year in patients with spontaneous type 1 pattern.                                                 They suggested that presentation of sudden cardiac death or inducable ventricular arrhythmias at the time of VP study were independent risk factors associated with arrhythmic events in drug induced Brugada syndrome. However, if a patient was asymptomatic and had no inducible ventricular arrhythmias they had a significantly better prognosis with drug induced Brugada syndrome over a spontaneous type 1 pattern.                                                 Thus, they concluded that even in drug induced Brugada syndrome sudden cardiac death is possible. However, in asymptomatic patients without a prior clinical presentation of sudden cardiac death or inducible ventricular arrhythmias during electrophysiology study, they may be relatively safer than their spontaneous type 1 counterparts.                                                 This study highlights the importance of stratification of patients into the mechanism of how their genetic channelopathy presents whether as a spontaneous finding or as a finding in the setting of other events. Further prospective analysis, however, is needed to best guide how to manage these patients and in whom to put a defibrillator as I would note that almost 37% of these patients actually had an ICD placed with the vast majority without incident events.                                                 Speaking of implantable devices we next move to the realm of ICD pacemaker and CRT, and specifically we review the publication by Samar, et al., published in Jack Clinical Electrophysiology this past month on the diagnostic value of MRI in patients with implanted pacemakers and implanted cardiover defibrillators across the population.                                                 Does the benefit justify the risk of proof of concept study? Increasingly, MRIs are being done in patients with even Legacy defibrillators and permanent pacemakers. However, when assessing the benefit versus the risk it's important to understand did the MRI actually change outcomes, and this was a specific question that the authors tried to answer.                                                 They took patients with conventional or Legacy pacemakers or ICDs, and tried to evaluate what the actual benefit was on those patients in whom an MRI was done. They specifically asked four questions, one, did the primary diagnosis change, two, did the MRI provide additional information to the existing diagnosis, three, was the pre-MRI or tentative diagnosis confirmed, and four, did the patient management change?                                                 They noted there were no safety issues encountered in any of the 136 patients an MRI was performed. In 97% it was felt that MR added value to the patient diagnosis and managements, with 49% of investigators feeling that MR added additional valuable information to the primary diagnosis, and in nearly a third the MR actually changing the principle diagnosis and subsequent management of the patient.                                                 Increasing evidence suggesting that MRI can be safely performed even in Legacy pacemakers and ICDs, and the fact the MRI can wield important evidence related to diagnostics needs to be taken into consideration as investigators and other centers try to identify methodologies for safely performing MRIs in these patient cohorts.                                                 It seems thus far like MRI might justify risk of these procedures under controlled settings. Next, we move also within the realm of implantable cardioverted defibrillators, but to a different assessment published by Kawada et al., in this past months issue of Heart Rhythm where they sought to evaluate the comparison of longevity in clinical outcomes of implantable cardioverted defibrillator leads among manufacturers.                                                 They specifically sought to assess the longevity of [Lynox 00:42:35] SSD by [Atronic 00:42:36] leads compared with Sprint Fidelis by Matronic, Sprint Quattro by Matronic, and Endotac Reliance by Boston Scientific Leads. The reasoning for this was early failure of some of the biotronic Lynox leads has been reported. Thus, they retrospectively reviewed patients undergoing implantation with these different lead approaches between 2000 and 2013.                                                 They noted failure rates of the Lynox versus Spring Fidelis versus Endotac leads where 3.2% for a year, versus 3.4% for a year, versus 0.61% for a year respectively. No lead failure was notable with a followup [inaudible 00:43:13] in Sprint Quattro leads, thus, they felt that the survival probability of Lynox leads was comparable to Sprint Fidelis leads, and lower than that of Endotac or Sprint Quattro leads.                                                 They found that age was the primary predictor of Lynox lead failures with the patients less than 58 years old had significantly increased risk of lead failure compared with those greater than 58 years old, thus, they concluded that this was a first description of a lower survival rate for Lynox leads in an aging population.                                                 Early identification of leads that might be at risk of failure is critical in patient risk stratification. The finding that there might be other leads that might be at risk of failure highlights the importance of close monitoring of these leads in contribution to register data.                                                 I would note that within this study that it was primarily done at one center and the vast majority of patients actually received Lynox leads. Thus, further evidence was clinically required for more centers to understand what the mechanism of this risk is, and also whether the risk is born out consistently across multiple centers particularly because the vast minority got the one lead, but didn't have any lead failure encountered for.                                                 Further, speaking about defibrillators we focus on the different mechanism of failure, and specifically the publication by [Thogersen 00:44:38] et al., published in last months' edition of Circulation And Arrhythmia Electrophysiology entitled Failure To Treat Life Threatening Ventricular Tachy Arrhythmias In Temporary Implantable Cardioverted Defibrillators Implications For Strategic Programming.                                                 In this publication they did not so much focus on lead failure, but the failure the ICD due to potential strategic programming decision making on appropriately treating ventricular tachy arrhythmias. Their current consensus recommendations as far as using a generic rate threshold between 185 and 200 beats per minutes in primary prevention ICD patients, thus, they sought to determine in the case series what the relationship between program parameters and failure of modernizing ICDs to treat for VF actually worked.                                                 Between 2015 and 2017 at four institutions they reviewed cases where normally functioning ICDs failed to deliver timely therapy for VF. There were a small number of patients noted fitting this criteria with only 10 ambulatory patients. Five actually died from their untreated VF, whereas four had cardiac arrests through a witness requiring external shocks, and one was ultimately rescued by a delayed ICD shock.                                                 The main reason that they were not appropriately treated were that the ventricular fibrillation event did not satisfy the programmed detection criteria in nine out of ten patients. Seven of the patients had the slowest detection rates consistent with generic recommendations, but were never tested in the peer review trial for the manufacturers ICDs.                                                 Namely, the decision making on the appropriated generic rate threshold was tested on specific manufacturers ICDs, but didn't apply the decision making on programming on other manufactures ICDs. In some cases manufacturers specific factors were interacting with fast detection rates to withhold therapy such as enhancement in MIC wave oversensing.                                                 Thus, they demonstrated that in this population untreated VF despite recommendation programming, accounted overall for 56% of sudden deaths and 11% of all deaths in the overall cord of patients during the study period.                                                 Thus, over half of the cases where sudden death occurs in patients with ICDs appears to be due to untreated VF despite recommended programming. Thus, they concluded that these unanticipated interactions or complex decision making regrading generic program of parameters might in part lead to withholding of therapy inappropriately in ventricular fibrillation.                                                 This publication highlights the importance of thoughtful decision making when translating evidence based detection parameters both between manufacturers and applying them across individual patients.                                                 While the overall number of patients is quite low, mainly only ten patients who were affected by this event, the number of patients dying as a result of it is fairly high in terms of a percentage with 56% of sudden deaths occurring as a result of untreated VF from variation from recommended programming.                                                 Closer attention needs to be paid to understanding how to better assess which patients would benefit from the current generic rate thresholds as opposed to who will be harmed by it. It is possible that one size fits all approach will always result in some harm to some, while benefit to others as potentially cutting down the lower rate cutoff in some patients might lead to inappropriate therapies, which might be as life altering as untreated VF in many patients.                                                 Finally, keeping within the realm of defibrillation we review an article by [Layva 00:48:24] et al., published in last month's edition of The Journal of American College of Cardiology entitled Outcomes of Cardiac Resynchronization Therapy With or Without Defibrillation in Patients With Nonischemic Cardiomyopathy.                                                 There are several recent studies that have started to cast doubt on what the incremental benefit of defibrillation adage cardiac resynchronization therapy actually is in nonischemic cardiomyopathy.                                                 However, we also know that in patients with scar noted on MRI that there can be an increased risk of ICD therapy, thus, part of the difficulty that some individuals have is how we define the nonischemic cardiomyopathy cohorts. Namely, is all nonischemic cardiomyopathy crated equal and we can better risk stratify this population to subtypes some of whom might benefit from primary correction defibrillators and some of whom might not?                                                 Thus, in this study they aimed to determine whether CRTD is superior to CRTP in patients with nonischemic cardiomyopathy based on the presence or absence of left ventricular midwall fibrosis detected by cardiac magnetic resonance.                                                 There were a total of 68 patients who had midwall fibrosis, and 184 patients who had not, and all of them underwent the evaluation prior to CRT implantation. They noted that the presence of midwall fibrosis was an independent predictor of total mortality with a hazard ratio of 2.31 as well as total mortality or heart failure hospitalization.                                                 This sudden cardiac hazard ratio was about 3.75 with an increased risk attributable to the presence of midwall fibrosis. They also noted that total mortality or heart failure hospitalization, and total mortality or hospitalization for major adverse cardiac events was significantly lower in patients with CRT defibrillator than with CRT pacemaker in those with midwall fibrosis, but not in those without midwall fibrosis.                                                 These findings highlight that in some patients with nonischemic cardiomyopathy CRTD may be superior to CRTP, though these might be guided by the presence of abnormal substraights. The evaluation of what nonischemic cardiomyopathy means in an individual patient needs to be closely considered.                                                 Nonischemic cardiomyopathy is a blanket term for all those patients who do not have an ischemic cardiomyopathy and who may or may not have been fully evaluated for discrimination of another type of myopathy such as infiltrated myopathies for example sarcoidosis.                                                 The value of cardiac magnetic resonance imaging is being increasingly understood as it applies to both risk stratification, nonischemic cardiomyopathy, as well as the value in decision making as far as treatment of these patients. In a recent publication published this past month as well in Jack Electrophysiology, by [inaudible 00:51:13], et al., they reviewed the efficacy of implantable cardioverted defibrillator therapy in patients with nonischemic cardiomyopathy based on a meta analysis of existing trials.                                                 They demonstrated in a meta analysis of randomized controlled trials that compared to medical therapy ICD has significantly improved survival among patients with nonischemic cardiomyopathy with an injection fraction of less and equal to 35%. However, CRT defibrillator overall was not associated with statistically significant mortality death when compared to CRT pacemaker.                                                 These findings are actually complimentary to each other, but need to be considered in context. One of the indications for the recently published Danish study was the fact that not only is CRT being increasingly utilized appropriately in patients with nonischemic cardiomyopathies, but also guideline directed medical therapy has improved over the course of the last several years since the initial trials of defibrillator therapy as primary prevention.                                                 Furthermore, the trial was actually powered based on a 25% reduction in overall events. Thus, even if there's a smaller benefit it would not necessarily be powered to identify if this is statistically significant. One issue as stated is the fact that nonischemic cardiomyopathy might be a milieu of different causes in individual patients. Some of whom might be at high risk for sudden cardiac death and some of whom might not.                                                 The publication by Levya, et al., highlights that better attempts at risk stratification on the basis of either MRI or other modalities might be important in helping us further assess who actually benefits from ICD, however, when mixing in prior trials with more recent trials that existed at different areas of medical therapy, and different areas of appropriate use of devices such as CRT it is critical to consider whether or not the same cutoffs, the same power calculations still apply.                                                 It is doubtless that defibrillator therapy is needed in many patients with both ischemic and nonischemic cardiomyopathy even with improved therapies for these patients otherwise. However, this multitude of publications coming out to improve our assessment of the utility of ICDs should not necessarily call into question of whether or not ICDs are merited at all, but should call into question whether we understand and have come to the best form of risk stratification for those patients who would most benefit, and thus this is an opportunity for us to identify those patients better.                                                 Next, we will move to the realm of supraventricular tachycardia's and specifically an article published by [Yang 00:53:41], et al., in the last month's edition of Heart Rhythm, entitled Focal Atrial Tachycardia's From The Parahisian Region, Strategies From Mapping And Cather ablation.                                                 With focal atrial tachycardia's from the parahisian region can potentially be targeted from multiple different regions, the right atrial septum, the noncoronary cusp, and the right middle septum. However, the optical mapping and ablation strategy for these arrhythmias remains unclear, and thus they sought to investigate electrophysiology characteristics in optimal ablation sites for parahisian [inaudible 00:54:10] from these different areas.                                                 They reviewed 362 patients with atrial tachycardia's undergoing catheter ablation. They did DCG analysis and electrophysiology studies extensively on these patients. Overall, 91 patients had a parahistian origin. An ablation was successful in a majority of these up to 94.5%.                                                 The majority of these patients had their AT successfully eliminated from the noncoronary cusp with about 44 of the 91 having it targeted from this region, with the remaining 23 from the right atrial septum, and 19 from the right middle septum. They noted those who had an earliest potential at the distal HIS catheter tended to have their site of origin more successfully ablated from the noncoronary cusp.                                                 However, those with a greater [inaudible 00:54:55] in the proximal HIS catheter tended to more likely have successful ablation from the right atrial septum or right middle septum. The mean timing of the A potential in differentiating right and middle septum ATs from right atrial septum ATs, was that they attended to be later in right middle septum ATs, than right atrial septum ATs, or noncoronary cusp ATs.                                                 They noted that for atrial tachycardia's arising from the right atrial septum and right middle septum, an A to V ratio less than 1.22 predicted safe and successful ablation with a sensitivity of 88.4% and the specificity of 91.7%. Thus, they concluded that activation sequence and timing of the A and HIS catheter could provide clues for where the most likely successful site of ablation would occur for parahisian tachycardia's.                                       

Jane Ferguson:                Hello, and welcome to episode one of Getting Personal: Omics of the Heart, a podcast from the Functional Genomics and Translational Biology Council of the American Heart Association. I'm Jane Ferguson, the current chair of the FGTB Professional Education and Publications Committee. This monthly podcast will bring you up to date with the latest in genomics, other omics technologies, and precision medicine as they relate to cardiovascular and metabolic disease.                                            In each episode, we'll give you an overview of some of the latest research to be published, and delve deeper into topics of particular interest. Whether you're a clinician, researcher, genetic counselor, or other healthcare or science professional, we hope these podcasts will be informative, and help you stay up to date with the latest developments in this exciting field.                                            In this episode, my colleague Naveen Pereira talks to Amit Khera about his recent publication with Sek Kathiresan and colleagues in the New England Journal of Medicine entitled Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease, and we highlight a recent AHA scientific statement on the use of genomics. But first, Naveen and I will give you a round up of some interesting papers from the past month. Naveen Pereira:              So Jane, there was this really interesting paper in the American Journal of Medicine whether we can use gene expression signatures along with other clinical covariates to predict the presence or evaluate whether symptoms are suggestive of obstructive coronary artery disease. Jane Ferguson:                Yes. This paper was published online on the 16th of December 2016. It comes from Joseph Ladapo, Mark Monane and colleagues. They carried out this study in 566 patients from the PRESET Registry, which enrolled stable, nonacute adults presenting with typical or atypical symptoms that were suggestive of obstructive coronary disease.                                            What they did was calculate an age/sex/gene expression score, or ASGES score. They included gene expression, which they measured in a blood sample collected in a PAXgene Tube, and this score ranges from 1 to 40. They've previously validated this, and a score less than or equal to 15 indicates that a symptomatic patient is very unlikely to have obstructive coronary artery disease. The genes they measured include 23 genes that are selectively expressed in circulating neutrophils, NK cells, and B- and T-lymphocytes. Naveen Pereira:              So really, this expression reflects inflammation, and the hypothesis being perhaps these inflammatory markers are very indicative of the presence of obstructive coronary artery disease, or plaque rupture I guess, huh? Jane Ferguson:                Yes, exactly. What they actually found was that individuals with high scores were referred to cardiology or advanced cardiac testing at far greater rates, and then even of subjects with low scores who did undergo additional testing, none of them had any detectable abnormality. Then, in subjects with high scores who did undergo further testing, 14% had abnormal findings. So after a year of followup, 1.2% of patients with an ASGES score below 15 had an adverse event, compared to 4.5% of those with elevated scores. Naveen Pereira:              So a fairly high negative predictive value, huh Jane? Jane Ferguson:                Right. Right, exactly. Naveen Pereira:              Did you find any limitations, Jane, in this study? Jane Ferguson:                There were some. Well firstly, it's worth noting that the score itself, and this test, has been developed by CardioDx, and a number of authors on this manuscript are affiliated with CardioDx. In addition to that, they did not include a control group in this. That certainly is somewhat of a limitation, but the authors say that this is probably still useful, and it may have some clinical utility in guiding decision making for patients with obstructive CAD. However, whether or not this is actually true will probably require some additional testing. Naveen Pereira:              So quite a foray into using this perhaps in the emergency room or in hospital. So I guess our audience should look out for this in the American Journal of Medicine, December 2016. Jane Ferguson:                Yeah. Naveen Pereira:              So there was another paper that we kind of thought was interesting, Jane, from the European Heart Journal. Jane Ferguson:                Yes, exactly. This comes from Jozef Bartunek, and Andre Terzic, and their colleagues, and they were reporting this on behalf of the CHART Program. Naveen Pereira:              So this was published on January 15, 2017. Jane Ferguson:                Yeah. This was a prospective, randomized, double-blind, sham-controlled trial, which was the Congestive Heart Failure Cardiopoietic Regenerative Therapy, or CHART-1 trial. In this trial, they were aiming to test safety and efficacy of delivery of cardiopoietic cells. They recruited subjects who had symptomatic ischaemic heart failure, and they consented to bone marrow harvest and mesenchymal stem cell expansion. They ended up randomizing 315 subjects.                                            They received cardiopoietic cells delivered endomyocardially by a retention catheter, or either a sham procedure. The outcome that they were looking at was a hierarchical score, which is assessed 39 weeks post-procedure. That score comprised all-cause mortality, the number of worsening heart failure events, the Minnesota Living with Heart Failure Questionnaire, a difference in the six minute walk test, change in left ventricular end-systolic volume, and change in left ventricular ejection fraction. So it was interesting. They found a neutral effect on the primary end point, but they did find some evidence of benefit in subgroup analyses, which were based on baseline heart failure severity. Naveen Pereira:              But and this was not designed to show efficacy, because it was primarily a safety trial. Is that right, Jane? Jane Ferguson:                Yes, exactly. Naveen Pereira:              Right. Jane Ferguson:                Overall, they found that there were no indications for concern regarding safety, so I think they've shown that certainly this is a technique that is safe and is well-tolerated, and I think it's really quite exciting. Future studies that are adequately powered, particularly looking at subgroups of individuals, may actually identify patient populations that would derive particular benefit from cardiopoietic cell therapy. Naveen Pereira:              Fascinating, so it'll be interesting to see what the Phase III clinical trial will show. Overall, a new foray into regenerative medicine. Jane Ferguson:                Yeah, yeah. Really interesting. Naveen Pereira:              Hi everybody. My name is Naveen Pereira. I'm from the department of cardiovascular diseases at Mayo Clinic in Rochester, and on behalf of the Functional Genomics and Translational Biology Council of the American Heart Association it gives me great pleasure to interview Amit Khera. We are going to be discussing this very exciting paper that was published in The New England Journal of Medicine on November 13, 2016, titled Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. Amit, welcome. We are so glad you could make it. We really appreciate you doing this for us. Amit Khera:                      Naveen, thank you so much for having me. It's a real pleasure. By way of introduction, as you said my name is Amit Khera, I recently joined as a staff cardiologist at Massachusetts General Hospital in Boston where I see both general cardiology patients and also work in the prevention center. But one of the things I've noticed is that many of us have heard a lot about precision medicine, and how we can incorporate genetics into some of our clinical decision making, or risk stratification. So I've really been working with Sek Kathiresan at both Mass General and the Broad Institute to get training in both genetics to complement some of the clinical medicine aspects in order to help us get at some of those questions. Naveen Pereira:              Fantastic. Amit, what got you interested in genomics? Amit Khera:                      Sure. Well, you know for a complex disease like coronary artery disease, and risk of a heart attack, we've really known for a long time, like since the 1960s that there is a familiar pattern, meaning that if your brother or your father had a heart attack at a young age, your risk of having one is increased by almost a factor of two. It's really been only recently that the technology has allowed us to get at those questions, and really isolate the exact genetic determinant.                                            So really in the last 10 years, we've been able to identify a large number of variants that influence an individual's risk of coronary artery disease. So it really an opportunity to be in a place where the technology was coming along, where we have discovered all these variants, clinical medicine of course has come a long way since the 1960s as well. So the idea was to really put these two bodies of work together, and see what we could come up with. Naveen Pereira:              Yeah. This is very exciting. Amit, I completely agree with you. In our clinical practice we see patients with strong familial history of coronary artery disease, so certainly inheritance has been suspected for some time, and in fact genome-wide association studies have been done to identify loci for coronary artery disease.                                            As you know, the effect size of these individual variants have been small. And so groups have got together to form genetic risk scores, where they take kind of an aggregate of the effect of these individual variants, and we think this is more helpful. And this is what you did for your paper, so can you describe to us a little bit about how you derived the genetic risk score that you applied in this great paper? Amit Khera:                      Sure. The first aspect of our paper involved proving basically that we could quantify someone's genetic risk for having a heart attack. So in order to do that, as you said, we took advantage of a number of previously published genome-wide association studies. There are about 50 genetic variants all across our genome and different chromosomes that we know are strongly linked to coronary artery disease from a statistical standpoint, but actually might only have a very modest impact on coronary disease.                                            So let's say any individual could have a maximum of 100 risk variants. Now, some people might have inherited just by chance 80 variants, and other people might have inherited only 20. So we basically genotyped, meaning measured all 50 genetic variants in a large number of people, and then we said, "Those who are in the top quintile," meaning the top 20% of the genetic risk score, we're going to say "those people are at high genetic risk." And by contrast, if you're in the lowest quintile, we said, "Okay, those people are at low genetic risk." Naveen Pereira:              Right. Amit Khera:                      Then the question became okay, well does that categorization actually predict your risk of having a heart attack? So in order to do that, we analyzed over 50,000 individuals from three different prospective cohort studies, and what we found actually was that if you compare the high genetic risk to the low genetic risk people, their risk for having a coronary event over prospective follow up was increased by about 91%, meaning almost two fold. Naveen Pereira:              Wow. Oh, that's amazing. So using the genetic risk score, you could almost predict a doubling of the risk for coronary events. That's fantastic. Can you describe these populations briefly, Amit? Who are these people that you applied the genetic risk score to? Amit Khera:                      Sure. So we took advantage of three prospective cohort studies. The first was a Atherosclerosis Risk in Communities study, and that was a community based population of about 8,000 people. The second was the Women’s Genome Health Study, over 20,000 women who were originally recruited as part of a randomized control trial, and the third was the Malmö Diet and Cancer Study, which again had more than 20,000 individuals.                                            The really nice thing about these studies was that they were asked questions in a similar way, and they were followed ... in each case, participants were followed for about 20 years. So we really had a long time to observe what happened to these folks over time. Naveen Pereira:              So these are really longitudinal cohorts, not specifically disease oriented cohorts, but just community based, Amit? Amit Khera:                      That's exactly right, and in fact none of the individuals had coronary disease at baseline. They were all disease free- Naveen Pereira:              I see. Amit Khera:                      ... and then we followed them over 20 years to see who developed the coronary artery disease and who did not. Naveen Pereira:              So this is really applicable to the general population. Amit Khera:                      I do believe that these risk estimates would for sure hold true. Naveen Pereira:              Okay, wonderful. So Amit, you know you have the genetic risk score for coronary artery disease, and you have some great longitudinally followed population based cohorts, and you were studying a specific phenotype, so can you describe to us the phenotype? Amit Khera:                      Well, the primary outcome phenotype was incident coronary events, and those were all adjudicated by different committees, but it basically involved individuals who had either a new heart attack or myocardial infarction, they had to have one of their vessels either stented or bypassed via revascularization, or in fact it was determined that they died from coronary artery disease. So that was the outcome which we were trying to predict. Naveen Pereira:              Amit, let's get straight into it. What did you find? Amit Khera:                      So as a preventive cardiologist, I often see patients in my clinic who come to me and they say, "You know, almost everyone in my family has had a heart attack." Oftentimes at a very young age, and in some cases that can lead to almost a sense of determinism, where they feel like maybe they are unable to control their fate. So our primary question was a really a pretty simple one, which is to what extent can a healthy lifestyle offset someone's genetic risk of coronary disease.                                            So as I mentioned, we had a way of quantifying someone's genetic risk, and then we next said, "Okay, we want to quantify someone's lifestyle risk." So for that we kept it pretty simple. We had four criteria of what makes up a healthy lifestyle. First, no current smoking. Second, avoiding obesity. Three, regular exercise, and fourth, adhering to a healthy diet. And we said, "Okay, if you have at least three out of those four," we gave you a pass and said "you had a favorable lifestyle." Now if you had only zero to one out of those four, you had an unfavorable lifestyle.                                            One of the interesting things was that actually the genetic risk and the lifestyle risk actually were totally independent. There was no association for example between those who had high genetic risk and what their lifestyle was. So it really reinforced longstanding views that genetics and lifestyle are really independent axes of someone's individual level of risk. Now- Naveen Pereira:              So both, Amit, both could contribute to your individual risk for coronary artery disease? Amit Khera:                      Exactly. As I mentioned, the high genetic risk versus low genetic risk, there was about a two fold difference in risk, and we saw an almost identical pattern versus a favorable lifestyle versus an unfavorable lifestyle. There was about a two fold risk [inaudible 00:17:08]. Naveen Pereira:              Interesting. Amit Khera:                      Then that got us to the next question, which is to say if we analyze only those at high genetic risk so everyone had a similarly increased degree of genetic risk, to what extent could that risk be offset by a favorable lifestyle? This really gets back to the questions and the conversations we have with our patients who have a family history all the time. What we found there I think was a nice message, was that if you are at high genetic risk, you could actually decrease your risk by about 50% if you adhered to a favorable lifestyle, as compared to those with an unfavorable lifestyle.                                            So for example, when we looked at it in absolute terms, in terms of a 10 year risk of having a coronary event, in one of the cohorts, those with a high genetic risk but an unfavorable lifestyle had about an 11% chance of having a coronary event, versus if you had the same high genetic risk but a favorable lifestyle, your risk was only about 5%. And we saw that, a very consistent pattern across all the cohorts and all the categories of genetic risk, that those who had a favorable lifestyle ... the risk was decreased by about 50% in those with a favorable lifestyle. Naveen Pereira:              So that's fascinating, Amit. When physicians see a patient who have a really strong history of coronary artery disease within the family, and come up to you and say, "Doc, am I destined to have a heart attack?" You know, now with the availability of genotyping, with direct to consumer testing, people can find out their genetic risk. So they may not necessarily be doomed. Their fate is not predetermined. What you're suggesting is that fate can be modifiable. Amit Khera:                      Right. I think certainly for coronary disease your DNA is not your destiny, at least for these common variants. I think we provide evidence that really lifestyle factors powerfully modify your risk, really regardless of your genetic risk profile. Naveen Pereira:              So Amit, can we make any recommendations based on the results of your paper? Amit Khera:                      Well, I think ... The American Heart Association has really endorsed these four lifestyle criteria as a way of improving the population's health in the population as a whole, and I think actually that our results actually support that. Which is to say that this really supports the fact that these healthy lifestyle parameters are critically important for everyone, and I think that's a good starting point.                                            Genomic medicine is actually in its early days, but really what we hope to do is first to identify individuals, a subset of the population, who are at increased risk for a disease like heart disease, and I think we've shown that we can actually do that reasonably well. Like 20% of the population has a double risk. And the second part is actually to disclose this risk to both the patients and their providers in a way that's meaningful. And third, is actually demonstrate that we can actually implement the therapy to mitigate this increased risk.                                            So I think we, in this paper, we provided evidence that a healthy lifestyle can mitigate that risk. Papers from our group, both published and some in press, have actually demonstrated that taking a statin can also powerfully modify this increased risk. And you might imagine that there may be other interventions that ... especially if an intervention has increased risk, you really may want to target it to those people who actually ... if a medicine has increased side effects, you may want to target it to those at the highest risk. I think that, you know, this polygenic risk score does provide at least one way of stratifying people into those high risk groups. Naveen Pereira:              Yeah. Amit, really impressive results, 50% relative risk reduction in a high genetic risk population. You make a compelling argument. Obviously, however, this is not a prospective randomized clinical trial. It's really hard to do these. You had the advantage of well designed cohorts to study this in a cross sectional way. We don't know how these behaviors change. So these are some of the limitations, but the results are quite compelling, and contribute to the literature. Any other comments, Amit? Anything else that we should take home here? Amit Khera:                      No, I think as you said, there are some limitations. I think our really goal was to lay the foundation for future efforts where we really think about what the optimal way is for genetic information to be integrated into routine clinical practice to help prevent disease, and that's really what our group is planning on focusing on for the future years. Naveen Pereira:              We look forward to hearing more exciting results from your laboratory, Amit. It's been a pleasure. We should end I guess with a quote from William Shakespeare, "It's not in the stars to hold our destiny but in ourselves." Correct? Amit Khera:                      Thank you very much. Sounds great. Naveen Pereira:              Thanks, Amit. Jane Ferguson:                So as we just heard from Naveen and Amit, the combination of genetic risk and modifiable lifestyle parameters are crucial in determining CAD risk. A recent AHA statement from the FGTB Council focused on this topic. The statement, entitled Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment, focused on how dietary and genetic contributors to disease have been studied in the past, and how emerging omics technologies can be used to rapidly advance these fields.                                            Genomics, transcriptomics, metabolomics, proteomics, lipidomics, epigenetic profiling, and metagenomic characterization of the microbiome can all be used alone or in combination to better understand mechanisms underlying gene-environment contributions to disease. While the ultimate goal would be the development of improved therapeutic options, including personalized and precision approaches, a considerable amount of research remains to be done before this goal can be clinically implemented. You can read this statement in the June 2016 issue of Circulation: Cardiovascular Genetics. Naveen Pereira:              So, Jane, this has been an exciting first podcast. I really look forward to doing more with you. Jane Ferguson:                Yeah. I think this is great, so thank you everyone for listening, and happy heart month. We will look forward to bringing you a podcast again next month. Naveen Pereira:              Thank you.

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Youth National University of Singapore. Coming right up, we will be discussing fascinating new data on the prevalence of subclinical coronary artery disease in masters endurance athletes but first, here's your summary of this week's journal. The first paper provides insight into ischemic cellular post conditioning. Now, we know that cardiosphere derived cell therapy has been utilized as a strategy to treat ischemic heart disease and reduce chronic scar burden when administered months after myocardial infarction. In the current study, by first author Dr. de Couto, corresponding authors Dr. Marban and Berman from Cedars-Sinai Heart Institute in Los Angeles, California, the authors used rat and pig models of myocardial infarction to show that exosomes, which are nanosize lipid bi-layer vesicles, actually mediate the cardio protective effects of cardiosphere derived cells when administered after reperfusion of myocardial infarction.                                                 They further show that treatment with either cardiosphere-derived cells or their secreted exosomes reduce infarct size and improved functional recovery. Using RNA sequencing to determine exosome content and alterations in gene expression profiles on macrophages from cardiac tissue or bone marrow, they found that a specific micro RNA species miR 181-B within the exosomes, acted on macrophages and was implicated as a key mediator of the cardio-protective benefits. Thus, this study gives new reason to test the idea that allogeneic cardiosphere-derived cells may be efficacious in preventing scar formation and improving cardiac function, when given in the earlier reperfusion period. The data further support that exosomal transfer of miR 181-B from these cardiospheric-derived cells into macrophages underlie the cardio-protective effects after reperfusion.                                                 The next study describes a potential new therapeutic strategy for vasoproliferative retinopathy which can underlie age-related macular degeneration, the leading cause of blindness in industrialized nations. First author, Dr. Bucher, corresponding authors Dr. Yea and Friedlander, from the Scripps Research Institute in La Jolla, California used rodent models of retinal neo-vascular disease to show that Tspan-12, beta-catenin signaling plays an important role in the development of vasoproliferative retinopathy. As background, Tspan-12 belongs to the Tetraspanin family, which mainly includes cell surface proteins characterized by four transmembrane domains and two extra cellular domains.                                                 Members of the Tspan family participate in a diverse cellular processes and act as signaling platforms by forming Tspan-enriched micro domains in plasma membranes. The authors went further to use a novel phage display combinatorial antibody library to specifically design a Tspan-12 blocking antibody which is capable of interacting with human and mouse Tspan-12 antigen. They then provided strong evidence that the Tspan-12 blocking antibody prevents developmental pathological neovascularization in  murine models of vasoproliferative retinopathy. Combination therapy with a known anti-VEGF agent demonstrated significant synergy supporting the potential clinical use of the anti-Tspan-12 antibody as a novel angiomodulatory agent.                                                 The next study addresses the paradox that blacks have higher coronary heart disease mortality compared with whites, but non-fatal coronary heart disease risks may be lower for black versus white men. To address this paradox, first author Dr. Colantonio, corresponding author, Dr. Safford and colleagues from Weill Cornell Medical College in New York, compared fatal and non-fatal coronary heart disease incidents and case fatality among blacks and whites in three studies. The Atherosclerosis Risk in Communities or ARIC study, cardiovascular health study, and reasons for geographic and racial differences in stroke or regards study, all stratified by gender.                                                 They found that the incidents of non-fatal coronary heart disease was consistently lower among black versus white men, although black men have a higher burden of unfavorable social determinants of health and cardiovascular risk factors and a higher fatal coronary heart disease incidents. Following adjustment for social determinants of health and cardiovascular risk factors, black men and women had a similar risk of fatal coronary heart disease, but a lower risk of non-fatal coronary heart disease compared with white men and women respectively. Finally, blacks with incident coronary heart disease had a higher case fatality compared with whites and the difference remained similar after adjustment for social determinants of health and risk factors. Thus, there is an apparent lower risk for non-fatal coronary heart disease among black versus white men and women, which needs to be further studied. Blacks have a higher risk of their initial coronary heart disease event being fatal compared with whites, highlighting the need for reinforcing primary prevention in this population.                                                 The next study provides important information on the burden of re-admissions after hospitalization for critical limb ischemia. First author, Dr. Kolte, corresponding Dr. Aronow and colleagues from Brown University in Providence, Rhode Island, used the 2013/2014 nationwide re-admissions databases to identify almost 61,0000 hospitalizations for primary diagnosis of critical limb ischemia during which patients underwent endovascular or surgical therapy. They found a 30-day re-admission rate of 20.4%. Independent predictors of 30-day re-admission included presentation with an ulcer or gangrene, age above 65 years, females, large hospital size teaching hospital status, known coronary artery disease, heart failure, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis. Interestingly, mode of revascularization was not independently associated with re-admissions.                                                 The most common reasons for re-admissions included infections, persistent or recurrent manifestations of peripheral artery disease, cardiac conditions, procedural complications, and endocrine issues. Finally, the costs of 30-day re-admissions for critical limb ischemia during the study period were 624 million U.S. dollars. Thus, this study provide knowledge of independent predictors and reasons for re-admissions that will help clinicians and hospitals to identify, develop, and implement strategies to reduce re-hospitalizations and healthcare costs associated with critical limb ischemia. The final study tells us that there may be a direct relationship between life-long exercise volume, and coronary atherosclerosis in athletes. Dr. Aengevaeren and colleagues from Radboud University Medical Center in the Netherlands, studied 284 middle-aged men engaged in competitive or recreational leisure supports, using contrast enhanced CT to assess coronary artery calcification and plaque characteristics.                                                 Participants also reported life-long exercise history patterns and exercise volumes were quantified as metabolic equivalent of task or met minutes per week. They found that participants in the more than 2,000 met minutes per week group had a higher prevalence of coronary artery calcification and atherosclerotic plaques. The most active group did, however, have a more benign composition of plaques with fewer mixed plaques and more often, only calcified plaques. These observations may explain the increased longevity typical of endurance athletes, despite the presence of more coronary atherosclerotic plaques in the most active participants. Well, that wraps it up for your summaries. Now for our featured discussion.                                                 Our current physical activity guidelines recommend 150 minutes of moderate exercise and that's supposed to protect against cardiovascular disease and increase longevity. However, what do we really know about the dose response relationships and the effects of exercises doses that exceed current recommendations. Well, recent data, including a paper in this week's issue, suggests that long-term, high volume endurance exercise may actually accelerate, rather than reduce coronary atherosclerosis. To discuss this exciting paper, we have the corresponding author, Dr. Sanjay Sharma, from Saint George's University of London, as well as editor of digital strategies and associate editor at UT Southwestern who handled this paper, Dr. Amit Khera. Welcome, gentleman. Dr. Amit Khera:                 Good morning. Dr. Sanjay Sharma:          Thanks for having us. Dr. Carolyn Lam:               First, Sanjay, oh yikes! As a runner and as a person who strongly advocates regular exercise, please, please, put us out of our misery. Tell us what you've found and what you think are the possible explanations. Dr. Sanjay Sharma:          I'm a runner too, and I don't think anyone would argue that the benefits of exercise on the cardiovascular system are unrivaled. People who exercise regularly do reduce their risk of an adverse event from a heart attack by 50% when they're in their 5th and 6th decade and they live around three years longer than people who don't exercise at all. Now as you rightly point out, the current recommendation suggests 2 1/2 hours of moderate physical activity per week and by that I would mean, at maximum, a 15-minute mile pace. Clearly, our endurance athletes exercise much, much more than that. They exercise 10 to 20 times greater than that volume and in parallel with this has been the emergence of a large number of people participating in marathon runs. For example, in Europe, there were two million marathon runs per annum and that figure's going up by about 5%.                                                 Coinciding with this burgeoning increase in endurance exercise, is the development of several reports that show that exercise may cause release of biomarkers of cardiac damage. Animal experiments have shown that exercise may cause scaring in the heart and human studies have shown that some marathon runners have more calcium in their coronary arteries compared to relatively sedentary individuals. One of the problems with these studies is firstly, the biomarker release is very transient, it goes away after about two days. Animal experiments cannot really reflect what goes on in human beings because they're artificial and animals are forced to exercise with electrical shocks, et cetera. The studies in human beings have been conducted in runners who have been former smokers.                                                 In fact, the most commonly reported study or cited study, contained individuals of whom 50% had risk factors for coronary artery disease. What we decided to do was to do a clean study, where we took 150 individuals who had none of the risk factors for coronary artery disease and 92 relatively sedentary controls who exercise within the normal limits. We have to exclude a lot of people because we have to exclude anyone that had ever smoked, anyone that had high blood pressure, high cholesterol, or a family history of permanent cardiac disease. We actually subjected them to all sorts of investigations and we found that a small number of male runners had more calcium in their arteries compared to sedentary individuals. Dr. Carolyn Lam:               Wow! Please tell us that there's something good that you can say about that. First of all, I really want to congratulate you on this most elegant study and Amit, I'm sure you put in what the editor's thought but we're just so proud to be publishing such a high quality study here. Amit, is there anything you might want to add of what the editors thought? Dr. Amit Khera:                 Sure, I first want to congratulate Dr. Sharma and his colleagues. This was a carefully done study and we've talked a bit about the coronary calcium but there was extensive investigation and I really think this advanced the field. Sounds like all three of us are runners, so this hit home to all of us and as he mentioned, this has been a very hot area and one that's been very controversial. I think here what we have is a manuscript that really helped move the field forward, helped us better understand the biology. The one thing I'll comment on that we found very interesting was the observation that those that were the masters athletes actually had more of a calcific phenotype, where as those that were not looked like a soft plaque phenotype, if you will. Actually, if you look, we have a companion article in circulation looking at sort of dose dependent finding a similar finding. My question, now turned back to Dr. Sharma is, what do you counsel your patients now with these findings? Has it changed now how you recommend exercise or your thoughts on how you counsel them? Dr. Sanjay Sharma:          Well, we examined 152 different athletes, or masters athletes in 92 controls. These athletes were aged 56 years old, who'd been training for 36 years and had immediate marathon number of 13. Now, what we've found in these individuals is that a small number of males, that's 11%, had a coronary artery calcium score of more than 300. Some men had more plaques than sedentary individuals and these plaques were distributed throughout all three coronary arteries. When we looked at the pathology of the plaques very carefully, we found that the plaques in the athletes were calcified. Indeed, 72% of athletes had very calcified plaques. We know that such calcified plaques are stable, they're less likely to fissure and are less likely to cause coronary thrombosis and therefore, acute myocardial infarction.                                                 This led us to propose that although exercise may be causing some atherosclerosis through the sheering and stressful source during exercise of the bending and kicking of vessels, we believe that the repair mechanism here is different to that seen in people who smoke or who have high cholesterol or high blood pressure. The repair mechanism results in very calcified and stable plaques in athletes and this may actually mitigate the risk of acute myocardial infarction and may explain why the number of people who actually suffer an acute myocardial infarction during a marathon run is very small, around 1 in 50,000, and no different to the number of people who suffer a sudden cardiac arrest playing football or basketball, due to congenital or inherited abnormalities of the heart.  Dr. Carolyn Lam:               Sanjay, those are just such important points to keep in mind as we read your paper. It did strike me as a significant minority, actually, of these long term endurance athletes who develop significant coronary artery calcification and it could potentially be a clinically benign phenotype. At the end of the day, this is a cross-sectional study, isn't it? We can't, I suppose, extrapolate into the clinical events. What are your postulations there and what could be future work that you're planning? Dr. Sanjay Sharma:          Well, you make a good point. This is a cross-sectional study and the demonstration of an increased cardiopathy calcium does not necessarily reflect future cardiac events. We have followed these individuals up for the last 18 months. These masters athletes and have not demonstrated a single one to develop an acute event that would last 18 months. We really don't know what the meaning of these plaques is. I think the only thing to do now, being we've got the liberty of having so many people that do marathon runs and so many people who've been exercising for three or four decades, we can actually do a prolonged follow up study, so the answers will be a while coming. To follow these people up with high calcium, just to see whether they do go on to develop adverse events in the future. All our study has shown is that some male athletes who've exercised lifelong get an increasing number of plaques. These plaques appear to be calcified and stable and the long term effects of such  plaques is unknown. Dr. Carolyn Lam:               Sanjay, just circling back to Amit's question earlier and maybe Amit, you could take it to after this. What do we recommend to our athletes who come in and have a high coronary artery calcium score? Do we tell them to stop? Dr. Sanjay Sharma:          I certainly wouldn't and I'm much less worried about an increase coronary calcium score in a lifelong runner or cyclist than I was 10 years ago. It appears that these plaques are there in some individuals, they are calcified, they appear stable. Given the fact that we know that coronary events during marathon running in experienced runners are very, very low indeed. I don't think I would be keen to do anything about it, not even consider stacking therapy based on our findings at present. As I said before, we do need longitudinal follow up to really identify all ascertain the precise implications of these plaques in masters athletes. Dr. Carolyn Lam:               Right, and this is again recognizing that your particular population was free of traditional cardiovascular disease. Of course, if we were to find these risk factors in our athletes, we would most certainly treat the traditional risk factors. Amit, anything to add there? Dr. Amit Khera:                 I think that was an excellent point about his approach to counseling patients. I will mention on the editorial staff, we felt like this was such an interesting area with emerging data and fast moving, that it was warranting of an editorial. I recommend people to look at the one by Aaron Baggish and Ben Levine. I think they had a very similar conclusion and that was that they don't necessarily proscribe exercise in patients with high coronary calcium but rather, focus on risk mitigation strategy, focusing on risk factors as we normally would do. I think the conclusions are similar and the thoughts in that editorial were insightful, pairing both of these papers and helping us make sense out of this really evolving field. Dr. Carolyn Lam:               Well, thank you Sanjay and Amit for this wonderful discussion. I learned so much as I'm sure our listeners did. You've been listening to Circulation On The Run. Tune in next week. 

The role of alcohol in the development of subclinical cardiovascular disease is unclear. We examined the association between alcohol consumption and markers of subclinical cardiac damage and wall stress.

  Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Our interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:     The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.     In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].     These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.     In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.     The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.     During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.     In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.     The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.     They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.     The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.     Well, those were your summaries! Now, let's on to Rome.     Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]     Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.   Dr. Eric M. : Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.     What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.     With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.   Dr. Carolyn Lam: That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.   Dr. Mark P: Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.     When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.     What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.     We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.   Dr. Carolyn Lam: OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?   Dr. Mark P: Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.   Dr. Carolyn Lam: With bypass compared to medical, yes.   Dr. Mark P: Exactly.   Dr. Eric M. : I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.   Dr. Carolyn Lam: That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?   Dr. Eric M. : I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.   Dr. Mark P: Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.   Dr. Carolyn Lam: You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.   Dr. Mark P: I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for  for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.   Dr. Carolyn Lam: Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.   Dr. Nancy S.: So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.     I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.   Dr. Carolyn Lam: Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?   Dr. Mark P: So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".   Dr. Carolyn Lam: Kudos to you, Nancy! And from your point of view, was it fun?   Dr. Nancy S.: It actually was fun.   Dr. Carolyn Lam: (laughs)   Dr. Nancy S.: You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.   Dr. Carolyn Lam: [inaudible 00:21:34] how long?   Dr. Nancy S.: We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.   Dr. Eric M. : First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.     A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.   Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in next week for more.    

  Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.     In just a moment, we are going to be discussing the feature paper on results of the RE-LY trial in patients with valvular heart disease. Yes, you heard me right, this means dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. You need to listen to this discussion with first author Dr. Michael Ezekowitz, but first here is a summary of this week's issue.     In the first study, Dr. Norby and colleagues from the School of Public Heath University of Minnesota assessed trajectories of cardiovascular risk factors and the incidence of atrial fibrillation over 25 years in the ARIC study or the Atherosclerosis Risk in Communities Study. They first assessed the trajectories of cardiovascular risk factors in more than 2,400 individuals with incident atrial fibrillation and more than 6,400 matched controls. Next, they determined the association of those risk factor trajectories with the incidence of new atrial fibrillation among more than 10,500 individuals free of atrial fibrillation at baseline.     The main finding was that stroke, myocardial infarction and heart failure risk increase steeply during the time close to diagnosis of atrial fibrillation. All cardiovascular risk factors were elevated in atrial fibrillation cases compared to controls more than 15 years prior to the diagnosis. A trajectory analysis showed not only the presence of the risk factors such hypertension and obesity, but also their duration which was more informative in determining the risk of atrial fibrillation compared to a one time clinical measurement.     Finally, they identified diverse and distinct trajectories for the risk factors findings that carry implications for the different roles of different risk factors in the pathogenesis of atrial fibrillation. The findings of this very significant study also highlight the need to establish preventive strategies that address risk factors decades before atrial fibrillation diagnosis.     The next study is by first author Dr. van der Valk and corresponding author Dr. Strauss from the Academic Medical Center in Amsterdam. These authors aimed to better understand the underlying mechanisms responsible for atherogenicity of lipoprotein a or LPa. The authors achieved this aim by a combination of three approaches. First, in vivo magnetic resonance imaging using 18F-FDG PET/CT and SPECT to measure atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Secondly, ex vivo analysis of monocytes using facts analysis, inflammatory stimulation assays and trans endothelial migration assays. Third, in vitro studies on monocytes using an in vitro model for trained immunity.     Their main findings were that, firstly, individuals with elevated LPa had increased arterial wall inflammation in vivo. Secondly, that monocytes from these individual remain in a long lasting activated state ex vivo, and finally, that LPa elicited a pro-inflammatory response in healthy monocytes in vitro, an effect that was markedly attenuated by removing or inactivating oxidized phospholipids on LPa.     In summary, this study nicely shows that LPa induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its oxidized phospholipid content. The clinical implications are therefore, that oxidation's specific epitope targeted therapy using for example specific antibodies as single gene antibodies may bear clinical potential to modulate the arthrogenic impact of LPa.     The final study is from first author Dr. Mazen, and corresponding author Dr. Ouzounian from Toronto General Hospital and University of Toronto in Ontario, Canada. These authors sought to compare the long term outcomes of patients undergoing the Ross procedure compared to mechanical aortic valve replacement in a propensity match cohort study of 208 pairs followed for a mean of 14 years.     They found long term survival and freedom from re-intervention were comparable between the Ross procedure and mechanical aortic valve replacement. Of note however, the Ross procedure was associated with improved freedom from cardiac and valve related mortality, as well as a significant reduction in the incidence of stroke and major bleeding. This paper provides important evidence that supports continued used of the Ross procedure in properly selected young adult patients in specialized centers.     What this means is having experienced surgical teams dedicated to mastering the technique and committed to carefully following up the patients for possible late complications. This and more is discussed in a provocative editorial by Dr. Schaff from Mayo Clinic Rochester, Minnesota who provocatively entitled his editorial 'The Ross Procedure: Is it the Preferred Procedure or Double, Double Toil and Trouble?'     Those were all summaries, now for our featured paper.     I am so excited to be joined from all over the world to discuss the featured paper today, and that is on the comparison of dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. To discuss this first we have, first and corresponding author, Dr. Michael Ezekowitz from the Sidney Kimmel Medical College at Thomas Jefferson University and Lankenau Medical Center in Philadelphia, as well as from the Cardiovascular Research Foundation in New York. Welcome Michael.   Michael: Thank you very much.   Carolyn: Michael, you're calling from South Africa aren't you?   Michael: I am indeed.   Carolyn: That's wonderful. We're very honored to have Dr. Shinya Goto Sensei, Associate Editor of Circulation from Tokai University Japan. Hello Shinya.   Shinya: Hello Carolyn, thank you very much for your invitation to such an excited podcast. I enjoy podcast every week.   Carolyn: I love this and it is extremely exciting and the most global discussion that we have had so far, with calling in Japan and Singapore and South Africa. Indeed it's because we're discussing a very important problem globally. Michael first, when we talk about the RE-LY trial and the NOAC trials, we're always associating them with non-valvular atrial fibrillation, and yet your topic is discussing valvular heart disease from RE-LY. Can you please start by clarifying that?   Michael: I think the reason we wrote this paper is that there is a misunderstanding of the patient populations that was studied in all the NOAC trials because they were characterized as having non-valvular atrial fibrillation. That's only partially true because in all the trials, patients with mechanical heart valve and hemodynamically significant mitral stenosis were excluded, and yet there were many patients with valvular disease that were included. In the RE-LY trial which is the focus of this particular paper, 25% of the patients had some form of valvular disease that were recruited into the study. So the term non-valvular is misleading.   Carolyn: That is such an important clarification, and it's an issue that I see a lot in Singapore. Frankly, lots of patients with atrial fibrillation have some valve disease even if you exclude prosthetic valves, significant mitral stenosis or valvular heart disease requiring intervention. We're very clear not that this is the patient population you're referring to. Shinya, I want to bring you into this. I see lots of these patients, how about you?   Shinya: The same. Majority of patients have valvular heart disease, small mitral regurgitation is very common. We are excluding only clinically overt mitral stenosis and basically mechanical heart valve in all the newest trials. As Michael pointed out, it is very important to correct misunderstanding. Non-valvular atrial fibrillation, we used in the clinical trial is all atrial fibrillation except clinical overt mitral stenosis and prosthetic for mechanical heart valve.   Carolyn: Exactly. A great foundation for us to get our understand right before we discuss the findings. Michael, could you please give us the top line result and tell us what do the results mean for your own clinical practice?   Michael: Basically, it means that the patients with valvular heart disease that were included in the trial, and these included patients with mitral regurgitation with was the most common lesion, mixed aortic valve disease, tricuspid regurgitation, and also it turned out that there were 192 patients that had mild mitral stenosis. Those with mitral stenosis were presumed to be rheumatic in ideology, and they did have a profile of having rheumatic heart disease, that there were more females, they were younger, there was a high incidence of heart failure and a high incidence of TIA and stroke.     The bottom line here is whether the patients had mild mitral stenosis or the other forms of valvular disease that I just mentioned, that they benefited in an identical fashion from the 150 milligram BID dose of dabigatran and the one 110 milligram BID dose of dabigatran as those patients without any valvular disease. The bottom line is that clinicians can use dabigatran with equal confidence in these patients with valvular disease as in patients without valvular disease.   Carolyn: Thank you Michael, that was very reassuring and something that is very clinically important. Shinya, I'm going to ask a different question. First, maybe your take on the findings, and secondly, what was it like handling this paper across the globe as the Associate Editor Managing this?   Shinya: That is a very important point. The past as Michael pointed out, this paper is very important to remind the clinician of non-valvular atrial fibrillation is not really non-valvular atrial fibrillation, and there is no difference between valvular atrial fibrillation except mitral stenosis and prosthetic valve. The result is similar to non-valvular atrial fibrillation in regard to the effect of dabigatran or by warfarin. That is the one point I have to assure. As a part, it is very important. We are now including many patients not limited in that North America, Europe. We are participating a huge number of patients from Asia. The results is applicable to the global level. We are now leading in that global evidence-based world and RE-LY is one of the good example for the global trial testing the hypothesis with [inaudible 00:13:58] over warfarin.     Michael made a very good summary of that, not only limited to RE-LY, he talked about as our trial like ARISTOTLE and the ROCKET trial. All of the NOAC trial include patient who is valvular heard disease, and the exclusion criteria is a little bit different. Michael beautifully summarized that difference in the table, in his paper.  There is a strong intention to publish this paper integration from all the editorial of old member. This is a very nice paper.   Michael: He's been very kind, that's very nice. That's true. In fact, the results in RE-LY were compared in an indirect fashion with the other trials, ROCKET and ARISTOTLE, through have published similar papers on patients with and without valvular heart disease. Just in summary, the bottom line is that this finding in RE-LY is highly reproducible in the other two trials so this is an important finding that is reproducible and true of the three novel agents that had looked at this in detail.     The other point that was raised is that there were differences in the exclusion criteria in these trials, but at the end of the day, the Europeans and the Americans in terms of guidelines, had fairly similar recommendation. For instance in the United States, it was felt that all patients with valvular disease could be anti-coagulated with the novel agent unless they had rheumatic mitral stenosis, mechanical or bioprosthetic heart valves, or patients that had undergone a prior mitral valve repair. The emphasis was that all other patients could be included.     The Europeans differed slightly and that they agreed that mechanical prosthetic valve and moderate to severe mitral stenosis should be excluded, but they were somewhat more global in recommending inclusions of all other valvular conditions. There is a slight difference then between the European and the American recommendations and guidelines.   Carolyn: On that note of looking across the world at the guidelines and what these results mean, it really leaves me to congratulate you Michael on such an excellent paper, and Shinya for just managing this paper so well.   Michael: Thank you.   Shinya: Thank you very much for your invitation. Bye-bye.   Carolyn: You've been listening to Circulation on the Run. Thank you for joining us today.    

  Carolyn: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Have you wondered which anti-platelet agent you should use in your patients with diabetes and coronary artery disease? Well, our feature paper deals with just this topic, so stay tuned, I'll be write back with it's author and associate editor. First, here's your summary of this week's journal: The first paper unravels novel peptides involved in atrial extracellular matrix remodelling in atrial fibrillation. This is work from first author Dr. Barallobre-Barreiro, corresponding author Dr Mayr from King's College London, and colleagues. They used novel mass spectrometry methods to analyze extracellular matrix in human atrial appendages from patients undergoing coronary artery bypass surgery.     Now, previous proteomic studies have examined the cellular proteome, but this is the first study to comprehensively characterize extracellular matrix proteins in human cardiac tissues, including the identification of glycosylation sites. They found extensive cleavage in the protein core of decorin which is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis and a variety of other extracellular matrix cell signalling molecules. Decorin processing differed between human ventricles and atria and was altered in disease. It's C-terminus which is important for the interaction with connective tissue growth factor was predominantly detected in ventricles compared to atria. In contrast, atrial tissues from patients in persistent atrial fibrillation had higher levels of full length decorin, but also harbored a unique cleavage site that was not found in atrial appendages from patients in sinus rhythm. This unique cleavage site preceded the M-terminal domain of decorin and altered the binding capacity for myostatin, this altering muscle growth.     The cleaved decorin peptide antagonized myostatin, such that myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and in hearts of decorin-null mice. Furthermore, a synthetic peptide corresponding to this decorin region, those dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. This is clinically important because mystatin inhibition has been implicated as a substrate for atrial fibrillation. This study therefore provides first evidence that peptides generated from the cleavage of extracellular matric proteins such as decorin, constitutes a local regulatory mechanism for growth factors in human cardiac tissue.     The next study looked at therapeutic hypothermia in patients with out of hospital cardiac arrest, and questioned if it may be most effective when induced early during cardiopulmonary resuscitation or CPR, in contrast to prior trials that looked at therapeutic hypothermia induced only after return of spontaneous circulation and hospital admission. This is the RINSE trial from Professor Bernard and colleagues from Ambulance Victoria Australia, which was a multi center randomized controlled trial which assigned adults with out of hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to two liters of cold saline, or standard care. The primary outcome measure was survival at hospital discharge. Secondary end points included return of spontaneous circulation.     The trial was unfortunately closed early at forty-eight percent of the recruitment target, due to changes in temperature management protocols at the major receiving hospitals. Still, a total of one thousand, one hundred and ninety-eight patients were randomized. Six hundred and eighteen to therapeutic hypothermia during CPR, and five hundred and eighty to standard pre-hospital care. Overall there was no difference in outcomes at discharge. In patients with an initial shockable cardiac rhythm there was lower rate of return of spontaneous circulation in patients who received cold saline compared with standard care. Thus, although this trial was stopped early, the data suggests that induction of mild therapeutic hypothermia using a rapid infusion of large volume intravenous cold saline during CPR did not affect outcomes at hospital discharge and may in fact cause harm in the subset of out of hospital cardiac arrest patients who present with shockable rhythm.     The last study provides the first generalizable risk score for sudden cardiac death among American adults from the general population without a history of cardiovascular disease. This large study from Dr. Deo of University of Pennsylvania, and colleagues, derived a sudden cardiac death prediction model using the Atherosclerosis Risk in Communities or ARIC cohort, and validated it in the Cardiovascular Health Study or CHS cohort. They found that the twelve independent risk factors in the ARIC study included age, male sex, African American race, current smoking, systolic blood pressure, use of [anti-hypotensive 00:06:00] medication, diabetes, serum potassium, serum albumin, HDO, estimated GFR, and QTC interval. Over a ten year follow up period this model combining these risk factors showed good to excellent discrimination for sudden cardiac death risk. In fact the model slightly outperformed that of the 2013 ACC AHA pooled cohort risk equations.     Finally, they also showed in the echocardiographic sub-cohort that a left ventricular ejection fraction less than fifty percent was present in only 1.1 percent of these participants and did not enhance sudden cardiac death prediction. This study importantly contributes to the distinguishing of sudden cardiac death risk across the general population, and the results can help target future strategies aimed at sudden cardiac death prevention for the highest risk subgroups in the American general population. That does it for the summaries. Now for our feature paper.     For our feature paper today we are discussing the super important issue of anti-platelet therapy in type 2 diabetes with coronary artery disease. Joining me today are the corresponding author, Dr. Dominick Angiolillo from the University of Florida College of Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate Editor from Paris, France. Welcome gentlemen.   Dominick: Thanks for having us.   Gabriel: Hello.   Carolyn: Dominick, I'd really like to start with you. Your paper entitled the OPTIMUS-4 Study, is really a study of the pharmacodynamic comparison of Prasugrel versus Ticagrelor in these patients with type 2 diabetes and coronary artery disease. The whole question is, what was the rationale to look at the pharmacodynamics?   Dominick: As the title of the study says, OPTIMUS-4, it means that there was an OPTIMUS-1, 2 and 3 in the past, which means that there's a lot of thought that went into this and a lot of background information. The rationale for this specific study was that we're all well aware of the fact that patients with diabetes have high platelet reactivity, which may be one of the reasons why they have a higher risk of recurrent atherothrombotic events. Therefore, the need to define ways to optimize their anti-platelet effects, their levels of platelet inhibition. In this specific study we took an approach of looking at the novel, although we cannot call them novel nowadays, but the newer P2Y12 receptor inhibitors Prasugrel and Ticagrelor. Looking at them in a head to head comparison from a pharmacodynamic standpoint to see if one drug would be superior than the other, again, in terms of a platelet inhibitory effect.     This is the rationale, and just to expand a little bit on this, there's been a perception, again I want to underscore a 'perception' that based on subgroup analysis of the larger clinical trials, that Prasugrel is a superior drug for patients with diabetes. We do know that there's a benefit also with Ticagrelor compared with Clopidogrel, although the absolute risk reductions in the studies led to a perception that Prasugrel would be a better drug. We said to ourselves, "Well, we're never going to have a large scale head to head clinical comparison, why don't we do a head to head pharmacodynamic comparison to see if there are any differences?" This was the overall rationale for conducting this specific study.   Carolyn: That really sets a background perfectly. Tell us about the main findings.   Dominick: The main finding was as follows, we conducted a very detailed pharmacodynamic study, this was a prospective randomized double-blind double-dummy crossover study, with all patients on the background of aspirin therapy. We looked at platelet reactivity, using a variety of assays, I like to say it in every possible salsa that you can imagine. The primary end point which is platelet reactivity at one week into two drugs, using an [ADP 00:10:00] specific assay, actually showed that Ticagrelor was superior to Prasugrel in terms of platelet inhibitory effects. That was the only time point where it was shown, but the study was actually designed to show the opposite, so it was a very interesting finding, while with all the other time points there were no differences between the platelet inhibitory effects between the two drugs.     The other thing that we did look at, which gives a little bit of a novelty to this study is, we went beyond just looking at ADP induced effects, which is the target for these two drugs, we looked at other signalling pathways which one would not believe to be necessarily affected by P2Y12 inhibitors, and we found these also to be reduced by both drugs to a similar extent.   Carolyn: Fascinating. I'm going to get to your second point a bit later. First, that first finding that surprisingly Ticagrelor appeared to perform better using one of the specific assays and so on, I'd really like Gabriel's opinion there. What do you think is the overall clinical implications or what was the message that the editorial board was hoping to get across to the audience? Because I noticed you invited an editorial as well, a beautiful one written by Dr. [Star-ee-an 11:36] Parker. What was the thinking behind that?   Gabriel: I think this is really a very important paper and I'm delighted that Dominick Angiolillo and his team submitted it to Circulation, in fact to be frank, we invited that paper after seeing his presentation at the ACC earlier this year. The reason that paper caught everybody's attention in the editorial board was that it's addressing a frequent and deadly disease, diabetes, that kills really patients with cardiovascular disease. There's a critical issue in the treatment because of the limitations of Clopidogrel because of the increased platelet reactivity in diabetics, and there's tremendous interest in the novel P2Y12 inhibitors Prasugrel and Ticagrelor, and of course any hint of differences between these agents has major clinical implications. In addition, I think I can state that Dominick's team is really one of the premiere international teams looking at this exact issue, platelet reactivity in diabetics. What they did was really state of the art rigorous clinical investigation by a highly skilled team, looking rigorously at a double blind crossover designed four different assays looking at platelet function and platelet response, looking both at the effect of a loading dose and the maintenance dose.     To me, the message is not a minute difference between the treatments, in fact I think that even though it's the primary outcome and it does show a slightly greater response with Ticagrelor than with Prasugrel, the overall most of the other assays at the other time points show a consistent good response with both agents. To us, and to me, the message is that the novel agents are clearly superior to Clopidogrel as we've seen in the clinical trials, but they are fairly consistent in their benefit, and it's reassuring to see this not in healthy volunteers but in actual patients with stable coronary artery disease. I think it was really important to show that. Certainly platelet reactivity doesn't summarize entirely the effects of any drug, and there might be platelet independent effects of Ticagrelor mostly and possibly Prasugrel, but I think on the platelet side, I think that this paper really nails it.   Carolyn: I read that editorial and really agree that that puts everything in perspective really well. I particularly like the figure that accompanied the editorial. In case any of our listeners out there don't really remember all the different pathways and how Prasugrel and Ticagrelor and Clopidogrel are metabolized differently, I'd really refer everyone to that figure as well. Just want to pick up on one of the points that both of you mentioned, and that is the non ADP induced platelet reactivity that Prasugrel and Ticagrelor both seem to have an affect on and so on, and if they're so effective, Dominick, is there still a role for aspirin co-administration with these new anti-platelet agents?   Dominick: The study clearly puts a little bit more beef, let's put it this way, to some of the ongoing clinical studies looking at whether we need aspirin in the patients treated with one of these newer P2Y12 receptor inhibitors. There are a series of ongoing studies out there. There's a laundry list, so I'm not going to go into the details. It does highlight that maybe when you have ultimate P2Y12 blockade, which is a key signalling pathway and blocks other responses by virtue of the fact that there's an interplay between this pathway and others, maybe you do not need this additional anti-platelet agent such as aspirin, which we know there's associated with potential bleeding particularly gastrointestinal side effects.     Having said that, this is not something that I'm advocating at time, but what I am saying is that we'll need to look into the results of the clinical trials. I believe that this study is an additional piece of evidence from an ex vivo standpoint to prior in vitro studies showing that aspirin is not associated with additional platelet inhibitory effects, at least not substantial platelet inhibitory effects. One can say that you may get away with just one of these newer agents. Again, this is based on pharmacodynamic findings, let's just wait for the clinical trial results.   Carolyn: I think that's so fairly put, and I learnt so much just listening to this conversation. Thank you so much for joining me today. Any last words from Gabriel?   Gabriel: Yeah, I'd like to make a couple of points as an Associate editor for Circulation. The first one is, this paper was picked up when we saw Dominick's team's presentation at the ACC, and I think it exemplifies that we really want to pick up the best science from the meetings, either before the meetings and publish it simultaneously as much as possible, but sometimes also at the meetings, so expect to see Circulation Editors at your presentations and maybe you'll seduce them enough with your science that we'll get good science submitted to the journal. The other aspect to it is also that I think with the new editorial board there's really a focus on trying to make the journal very international in it's approach, and I think it's fitting that I am Associate Editor from Europe and I think there's no more international a scientist than Dominick Angiolillo who's not only a good friend but also has been trained in Italy, has practiced in Spain, and now works in the US. I think he embodies how science transcends boundaries and borders. I think there's a definite international outlook to Circulation, and we're looking for great science from anywhere in the world, not solely the US.   Carolyn: Thank you so much Gabriel. Thank you so much Dominick. Thank you listeners for listening today, you've been listening to Circulation on the Run. Don't forget to join us next week for more summaries and highlights.    

Benefits of exercise differ by sex and race (Podcast) Dr. Tedd Mitchell, Cooper Clinic president and CEO is interviewed by Todd Whitthorne, and talks about how the benefits of exercise differ by sex and race.   The study, reported in the Journal of Lipid Research (August 2009 issue), began in the late 1980s, and used data from more than 15,000 middle-aged African American and Caucasian men and women (already participating in the Atherosclerosis Risk in Communities Study). Researchers wanted to evaluate the benefits of one hour of “mild” or 30 minutes of “moderate” exercise on HDL, the healthy cholesterol.   “Mild” exercise activities included walking for pleasure, bowling, and weight lifting, while “moderate” exercise included playing basketball, hiking, and modern dance. Researchers found that either an hour of mild exercise or a half hour of moderate exercise each week increased the level of heart healthy HDL cholesterol. Regarding triglycerides and LDL (lousy) cholesterol, the impact exercise has is less clear. Researchers saw a reduction in triglycerides in Caucasians, but not in African Americans. And, researchers found that the LDL cholesterol level was reduced, but only in women.   Dr. Mitchell says the big takeaway from this study is that exercise is good, and for health benefits we don't need that much, and that consistency with exercise, not intensity, is the key. One hour of mild exercise, or 30 minutes of moderate exercise positively impacted HDL cholesterol levels.   Jill Turner is VP of Operations for Cooper Concepts, the company that markets Cooper Complete nutritional supplements. Jill regularly contributes information to the Cooper blog. Email jsturner@cooperwellness.com or call 972-560-3262 with your questions and comments.   Reference Information Atherosclerosis Risk in Communities Study http://www.cscc.unc.edu/aric/   Atherosclerosis Risk in Communities Study: Community Surveillance and Cohort Morbidity/Mortality Follow-up http://www.cscc.unc.edu/aric/visit/General_Description_and_Study_Management.5_1.pdf   Benefits of exercise differ by sex and race http://www.reuters.com/article/healthNews/idUSTRE5862SY20090907