Podcasts about chadsvasc

Découvrez en 15 minutes avec Pr Popovic, cardiologue au CHRU de Nancy, l'essentiel à savoir concernant l'utilisation des anticoagulants oraux directs (AOD = NACO) en MG. ✅ Quelles sont les différences entre les 2 classes d'AOD ? ✅ Quelles sont les indications actuelles des AOD ? ✅ Quelles sont les différences de maniement par rapport aux AVK ? ✅ Quelles sont les posologies recommandées ? ✅ Quels sont les 3 points essentiels à surveiller dans la prescription des AOD ? ✅ Que faire quand un patient a une indication d'AOD et d'antiagrégants plaquettaires ? Marre de perdre du temps dans vos formations DPC ? Abonnez-vous ici

I am thrilled to introduce you to Midge Bowers.Not only is Midge a Clinical Professor and Director of the cardiovascular specialty at Duke University School of Nursing, she practices as a nurse practitioner in a Heart Failure Access Clinic.She's an expert in cardiology, a seasoned healthcare educator, and shares so much incredible knowledge in this jam-packed episode.In this episode, we covered:The importance of looking beyond creatinine levelsHow to focus on practical aspects of echosDemystifying anticoagulation choicesPractical tips on adjusting Warfarin dosagesReversal agents and safety measuresThis barely scratches the surface of the wealth of information Midge provides.0:00 - 3:35 - Introduction and Overview3:36 - 8:39 - Importance of Monitoring Creatinine and GFR 8:40 - 15:06 - Impact of New Medications on Kidney Function15:07 - 20:30 - Understanding Echo Results: Akinesia, Hypokinesia, and EF20:31 - 25:01 - Interpreting Trends in Echo Reports25:02 - 31:17 - Anticoagulation Choices: Warfarin vs. DOACs 31:18 - 38:15 - Adjusting Warfarin Dosages and INR Monitoring38:16 - 42:42 - Assessing Bleeding Risks with CHADS-VASc and HAS-BLED 42:43 - 46:03 - Reversal Agents and Safety in Anticoagulation46:04 - 53:41 - Managing DOACs in Different Clinical Scenarios Read the full blog here.______________________________Please note: This episode is intended only for medical providers and students learning to be medical providers. Hosted on Acast. See acast.com/privacy for more information.

Take Home Points: Patients with recent onset atrial fibrillation can safely be cardioverted if they are 1) on anticoagulation 2) Low risk based on CHADS-VASC with onset < 48 hours or 3) High risk based on CHADS-VASC with onset < 12 hours. In anaphylaxis, think, “If A, B or C, give E.” If the patient ... Read more The post REBEL Core Cast 110.0 – On Shift Learning Pearls appeared first on REBEL EM - Emergency Medicine Blog.

Coated vs uncoated ASA, a new trial in CAD, conflicts of interest, first AF in the hospital, and changing HTN scoring and CHADSVASC are the topics John Mandrola, MD, covers in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. ASA No Benefit of Enteric-Coated Aspirin vs Uncoated in CVD https://www.medscape.com/viewarticle/997119 -  JAMA Cardiology: Coated vs Uncoated ASA https://jamanetwork.com/journals/jamacardiology/fullarticle/2809795 -  ADAPTABLE https://www.nejm.org/doi/10.1056/NEJMoa2102137 II. RECHARGE -  Revascularization Choices Among Under-Represented Groups Evaluation (The RECHARGE Program) https://www.pcori.org/research-results/2023/revascularization-choices-among-under-represented-groups-evaluation-recharge-program -  Gaudino/Stone: Reconsidering Coronary Revascularization Trials III. Conflicts of Interest -  Financial Conflicts of Interest in Public Comments on Medicare National Coverage Determinations of Medical Devices  https://jamanetwork.com/journals/jama/fullarticle/2808721 IV. First AF in the Hospital Decoding AFib Recurrence: PCPs' Role in Personalized Care https://www.medscape.com/viewarticle/997011 -  Annals of Internal Medicine: AF Recurrence https://doi.org/10.7326/M23-1411 V. Changing CHADSVASC Score -  JAMA Network Open: HTN Guidelines and CHADSVASC Up-Scoring  https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2809933 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

This week, join author Tristram Bahnson and Associate Editor Changsheng Ma as they discuss the article "Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results from the CABANA Trial." 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 of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Guess what, Greg? For today's feature paper, we are going to be looking at a very interesting analysis from the CABANA trial, this time, looking at the association between age and outcomes of catheter ablation versus medical therapy for atrial fibrillation. Cool, huh? Okay, but first, let's go through some other important papers in today's issue. Why don't I let you go first? Dr. Greg Hundley: Well, Carolyn, my first paper pertains to the cost effectiveness of coronary artery bypass surgery, and it comes to us from the STICH trial. Dr. Carolyn Lam: Ah, very important question, but please remind us what the STICH trial is again. Dr. Greg Hundley: Right, Carolyn. So the Surgical Treatment for Ischemic Heart Failure trial, or STICH demonstrated that coronary artery bypass grafting reduced all-cause mortality rates out to 10 years compared with medical therapy alone in patients with ischemic cardiomyopathy and reduced left ventricular function, defined as an ejection fraction of less than or equal to 35%. Now in this study, the authors led by Dr. Derek Chew at University of Calgary examined the economic implications of these results using a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG versus medical therapy alone, using patient-level resource use and clinical data collected from the STICH trial. Dr. Carolyn Lam: Again, really important study. And what did they find? Dr. Greg Hundley: Right, Carolyn. So first, using their patient-level simulation model incorporating resource use and clinical data collected from the STICH trial, they found that coronary artery bypass grafting was estimated to cost $63,989 per quality-adjusted life year gain compared to medical therapy alone. Second, in STICH eligible patients with left ventricular ejection fraction of less than 35% in coronary artery disease amenable to CABG, routine use of CABG increased the quality-adjusted life expectancy compared to medical therapy alone for an increased cost within current benchmarks for good value in healthcare within the United States. Then finally, Carolyn, together with the improved clinical outcomes seen in the 10 year extended follow-up of STICH, the findings in this study provide additional economic support for the use of coronary artery bypass grafting in patients with ischemic cardiomyopathy eligible for STICH. Dr. Carolyn Lam: Wow, thanks Greg. Well, this next study contributes to the understanding of the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease. Interesting? Well, listen up. This is from Dr. deVries from UT Health Science Center at Houston and colleagues who aimed to quantify remaining lifetime risk and years free of coronary heart disease according to polygenic risk and the AHA's Life's Simple 7 guidelines in the population base cohort of ARIC. As a reminder, the Life's Simple 7 by the AHA consists of smoking status, body weight, total cholesterol, blood glucose, blood pressure, physical activity, and diet. Dr. Greg Hundley: Ah, Carolyn. So genes versus lifestyle. So what did they find? Dr. Carolyn Lam: Participants with high polygenic risk may offset their lifetime risk of coronary heart disease by up to 50% through managing their health according to the Life's Simple 7's recommendations, depending on ancestry. Individuals with high polygenic risk scores and ideal Life's Simple 7 scores had 4.5 to 20 more coronary heart disease free years than individuals with high polygenic risk scores, but low Life's Simple 7 scores and again, depending on ancestry. Appropriate management of lifestyle and clinical risk factors of coronary heart disease play larger roles in the overall lifetime risk of coronary heart disease than presently available genetic information. Thus, communicating the effects of Life's Simple 7 measures and polygenic risk on coronary heart disease in terms of absolute risk may have important implications for education, policy, and environmental changes, which can benefit not only high risk individuals, but the whole population. Dr. Greg Hundley: Wow, Carolyn, really informative study and so nicely summarized. So Carolyn, my next paper comes to us from the world of preclinical science and it's from Professor Yan from Shanghai, Ruijin University School of Medicine. So Carolyn, previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure. However, the underlying mechanisms often remain unclear. Now since kinases have been reported to modulate mitochondrial function team investigated the effects of dual specificity tyrosine regulate kinase one B on mitochondrial, bio energetics, cardiac hypertrophy, and heart failure. Dr. Carolyn Lam: Wow. Okay. So what did they find Greg? Dr. Greg Hundley: Right, Carolyn. So this team found that Dual Specificity Tyrosine-Regulated Kinase 1B, our DYRK1B expression was clearly up regulated in failing human myocardium as well as in hypertrophic mirroring hearts and cardiac specific DYRK1B over expression resulted in cardiac dysfunction, accompanied by a decline in the left ventricular ejection fraction, as well as the fraction shortening. And it increased left ventricular myocardial fibrosis. Carolyn in striking contrast to DYRK1B over expression, the deletion of DYRK1B mitigated tack-induced cardiac hypertrophy and heart failure. In addition, the authors found that DYRK1B was positively associated with impaired mitochondrial bio-energetics by directly binding with stat three to increase its phosphorylation and nuclear accumulation. Thereby ultimately contributing toward the down regulation of PG C one alpha. Now, furthermore, the inhibition of DYRK1B or stat three activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bio-energetics. Dr. Carolyn Lam: Cool, Greg. So could you give us a take home? Dr. Greg Hundley: Right. So in summary then, Carolyn, taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1 beta in mitochondrial bio-energetics and the progression of cardiac hypertrophy in heart failure. Dr. Carolyn Lam: Fantastic. Thanks, Greg. Well, other papers in today's issue include an exchange of letters between Doctors Nie and Wollert on the article myeloid derived growth factor protects against pressure overload induced heart failure by preserving sarcoplasmic reticulum calcium, ATPase expression in cardiomyocytes. There's an AHA update [AHA Advocacy Page] paper by Dr. Churchwell on improving heart health through value-based payment. An ECG Challenge by Dr. Murphy on a “Curious ECG Morphology of a Cardiac Device.” An On My Mind paper by Dr. Figtree on “Sublingual Nitrates for Patients as a Default in the Post ACS Discharge Pack. Is the Time for a Rethink?” Dr. Greg Hundley: Right? Carolyn. Boy, this issue is really packed with great articles. There's a Perspective piece from Professor Stewart entitled “Myocardial Edema Provides A Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.” There's a wonderful Frontiers in medicine piece from Professor Kandzari entitled “A Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document from the Hypertension Academic Research Consortium.” And then finally, Carolyn, there's a Research Letter from Professor Wold entitled “E-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice. Well, Carolyn, how about we get onto those results from the CABANA trial?” Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Well, listeners, we are now here for our feature discussion and we have with us today, Dr. Tristram Bahnson from Duke University and one of our own Associate Editors, Dr. Changsheng Ma from Beijing. Welcome gentlemen. Tristram, we will start with you first. Could you describe for us some of the background pertaining to this particular research study and what was the hypothesis that you wanted to address? Dr. Tristram Bahnson: Sure. Being an active electrophysiologist, a challenge we've had over the years is to try to figure out for whom catheter ablation would be a preferred therapy. I've had the privilege of being part of the CABANA study team over the last several years. As listeners might recall, the CABANA trial was a very large trial looking specifically at hard endpoints, including mortality, to try to determine whether or not catheter ablation provides significant benefits to patient. Apart from what we already knew over the years, which is the catheter ablation was more effective than drug therapy to reduce AFib recurrences. That study, the CABANA proper study was published in 2019. Dr. Tristram Bahnson: In the course of that study, pre-specified subgroup analyses were done initially reporting unadjusted outcomes for important clinically relevant subgroups. We found in that initial study that patients with heart failure, minorities, and patients of young age in particular appeared to do better with catheter ablation than with drug therapy. So with that as background, the CABANA study team embarked to focus on each of those subgroups and the heart failure paper was published in 2021, the minorities paper also in 2021 and the subject of our discussion now, the relationship between age and outcome in the CABANA study cohort is a subject of study today. Dr. Greg Hundley: Describe just quickly Tristram the hypothesis you wanted to test here and then in order to test that hypothesis, what was the study population that you included and what was your study design? Dr. Tristram Bahnson: So the focus was on the relationship between age and outcome in CABANA, and this was pre-specified substudy of the CABANA population. So it's probably worthwhile going over who got into the CABANA trial and to remind folks the CABANA trial enrolled 2,204 patients across 126 sites at 10 countries and randomized them one to one to a treatment strategy of either catheter ablation or drug therapy for simple traumatic atrial fibrillation that in the judgment of the treating physicians warranted therapy, patients had to have had at least two episodes of PAF or one episode of persistent AFib documented by ECG or ambulatory recordings within the six months prior to enrollment and they hadn't have failed more than one anuric drug. In other words, they would have to have been reasonable candidates for drug therapy, should they be so randomized. Dr. Tristram Bahnson: In addition, patients that were less than 65 years of age, had to have some additional factors that would increase the likelihood that outcome events would occur. They had to have a CHADSVASC score greater than one. That was not required of the older subjects follow up was 48 and a half months for the population at large, with the interportal range of follow up between 30 and 62 months. The patients had regular follow up every three months for the first year and then six months thereafter. In addition, 1,240 patients received a recording device that allowed them to provide either prescribed episodic recordings or recordings for when they were symptomatic and they also provided 96 hour holters every six months throughout the duration of the trial. Dr. Tristram Bahnson: So that's the population that we were working with. The study design, as I said, focused on trying to tease out the relationship between age and outcomes and the primary outcomes of the CABANA trial included the primary outcome, which was a composite. It included all cause mortality, disabling, stroke, serious bleeding or cardiac arrest, and the key secondary endpoints that were looked at included mortality and cardiovascular hospitalization and AF recurrence. Dr. Greg Hundley: Very nice. Describe for us your results. Dr. Tristram Bahnson: So we actually took a deeper dive into the subgroup of age, and we did a couple things that we thought would be valuable. One was to consider age as a continuous variable because after all, it's pretty arbitrary to bin people into age groups. I think the initial analysis did so with the CABANA proper publication in 2019 to correspond with the break points that we use for CHADSVASC scoring, but we elected to consider age as a continuous variable and we also elected to do adjusted Cox proportional hazard models to account for the various clinical factors that of course varied with age, such as their CHADSVASC score, the occurrence of structural heart disease, like valvular heart disease or coronary disease, the proportion of women, which typically increases with age and did so in this population. The key endpoints that we examined were the CABANA endpoints, including the primary composite endpoint of total mortality, mortality, or CB hospitalization and AF recurrence. Dr. Tristram Bahnson: So at the end of the day, we had 766 patients who were less than 65, 1,130 that were between 65 and 74 and 308 that were greater than 75. Mind you, CABANA admitted patients with any kind of AFib. As a matter of fact, more than half of the study population had persistent or longstanding persistent atrial fibrillation, which is not typical of many studies that have been published, looking at the relative benefits of catheter ablation. We had an unexpected finding that was hinted at, at the initial CABANA study and that was the benefit of catheter ablation was greatest in the younger patients and the benefits of catheter ablation relative to drug therapy seemed to decrease with advancing age at enrollment, which was the age criterion that we based the analysis this on and that this effect was primarily driven by changes in mortality. Dr. Tristram Bahnson: For the composite endpoint in CABANA, which was total mortality, serious stroke, serious bleeding and cardiac arrest, we saw that the adjusted hazard ratio increased average of 27% for every decade in advancing age, where the age was defined as that at enrollment, and for the total mortality endpoint, the adjusted hazard ratio increased an average of 46% for every 10 year increment in age at enrollment. For all age groups, catheter ablation was superior to drug therapy, a relative to a reduction in AFib consistent with many other studies. The benefit was a reduction in the adjusted hazard ratio of about 50%. So catheter ablation was agnostic to age in terms of the benefit of reducing AFib, but was not agnostic to age with result to these mortality inclusive endpoints. We did notice that there was a trend towards a relative benefit of drug therapy for the oldest age group, but we interpreted that result with caution for a variety of reasons. The oldest age group was least well represented and comprised less than 10% of the CABANA population and less than half of the next best well represented age group, which was the less than 65's. Dr. Tristram Bahnson: In looking carefully at the data, we could find no plausible explanation for why the older age group might do better with drug therapy. Again, it was not significant by an intention to treat analysis, but there was a trend towards drug therapy getting better with the oldest age group. We noticed that there was no excess mortality in the old age group within six months of treatment, so it didn't seem like it was related to some adverse procedural effect. We saw no evidence of more advanced forms of AFib in the oldest age group, because they had as good AFib suppression as others, and had the same distribution of paroxysmal versus persistent forms of AFib as the other age groups. There was no difference in crossover after all, if more patients in the old age group crossed over from drug to ablation therapy, who might expect that to be a confounder. Dr. Tristram Bahnson: We did see something that was very unusual and unexpected, which is that the mortality of the oldest age group treated with drugs was actually less than their mortality in catheter ablation, which is the issue at hand, but also less than the other age groups, which was unexpected and even less than all but the youngest age group treated with catheter ablation. So we can't explain this finding. It was not statistically significant. At the end of the day, we don't believe that elderly patients who have drug refractory AFib that is symptomatic should be denied ablation. Dr. Greg Hundley: Well, thank you so much, Tristram, for these very intriguing results. Changsheng, you have many papers that come across your desk. What drew you to this particular paper? Dr. Changsheng Ma: Yes. Dr. Bunch and colleagues should be commanded for the understand and taking important subgroup analysis of CABANA study. There has also been interest in whether the risk and the benefit of ablation may be modulated by patient age. The current analysis suggests that the related benefit of ablation was characterized for those less than 65 years of age are a tiny bit by the increasing age. It is important to emphasize that the current analysis result should not be interpreted to suggest that the cancer ablation has less value in idly patients. As a casual ablation must treated before recurrence across all age groups. Dr. Changsheng Ma: The current analysis is assuming we should know age related increase in safety constant in patients and taking ablation therapy. So we must be cautious not to over incorporate the result of the sub-group analysis, especially in the context of CABANA trial, treating in the permanent effect of ITT analysis. So I think it can be a possible that reach age related gradings in the relatively treatment benefits of the ablation is finding a challenge. Secondly, the CABANA trial was not a oral subgroup analysis. So the variation of treatment effect across the different age group were in the further resource. That's my opinion. Dr. Greg Hundley: Thank you very much. Well, gentlemen, what do you see is the next study that needs to be performed in this sphere of research and Tristram, we'll start with you. Dr. Tristram Bahnson: Well, clearly the clinical task at hand, for those of us who treat patients is to advise patients about relative benefits of therapy when there are choices at hand. And in the case of atrial fibrillation, the fundamental choice obviously is whether or not to pursue catheter ablation or to pursue medical therapy, either for rhythm or rate control. An important part of that decision making is to understand which patients would derive the most benefit from one versus the other therapy. And that need is perhaps the genesis of why we embarked on these subgroup analysis, which admittedly need to be interpreted with caution are not powered to give definitive results, but can certainly help guide future research. So we have noted in the CABANA trial that heart failure patients might do better and that's consistent with other studies looking specifically at heart failure with reduced ejection fraction. So we're contemplating additional studies to help tease that population out since in CABANA, in particular, our heart failure population was mostly those with a preserved ejection fraction and clinical heart failure. Dr. Tristram Bahnson: With regard to age, I think it'll be important to do studies to try to understand what factors resulted in the young patients apparently doing better with ablation. Again, this is hypothesis generating in terms of our result with this paper. So it'd be very interesting to find out whether there are some subsets of patients with younger ages or patients who have the relevant characteristics of the young age patients who would derive particular benefit from catheter ablation. This would obviously require a variety of approaches, including prospective randomized studies and carefully done population studies. So this issue about which patients really derive a significant mortality benefit it from catheter ablation is an important one that has not yet been teased out completely. Dr. Greg Hundley: Thank you. And Changsheng, do you have anything to add? Dr. Changsheng Ma: Yes. I think two streams say it's a very important topic for, you know, who have more and more, the older patients. So we need to answer the question, how about the real influence of age on the outcomes of the atrial fibrillation patients with ablation. So in future, we should consider randomized trial, but I think it's very difficult. So maybe we have to wait more and more, you know, other study to have a trend, how about the outcome for all the patients. It becomes too difficult for a new randomizedtrial. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Tristram Bahnson from Duke University and Dr. Changsheng Ma from Beijing for bringing us the results from this substudy of the CABANA trial indicating that the mortality related benefits of catheter ablation for atrial fibrillation appeared to decrease for every 10 year increment in age, above the age of 65 years. 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 speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for please visit ahajournals.org.

Dica de prova: Como calcular o Chadsvasc? by Cardiopapers

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 of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, it's another double feature Tuesday and today we get to discuss two articles. One, some insights from the CREDENCE trial. And second, another article about left atrial appendage closure devices, some results from the PINNACLE FLX trial. But before we get to those, how about we grab a cup of coffee and dive into some of the other really interesting articles in this issue? Would you like to go first? Dr. Carolyn Lam: I would, because this next paper, right up your alley and I'm sure you'll like it. But first, we talk about mitral valve prolapse. Now, we know that's a frequent disease that can be complicated by mitral regurgitation, heart failure, arterial embolism, rhythm disorders, and death. Left ventricular replacement myocardial fibrosis is a marker of maladaptive remodeling and has been described in patients with mitral valve prolapse. However, the implications of this finding remain scarcely explored. So these authors, led by Dr. [Le] Tourneau from Hôpital Laennec in France, aimed at assessing the prevalence, pathophysiological and prognostic significance of left ventricular replacement myocardial fibrosis through late gadolinium enhancement by cardiac magnetic resonance in 400 patients with mitral valve products. I bet you like that, right Greg? Dr. Greg Hundley: Oh my gosh Carolyn, not only a favorite topic of cardiovascular magnetic resonance, but this is a really large patient population with mitral valve prolapse that underwent CMR. So tell us, what did they find? Dr. Carolyn Lam: So replacement myocardial fibrosis was observed in 110 patients, so that's 28% of the patients. It was associated with mitral valve apparatus alterations, left ventricular remodeling, and ventricular arrhythmia. The ventricular arrhythmias were more frequent in patients with replacement fibrosis, but were not associated with the grade of mitral regurgitation. In patients with trace or mild mitral regurgitation, the presence of replacement myocardial fibrosis was nonetheless associated with specific mitral valve apparatus alteration at normal left ventricular dilatation, not explained by volume overload and ventricular arrhythmias, suggesting the presence of a mitral valve prolapse-associated cardiomyopathy. Dr. Greg Hundley: Wow Carolyn, really interesting. So the late gadolinium enhancement and the evidence therefore of replacement myocardial fibrosis that was identified by CMR, maybe this particular study is suggesting that we might want to integrate that into the clinical workup of patients with mitral valve prolapse. Very interesting work, and great job on that fantastic CMR presentation. I must say, got to recruit you into the club. Dr. Greg Hundley: Well, my next paper is another wonderful paper from the world of basic science and it comes from Dr. Douglas Lewandowski at the Ohio State University College of Medicine. So Carolyn, the failing heart is energy starved with impaired oxidation of long chain fatty acids at the level of reduced carnitine palmitoyltransferase-1, or CPT-1, activity at the outer mitochondrial membrane. Recent work shows that elevated ketone oxidation and failing hearts as an alternate carbon source for oxidative ATP generation. So Carolyn, these authors hypothesized that another short chain carbon source, short chain fatty acids that bypass CPT-1, could similarly support energy production in failing hearts. Dr. Carolyn Lam: Wow. Okay, so what did they find? Dr. Greg Hundley: So Carolyn, the failing heart oxidizes short-chain fatty acids more readily than ketones, with short-chain fatty acids also displacing long-chain fatty acid oxidation to somewhat of a greater extent. So in particular, the short-chain fatty acid butyrate has a higher affinity for entry into mitochondrial oxidation at the enzyme, short-chain Acyl-CoA dehydrogenase than does the ketone 3-hydroxybutyrate at the hydroxy butyrate dehydrogenase and then also through the respective downstream metabolic pathways for each substrate. So Carolyn, failing hearts of rats and humans have increased levels of Acyl coenzyme A synthetase medium chain three enzyme, which can also oxidize short-chain fatty acids to enhance butyrate oxidation. Dr. Carolyn Lam: Wow, that really is interesting. I can't say that I would have predicted that result. So could you give us a clinical implication? Dr. Greg Hundley: You bet, Carolyn. A lot of basic science here. So here's I think what we can take home, and what we learned. So while ketones have been sought as a potential supplemental fuel to remedy the impaired oxidative metabolism of the failing heart, this study shows that failing hearts preferentially oxidize short-chain fatty acids over ketones and short-chain fatty acids may prove to be a more efficient energy source during pathological stress. Dr. Greg Hundley: Next, novel alterations in metabolic pathways, favoring short-chain fatty acid oxidation in the failing heart occur in patients with non-ischemic cardiomyopathy. Then finally, circulating ketones are not a unique, super fuel beyond the ability to bypass the inhibition of long-chain fatty oxidation in the failing heart, as do the short chain fatty acids. Dr. Carolyn Lam: Thanks, I like the way you broke down the clinical implications. Well, Greg, I've got a question for you. Have you ever thought that statins may do more than lower cholesterol, but depending on what you eat? Dr. Greg Hundley: Oh wow, Carolyn. We always hear about the pleiotropic effects of statins, but I never really thought that could depend on what you eat. Tell me, so what did these authors investigate? Dr. Carolyn Lam: Yeah, so this next paper is so interesting. It's from Dr. Hu from Huazhong University of Science and Technology in Wuhan, China and colleagues, who present a novel perspective on the story of the pleiotropic effects of statins, exactly like you said, Greg. They started with the premise that statins exert pleiotropic or cholesterol-independent effects by reducing geranylgeranyl pyrophosphate production. I'm not going to keep saying that, so geranylgeranyl pyrophosphate or GGPP, is how I'm going to refer to it. Dr. Carolyn Lam: So they developed a sensitive technique to quantify dietary GGPP, and conducted proteomics, RT-PCR screening, and western blot, to determine signaling cascades, gene expression, protein-protein interaction, and protein-membrane trafficking in wild-type and transgenic rats, focusing on models of pulmonary hypertension, given their interest in the potential therapeutic efficacy of statins in pulmonary arterial hypertension. Dr. Greg Hundley: Interesting, Carolyn. Really complex and sophisticated. So what did they find? Dr. Carolyn Lam: Okay, listen up. Red meat and soybean have a high content of GGPP and their ingestion increases GGPP plasma levels, but reduces the effects of statins in rat models of pulmonary hypertension. Ingestion of garlic extracts, rich in methyl-L-phenyl sulfonate, which is a natural inhibitor of GGPP production, decreases GGPP bioavailability, and rescues statin effects in pulmonary arterial hypertension models. So consequently, first of all, diet may influence the cholesterol-independent effects of statins and the data really raise a provocative question of whether populations in which the typical diet contains high amounts of soybeans of beef may benefit less from statins. All this is discussed in an elegant editorial by Dr. Thomas Eschenhagen from Germany, who really ends with saying the present study should be considered hypothesis-generating and stimulate retrospective analysis of clinical registries and existing large interventional trials to either validate or refute this hypothesis. Whatever the outcome, the study is a nice example of thorough scientific underpinning of the widely held maxim that we are what we eat. Dr. Greg Hundley: Oh, absolutely Carolyn. I think next time with my spaghetti, I'll have the- Dr. Carolyn Lam: Garlic. Dr. Greg Hundley: ... sauce with the garlic, but I won't add the red meats. Especially if I'm taking a statin. Dr. Carolyn Lam: Oh, that's what I was afraid you might say. Oh well, let me tell you about other papers in this issue. There's an ECG challenge by Dr. Del-Carpio Munoz and entitled A Carousel ECG Confusion. There's an on my mind paper by Dr. Hammond, on the importance of shared decision making for return to play after COVID-19. Dr. Greg Hundley: Great, Carolyn. So, in the mailbag, there's a really nice research letter from Dr. Robert-Ebadi evaluating the impact of the age-adjusted D-dimer cutoff to exclude pulmonary embolism. It's from a multinational prospective real-life study or the RELAX-PE study. Well Carolyn, it's another double feature Tuesday. How about we get off to understand a little bit more about those insights from the CREDENCE trial, and then also left atrial appendage closure devices? Dr. Carolyn Lam: All right, come on with your garlic breath. Dr. Greg Hundley: Well listeners, we are onto our feature discussions and we are very fortunate, we're going to have two feature discussions. Our first feature really addresses high blood pressure. And we have with us today, Dr. Brendan Neuen from the George Institute of Global Health in Sydney, New South Wales, Australia. And our own associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern in Dallas, Texas. Welcome to you both. Brendan, we're going to start with you. Could you describe the hypothesis that you wanted to test and what was your study population and your study design? Dr. Brendan Neuen: Well, thanks Greg. In this study, what we wanted to assess was the blood pressure lowering effects of the SGLT-2 inhibitor canagliflozin in people with type two diabetes and chronic kidney disease. The reason we thought that this is important is because what we know about the blood pressure lowering effects of these drugs is largely based on people with normal kidney function, with relatively less data in people with chronic kidney disease. So we aim to assess both the blood pressure lowering effects of SGLT-2 inhibition in chronic kidney disease, as well as treatment effects by baseline blood pressure and other blood pressure defined variables. This was conducted in the CREDENCE trial, which was a large primary renal outcome trial of the SGLT-2 inhibitor, canagliflozin, which enrolled about 4,400 people with type two diabetes and chronic kidney disease with a urine albumin to creatinine ratio greater than 300 milligrams per gram and a GFR greater than 30 at enrollment. This was a high risk hypertension population, about 30% of patients had apparent treatment resistant hypertension, about 60% of people had a GFR less than 60 and about 20% of people were on four or more blood pressure lowering agents. So really high burden of hypertension in the CREDENCE trial. Dr. Greg Hundley: Very good. Tell us a little bit about that design. So is this a randomized trial? Dr. Brendan Neuen: So CREDENCE was an event-driven randomized, double blind, placebo controlled, international trial. It was the first primary renal outcome trial of an SGLT-2 inhibitor, the primary results of which were reported in the New England journal in 2019. What this trial did, was it randomized participants, as I mentioned, with a GFR of greater than 30 and significant albuminuria and type two diabetes to either canagliflozin 100 milligrams or matching placebo in a one-to-one ratio with primary outcome overall of doubling of serum creatinine, kidney failure, cardiovascular or renal death. The trial was conducted in several, I think, 20 or 30 countries overall and enrolled at approximately 4,400 people, with participants followed for a median of about two and a half years. Dr. Greg Hundley: Excellent. So Brendan, tell us, what did you find? Dr. Brendan Neuen: So we found a couple of important findings with regards to blood pressure. Firstly, what we found was that canagliflozin reduced systolic blood pressure by about three and a half millimeters of mercury in the overall trial population. But most importantly, this blood pressure lowering effect was consistent across the number of blood pressure defined subgroups, including in people on multiple numbers of blood pressure lowering agents. So irrespective of the number of blood pressure lowering agents at baseline, and also irrespective of a history of apparent treatment-resistant hypertension at baseline, that was important. We also, secondly, found that the blood pressure lowering effective SGLT-2 inhibition was present very early at the first trial visit at three weeks. This effect was sustained over the duration of the trial. Dr. Brendan Neuen: Thirdly, we also found that canagliflozin reduced the risk of kidney failure and cardiovascular events, regardless of the number of blood pressure lowering agents at baseline and regardless of blood pressure, history of resistant hypertension. Finally, there is this often important question of how do these drugs reduce the risk of kidney failure and heart failure. So we did a mediation analysis, looking at to what extent the blood pressure lowering effect of this drug explains the treatment effect on these important outcomes. We found that only about less than 10% of the treatment effect on kidney failure and cardiovascular events was explained by blood pressure lowering. Dr. Greg Hundley: Very interesting and strong, powerful results. Well, now we're going to turn listeners to our associate editor, Dr. Wanpen Vongpatanasin. Wanpen, I know you see a lot of papers come across your desk at circulation, really focused on blood pressure and its lowering. What struck you about this paper, and then how do you put into context the results that Brendan just describe for us with all the other results that you see in new blood pressure lowering strategies? Dr. Wanpen Vongpatanasin: Yes, so I think this is very important study and add to a body of literature showing that the canagliflozin, like many SGLT-2 inhibitors, inducing significant lowering of blood pressure. If anything, because CREDENCE is not designed to be hypertension study the effects of blood pressure lowering my even be underestimated because the backup ground therapy allowed to be changed throughout the trial, depending on physician judgment. Also, I think the effects of many studies start to look at effects of SGLT-2 inhibitor on out of office blood pressure, like home blood pressure, or 24 blood pressure. Some even that we have published over the years, show more pronounced blood pressure lowering effects when measure outside the office. So I think that it is very interesting study but it could be not just only the drug that we use cardiovascular and renal outcome, but maybe a new class of antihypertensive medication that we could use for that purpose, although it has to be tested. Dr. Greg Hundley: Very nice. Well, Brendan, I want to turn back to you and then we'll come to Wanpen. Brendan, what do you think as a followup study to yours, what do you think is the next study that needs to be performed in this space? Dr. Brendan Neuen: Thanks, Greg. I think there's so much we still need to know about the blood pressure lowering effects of these drugs in people with advanced CKD. It would be very interesting to look at the DAPA-CKD trial, to look at the blood pressure lowering effects in people with advanced CKD not due to diabetes, so nondiabetic kidney disease. These patients also have a high burden of hypertension and whether or not these effects are also present in this population would also be important to know, and study patients with even more advanced kidney disease. That is being done in the EMPA-KIDNEY study with empagliflozin. Those results should be known in the next 12 to 24 months. Dr. Brendan Neuen: So, I'm studying this further in people with kidney disease. And also as Wanpen mentioned, looking at effects on blood pressure phenotype, you know, 24 hour blood pressure dipping status would also be important though, blood pressure variability, all those things can add to our understanding of the effect of these agents on blood pressure. Dr. Greg Hundley: Excellent. And Wanpen, do you have anything to add? Dr. Wanpen Vongpatanasin: Yes. I think one also very important study that helps someone with carrying in the future is in the CREDENCE, the people who are already treated with a mineralocorticoid receptor antagonist were excluded. So whether among resistant hypertension group, adding canagliflozin will be beneficial in those groups already treated MRA and lower cardiovascular outcome in already treated with MRA will be very interesting to see. Dr. Brendan Neuen: Yeah, I think that's a really important point to point out about the design of the CREDENCE trial, that patients who were on MRAs were excluded from the trial initially. This was due to early concerns that canagliflozin might increase the risk of hyperkalemia. I think that risk has now been put to bed in the other SGLT-2 inhibitor trials. We've got more data looking at the effects on serine potassium coming out soon, hopefully, but the other trials in which enroll more patients on MRAs, it will be very important to look at the blood pressure lowering effects in these populations. Dr. Greg Hundley: Excellent. Well, listeners, we've heard a great discussion today and we want to thank Brendan Neuen for bringing this wonderful science to us through circulation at the American Heart Association. We also want to thank our associate editor, Wanpen Vongpatanasin for being present today and helping us discuss how, in patients with type two diabetes and chronic kidney disease, describing that the blood pressure lowering effect of canagliflozin occurs early and appears sustained over the long term and therefore perhaps canagliflozin and can be used or considered as an adjunct blood pressure lowering medicine in addition to perhaps its protective effects on the kidney and other cardiovascular-related issues. Well now listeners, we've got another feature to get onto. So we're going to get to that second feature discussion right now. Dr. Greg Hundley: Well listeners, we are now turning to our second feature discussion and we're so fortunate today to have with us Dr. Saibal Kar from the Los Robles Regional Medical Center in Los Angeles, California, and our own associate editor, Dr. Mark Link from UT Southwestern in Dallas, Texas. Welcome gentlemen. Saibal, let's start with you. Could you describe for us the hypothesis that you wanted to test and what was your study population and your study design? Dr. Saibal Kar: Dr. Hundley, or if I could allow to call you Greg, thank you very much for asking me this question. The hypothesis was that we do know that the WATCHMAN device does prevent ischemic strokes. We do know that the first generation device has a few limitations. So there were some modifications made to the new WATCHMAN device, which is now called the WATCHMAN FLX. We thought that these changes should translate into better safety and better efficacy. So, that was the hypothesis of the study. The study population was patients with nonvalvular atrial fibrillation with a CHADS-VASc score of three or more, who had high risk of bleeding or patients who cannot take long-term anticoagulants. The study design was a single arm, prospective multicenter study with endpoints, which were based on performance goals from previous clinical trials. Dr. Greg Hundley: Excellent. Before we get to your results, Saibal how many patients and how many centers participated in your trial? Dr. Saibal Kar: So as the national principal investigator, I've never seen a study which was enrolled so fast. So the intended population was 400 patients in 29 centers and before half those centers could be activated, the study was over in four months. Dr. Greg Hundley: Congratulations. I think all of us that have ... especially in this pandemic era for recruiting so well, and tell us, what did you find? Dr. Saibal Kar: So what we found is that there were two endpoints, a safety endpoint and the efficacy endpoint. So the first thing that we found is that of the 400 patients, we could actually implant in 395 patients, device actually, which made the primary success rate over 98%. regarding the safety endpoint, we had a safety margin around 4% based on a performance score and set about 2.5, but the actual safety event rate was 0.5%, which was only two minor ischemic events, peri-procedural. There were no pericardial effusions in the first seven days, and there was no device embolizations at any time period, so that was the primary safety endpoint. So we were actually clearly safer than the first-generation device. Dr. Saibal Kar: When it comes to efficacy, it was an anatomical efficacy and we set the primary goal for the previous generation to be 99%. We've made a delta to make it about 97% effective, but we actually achieved an effective closure in 100% of patients. When I say effective closure, I mean that anyone with a peri device leak of less than five millimeters. Going into a little bit of granular detail, we actually found out that 90% of the patients actually had no leak at all. So we did at least achieve both the anatomical as well as the safety endpoints. Dr. Greg Hundley: Excellent. Well, listeners, we're now going to turn to our associate editor, Dr. Mark Link and Mark, I know you have many papers that pass through your hands. What attracted you to this paper. Then, these results really sound significant. Can you describe what impressed you also with the results of this study and how do they relate to other studies pertinent to implantation of devices in patients with atrial fibrillation? Dr. Mark Link: Yeah, we were interested in this paper at CERT because it's the next generation of the WATCHMAN. The numbers of patients that are being implanted with this device to prevent strokes is dramatically going up, but it's not a perfect device. So we were, as the EP community, very interested in the next generation device. We're obviously also interested in other competitors' device, but it's clear that the WATCHMAN is probably the world's leader in this time. So we knew that many of our people reading this magazine, reading the circulation, would want to see how the next generation turned out, was it really safer. That was really the primary goal of this study, it's really a safety study more than an efficacy study because the efficacy was defined by echo criteria, not by clinical criteria of stroke, which is the ultimate criteria. It was a well done study and the results came out more positive than I think even the investigators thought it was going to come out. So we liked it and that's why we did our best to get it published in circulation. Dr. Greg Hundley: Very good. So it sounds like great new innovation and very, very safe, especially relative perhaps to the first-generation device. So Saibal, can you tell us in just a few words, what do you think is the next study to be performed in this space? After you answer, Mark, we'll turn to you and basically ask the same question. Dr. Saibal Kar: Thank you very much, Greg. Transcatheter left atrial appendage closure has been approved by the FDA, specifically the WATCHMAN device, for patients who are candidates for long anticoagulation, but have limitations to long-term anticoagulation and therefore not for all-comers and there's a reason for that. The time has now come to actually evaluate this device for all-comers. That means all patients with nonvalvular atrial fibrillations who are suitable for anticoagulants. Therefore, the next best study is the CHAMPION trial. This study is going to be a randomized trial of the WATCHMAN FLX versus NOACs, or more correctly DOACs, in all-comers, patients with nonvalvular atrial fibrillation who require long-term anticoagulants. It's a 3,000 patients clinical trial with a one-to-one randomization to WATCHMAN FLX or the continuation of DOACs and the primary endpoints will be estimated at three years with a follow-up up to five years. Our goal is to show that we are non-inferior in comparison to stroke and death, and superior respect to long-term bleeding. Dr. Greg Hundley: Very good, and Mark? Dr. Mark Link: Yeah, I agree. The CHAMPION trial is the obvious next trial that everyone wants to see the results of, comparing this device to DOACs. Another trial or data I'd like to see is the immediate post-procedural anticoagulation. It's still an area that we don't have enough data to know how to treat these patients. Traditionally, they've been treated with warfarin and anti-platelet agents, but many of the patients getting this WATCHMAN have a relative contraindication to anticoagulation. So I'd like to see some data on shorter term duration of anticoagulation post-implant. Dr. Greg Hundley: Very good. Well listeners, we've had a wonderful discussion here and we want to thank the lead author, Dr. Saibal Kar and also our own associate editor, Dr. Mark Link, for really providing us with new information that this left atrial appendage closure device met the primary safety outcome in 99.5% of all of those implanted within seven days, what a remarkable finding. So, on behalf of 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, 2021.  

For this week's Feature Discussion, please join authors Michael Ackerman, Christopher Haggerty, editorialist Michael Rosenberg, and Associate Editor Nicholas Mills as they discuss the original research articles “Artificial Intelligence-Enabled Assessment of the Heart Rate Corrected QT Interval Using a Mobile Electrocardiogram Device,” “ Deep Neural Networks Can Predict New-Onset Atrial Fibrillation From the 12-Lead Electrocardiogram and Help Identify Those at Risk of AF-Related Stroke,” and “Trusting Magic: Interpretability of Predictions from Machine Learning Algorithms.”   TRANSCRIPT BELOW: 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 cohosts. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this week's feature, it's kind of a new thing for us. It's more than our double feature; it's actually a forum, where we're going to have two papers discussed, we'll have both authors represented from each of those two papers, we'll have an editorialist, and we'll have one of our associate editors. And the topic, Carolyn, just to keep you in suspense, is really on machine learning and actually how that can be applied to 12 lead electrocardiograms. But before we get to that, how about we grab a cup of coffee and start off on some of the other articles in this issue? Would you like to go first? Dr. Carolyn Lam: Yes, I would, but you're really keeping me in suspense. But first, let's focus on health related quality of life. We know that poor quality of life is common in heart failure, but there are few data on heart health related quality of life and its association with mortality outside of the Western countries. Well, until today's paper. And it's from the Global Congestive Heart Failure, or GCHF study, the largest study that has systematically examined health-related quality of life as measured by the Kansas City cardiomyopathy questionnaire 12, or KCCQ, and its association with outcomes in more than 23,000 patients with heart failure across 40 countries, in eight major geographic regions, spanning five continents. Dr. Greg Hundley: Wow, Carolyn. That KCCQ 12, that has been such an interesting tool for us to use in patients with heart failure. So what did they find in this study? Dr. Carolyn Lam: Really important. So the health-related quality of life differs considerably between geographic regions with markedly lower quality of life related to heart failure in Africa than elsewhere. Quality of life was a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and in both preserved and reduced ejection fraction. So there are some important clinical implications, namely that health-related quality of life is an inexpensive and simple prognostic marker that may be useful in characterizing symptom severity and prognosis in patients with heart failure. And there is certainly a need to address disparities that impact quality of life in patients with heart failure in different regions of the world. Dr. Greg Hundley: Very nice, Carolyn. Well, I'm going to turn to the world of basic science and bring us a paper from David Merryman from Vanderbilt University. So Carolyn, myocardial infarction induces an intense injury response, which ultimately generates a collagen dominated scar. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process post myocardial infarction. Now Carolyn, serotonin 2B receptor signaling has been shown to be harmful in a variety of cardiopulmonary pathologies, and could play an important role in mediating scar formation after MI. So Carolyn, these investigators employed two pharmacologic antagonists to explore the effect of serotonin 2B receptor inhibition on outcomes post myocardial infarction and characterized the histological and micro structural changes involved in tissue remodeling. Dr. Carolyn Lam: Oh, that's very interesting, Greg. What did they find? Dr. Greg Hundley: So Carolyn, serotonin 2B receptor antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated in their results by decreased scar thickness and decreased border zone area. Serotonin 2B receptor antagonism resulted in collagen fiber redistribution to a thinner collagen fiber. And they were more anisotropic. They enhanced left ventricular contractility and the fibrotic tissue stiffness was decreased, thereby limiting the hypertrophic response of the uninjured cardiomyocytes. Dr. Carolyn Lam: Wow. That is really fascinating, Greg. Summarize it for us. Dr. Greg Hundley: Yeah, sure. So this study, Carolyn, suggests that early inhibition of serotonin 2B receptor signaling after myocardial infarction is sufficient to optimize scar formation, resulting in a functional scar, which is less likely to expand beyond the initial infarct and cause long-term remodeling. The prolonged presence of the antagonist was not required to maintain the benefits observed in the early stages after injury, indicating that acute treatment can alter chronic remodeling. So Carolyn, it's really going to be interesting to see how this research question is pursued in studies of larger animals, including us, or human subjects. Dr. Carolyn Lam: Wow, that is really interesting. And so is this next paper. Well, we know that genetic variation in coding regions of genes are known to cause inherited cardiomyopathies and heart failure. For example, mutations in MYH7 are a common cause of hypertrophic cardiomyopathy, while mutations in LMNA are a common cause of dilated cardiomyopathy with arrhythmias. Now, to define the contribution of non-coding variations, though, today's authors, led by Dr. Elizabeth McNelly from Northwestern University Feinberg School of Medicine in Chicago and colleagues evaluated the regulatory regions for these two commonly mutated cardiomyopathy genes, namely MYH7 and LMNA. Dr. Greg Hundley: Wow, Carolyn. So this is really interesting. So how did they do this and what did they find? Dr. Carolyn Lam: You asked the top questions, because the method is just as interesting as the findings here. They used an integrative analysis that relied on more than 20 heart enhancer function and enhancer target datasets to identify MYH7 and LMNA left ventricular enhancer regions. They confirmed the activity of these regions using reporter assay and CRISPR mediated deletion of human cardiomyocytes derived from induced pluripotent STEM cells. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. Extending the strategy genome-wide, they identified an enhancer modifying variant upstream of MYH7. One specific genetic variant correlated with cardiomyopathy features derived from biobank and electronic health record information, including a more dilated left ventricle over time. So these findings really link non-coding enhancer variation to cardiomyopathy phenotypes, and provide direct evidence of the importance of genetic background. Beautiful paper. Dr. Greg Hundley: Very nice, Carolyn. Dr. Carolyn Lam: But let me quickly tell you what else is in this issue. We have an ECG Challenge by Dr. Lutz on flash pulmonary edema in a 70-year-old; there's an On My Mind paper by Dr. Halushka, entitled (An) Urgent Need for Studies of the Late Effects of SARS-CoV-2 on the Cardiovascular System. Dr. Greg Hundley: Ah, Carolyn. Well, in the mailbox, there are two Research Letters, one from Dr. Soman entitled (The) Prevalence of Atrial Fibrillation and Thromboembolic Risk in Wild-Type Transthyretin Amyloid Cardiomyopathy, and a second letter from Dr. Berger entitled Multiple Biomarker Approaches to Risk Stratification in COVID-19. Well Carolyn, now let's get on to that forum discussion and hear a little bit more about using machine learning in the interpretation of a 12 lead ECG. Dr. Carolyn Lam: Wow, can't wait. Thanks, Greg. Dr. Greg Hundley: Well listeners, we are here today for a double feature, but this double feature is somewhat unique, in that we are going to discuss together two papers that focus on machine learning applications as they relate to the interpretation of the electrocardiogram. With us today, we have Mike Ackerman from Mayo Clinic, Chris Haggerty from Geisinger, Mike Rosenberg as an editorialist from University of Colorado, and then our own Nick Mills, an associate editor with Circulation. Welcome, gentlemen. Well, Mike Ackerman, we will start with you first. Could you describe for us the hypothesis that you wanted to test, and what was your study population and your study design? Dr. Michael Ackerman: Thanks, Greg. The hypothesis was pretty simple, and that is could an artificial intelligence based approach, machine learning, deep neural network, could that solve the QT problem? Which is one of the big secrets among cardiologists, which, as you know, one of your associate editors, Sammy Biskin, published a sobering paper over a decade ago, showing and revealing the secret that cardiologists are not so hot at measuring the QT interval, and heart rhythm specialists sometimes don't get it right either. And we all know that the 12 lead ECG itself is vexed by its computer algorithms at getting the QTC just right, compared to those of us who would view ourselves as QT aficionados. And so we were hoping that a machine learning approach would solve this and help us glean, one, a very accurate QTC, as accurate as I can make it when I measure it, or core labs that do QT measuring for living. Dr. Michael Ackerman: And two, could we get that QTC from just a couple of leads to be as accurate as what the whole 12 lead ECG would be seeing so that we can move it to a mobile smartphone enabled solution? And so that was our hypothesis going forward, and we studied a lot of patients. And that's something that machine learning and the power of computation does, that in my world, I'm used to studying a hundred or a thousand patients with congenital long QT syndrome and thinking that I've assembled a large cohort, but for this study, we started with over two and a half million ECGs from over 650,000 people. And then ultimately, through training, testing, and validation of about 1.6 million ECGs from over a half a million individuals to sort of teach the computer or have the AI algorithm get the QT interval not too hot, not too cold, but just right. And as we'll discuss, I think we hit the mark. Dr. Greg Hundley: Thanks so much, Mike, what did you find? Dr. Michael Ackerman: Ultimately, we were able to show that with this drill, we could get the deep neural network derived QTC to be give or take two plus minus 20 milliseconds from what would the standard of care, and that being a technician over-read QTC. But then we took, I would say, pretty unique to AI studies, as many AI studies, just do training, testing, and validation for study number one. And then a future paper of a prospective study. But we did that prospective study within this single paper with a subsequent about two year enrollment of nearly 700 patients that I evaluated in our genetic heart rhythm clinic at Mayo Clinic. And half of those patients have congenital long QT syndrome, half did not. And what we showed was that the deep neural network derived QTC from a mobile ECG approximated the subsequent or the just prior 12 lead ECG within one millisecond, +/- 20 millisecond territory. Dr. Michael Ackerman: And it's ability to say is the QTC above or below 500, which we all know is sort of a warning sign, that's a very actionable ECG finding, do something about it, that that 500 millisecond cutoff by the deep neural network gave us an area under the curve of 0.97, which from a screening perspective, that AUC is far higher than a lot of AUCs for a lot of screening tests done in the cancer world and so forth. And so we think we are very close to what I've called a pivot point, where we will soon pivot from the way we've been doing the QTC since Eindhoven over a century ago to a fundamentally new way of deriving a QTC that's precise and accurate and mobile enabled. Dr. Greg Hundley: Very nice, Mike. So using machine learning to accurately assess the QTC from just two leads of an electrocardiogram. Well Chris, you also have a paper in this issue of circulation that pertains to another application of machine learning and looking at the electrocardiogram. Can you describe for us your study population, study design, and then also the question you were trying to address? Dr. Christopher Haggerty: Sure. Yeah, thanks Greg. Great to be here with you all today. Very similar to Mike's study, the motivation for us was we believe very strongly that there's opportunities with using deep learning applied to ECG data to uncover not only new knowledge latent in the ECG itself related to the current patient context, but also to try to predict future outcomes, future events. And that was really our motivation, was to take that paradigm of looking forward, in this case to predict new onset of atrial fibrillation within a year. We used our Geisinger patient cohort, which is a largely rural population in central Pennsylvania. We have very longitudinal data for a lot of our patients, which allows us to have this kind of design going back in our electronic health records, in this case, our ECG database to 30 plus years. Dr. Christopher Haggerty: Similar big numbers that Mike described, and in our case, 1.6 million ECGs over 430,000 patients used to train the model. And we had several different study designs that we employed. One just being a simple proof of concept, asking can we accurately predict new onset atrial fibrillation one year? And then a second study design that was intended to simulate a real world deployment scenario. Obviously the main rationale for trying to predict atrial fibrillation is to then be able to treat and try to prevent stroke. And so we tried to, as best we can in a retrospective fashion, simulate a scenario in which we might use this model to identify patients who went on to have a presumably AFib associated stroke. Dr. Greg Hundley: And what did you find, Chris? Dr. Christopher Haggerty: So I think there are three main findings that we highlighted here. So first, obviously we were building on the great work that Mike and some of his colleagues at the Mayo Clinic have done, showing that looking at AFib using deep neural networks needs to be feasible. We extended it in this case by looking out further than just an acute sense, looking at that one-year outcome. And we had an area under the curve for our proof of concept of 0.85. So area under the curve of 0.85 to identify patients with new onset of atrial fibrillation within one year in our millions of ECGs. Looking at it another way, the second main finding was that that one year prediction was shown to have prognostic significance beyond that one year, which is really interesting and warrants a lot of further study. Looking over 30 years of follow-up, patients predicted to be at high risk at baseline had a hazard ratio of 7.2 for developing atrial fibrillation, compared to those deemed to be low risk. Dr. Christopher Haggerty: And then really the third, and I think perhaps the most exciting finding that we had here, was this simulated stroke experiment that we had, where we identified patients from an internal stroke registry and identified patients who had new diagnosis of AFib at the time or up to a year after the stroke. So we can assume that they were an AFib associated stroke. And subsequently, or I should say previously, had an ECG that we could use to run through the algorithm to predict their atrial fibrillation risk. And we showed that the model performed well in this setting, that of the 375 strokes that we identified, for example, over a five-year period in our registry, we were able to identify 62% of them within three years based on that ECG. So a number needed to screen for an atrial fibrillation associated with stroke about 162, which compares favorably well to other screening techniques that are out there, obviously. So we took that as a great proof of concept that this type of AI technique might have benefits for screening for atrial fibrillation and preventing strokes. Dr. Greg Hundley: Well congratulations, Chris. Well, we're now going to turn to our associate editor, Dr. Nick Mills. And Nick, you have a lot of manuscripts come across your desk. What attracted you to these two papers, and what are the significance of the results as they apply to ECG applications as we move forward? Nick Mills: Thanks, Greg. Yeah, this is a rapidly growing field, where the availability of data scale with digital archiving and lots of really interesting new methodologies are available to our researchers. So we are receiving a lot of content in this area. What I loved about these two papers is not just the quality of the work, but also the really tangible benefits, potentially, for patients. So AI does not need to be complex, but it does need to solve a tangible problem. I guess what we look for in the journal, beyond the kind of innovation and methodology, is quality, and these studies used prospective validation, really reliable end points, ascertainments, transparency, reporting, all the things that we know are important for high quality clinical research. I think the idea that we can bring QT monitoring to the drug store on a portable device for our patients is potentially transformative. I also think that to take a technology, the electrocardiogram that we've been using for over a century, and provide new insights that go way beyond my ability to interpret the ECG, that might help us recommend a different course of action for our patients is also just really exciting. Dr. Greg Hundley: Very nice. Thank you, Nick. Well Mike ... we're going to turn to Mike Rosenberg now, listeners. And Mike wrote a wonderful editorial, and I would invite you to work through this. As you have an opportunity to read the journal and interact with it. Mike, there are two different types of machine learning, I think, that you described were used by the two respective investigative groups. Could you describe those for our cardiology listeners? What were the differences in those two approaches? Dr. Michael Rosenberg: Yeah, sure. And thank you for the opportunity to write the editorial. Two very fascinating papers. I should say that they both use the same approach of what's called supervised learning, where you basically have a set of data inputs, and you're trying to predict a labeled outcome. And what I talk about in the paper is that what we've learned is if you have enough data and enough computing power, you can predict almost anything highly accurately. What's interesting about the two papers, and what I sort of tried to contrast in the editorial, is that the one from the Mayo Group and Dr. Ackerman, was basically predicting what's already a known biomarker for sudden death, which is the QT interval. And essentially, almost trying to automate that process of predicting it accurately and in a way that, in essence, could allow a home monitoring of patients for QT prolongation, which obviously would be a huge benefit for clinicians, all those alerts and things, to be able to have patients taking drugs that are known to prolong the QT interval and feeling comfortable that if they have any prolongation, it could be detected accurately. Dr. Michael Rosenberg: The second one, which is sort of interesting, and in contrast is from the Geisinger Group and Dr. Haggerty, was the approach of ... where actually the prediction itself is actually the biomarker. And we don't actually know exactly what it's using, which I talk about a little bit of what that means and the implications clinically, but in essence, what they showed was that it actually is a very good biomarker and on par with what a lot of us would consider to be very strong predictors of agents. So I think it was two very interesting approaches to, again, applying the same type of machine learning, but really approaching it one from a more discovery side and another from sort of validated or almost automating something that we do on a daily basis. Dr. Greg Hundley: Thank you, Mike. So Mike, just coming back to you again, as we read the literature, and most of us are clinicians or researchers practicing, what should we look for when these new machine learning manuscripts and research studies come out as to gauge, "Ah, this is a really good study," or maybe not so much? Dr. Michael Rosenberg: Yeah. And it's a good question. I think one of the biggest challenges, as I talked about, is interpretability. I think in the clinical world, we're used to understanding the code for the variables that go into our risk prediction model. And so I think first and foremost is can I even understand what this is predicting or am I sort of expected to take the predictions as sort of a black box, it is what it is type of approach? I think that there's other things that I just look at when I'm reviewing these manuscripts. I mean, as I sort of mentioned, what these models are really doing, it's not anything magical. What they're doing is identifying patterns in the data and then using those to make predictions, again, toward whatever label that you've assigned them to. Dr. Michael Rosenberg: It's important that your data sets are split and that you're training at one data set and then testing it in one that's separate. And again, you can't ignore epidemiology. Is the data set that you're training it reflective of the population that you're going to be using those models in? And we know from outside of healthcare, there's issues with models that have been trained in one population where it's potentially biased or it's potentially offering predictions that are using information we may not necessarily want to use. Recidivism is a big example of that. So I think that that's, first and foremost, it's sort of taking a step back as a clinician and saying, "If this was a biomarker that someone was proposing to use to predict some new disease, what would I expect to use to evaluate that?" And that's probably what I would start with. Dr. Greg Hundley: Excellent. Well, I'm going to turn back and go back to our panelists here, listeners. And we're going to ask each of our panelists in about 20 seconds to describe for us what they think is the next most important aspect of research in their respective areas. So first I'll start with Mike Ackerman. Mike, can you tell us what's coming next in this area of assessment of QT prolongation or other aspects of the electrocardiogram? Dr. Michael Ackerman: I think next is implementing this in the real world. We are having our suite of the AI ECG as a  hypertrophic cardiomyopathy detector. We've shown that as an ejection fraction detector, and now as a QT detector in AFib, from our work and Chris's work. And for the QT itself, I think where we are is we're really, really close to now having a mobile enabled digital QT meter. And a digital QT meter, once FDA cleared, then allows the QTC to truly emerge as the next vital sign. And it really deserves to be a vital sign. We use it as a vital sign. We know I want to know my patient's QTC every bit as I want to know his or her weight, blood pressure, saturation. It's an actionable finding, and we're now getting really close. We're just on the cusp of having a true digital QT meter. Dr. Greg Hundley: Excellent. Chris? Dr. Christopher Haggerty: I think for us to, in part address some of the comments that Mike brought up about the reproducibility of these types of models, we're very keen to demonstrate the prospective capabilities of our models to enroll patients in a prospective fashion, run their ECG through our predictor, and then screen them for AFib to determine how well we actually do moving forward, instead of just relying solely on our retrospective data. So we're very excited to do that. We're ramping up for that trial now and hope to be able to demonstrate similarly positive findings from our technique. Dr. Greg Hundley: Great. How about you, Nick? Nick Mills: I'd like to see the same quality and rigor applied to the implementation of these technologies as we have to other important areas in cardiovascular medicine. I think that's a really important step, not just to develop the tools, but to demonstrate their value. But I also think what we've done so far is relatively simplistic. We've taken an ECG and we've ignored almost all the other information that we have in front of us. And as these algorithms are trained and evolved, these and other vital clinical biomarkers and information, and integrating them into these neural networks will really enhance their performance for predicting things that are less tangible, like sudden death in the future or stroke. Dr. Greg Hundley: And then finally, Mike Rosenberg. Dr. Michael Rosenberg: Yeah, I actually see two challenging areas in this field. One is the access to data. And I think one of the things that a lot of companies are realizing is that even if they make hardware, that the data may be more valuable than the technology that they're getting the data from. So I think one is figuring out ways to get access to data so that people can reproduce findings from these studies. And the second is deliverable. A bottle like this is not like the CHADS-VASc score that I can calculate in my head in the clinic. I mean I need a way to actually run these models within an EHR, within a computer system like that. And I think it's going to be a big challenge to take a model like this and to deploy it at scale the way we would with the drug or any other innovation. Dr. Greg Hundley: Fantastic. Well listeners, we want to thank Mike Ackerman from Mayo Clinic, Chris Haggerty from Geisinger, Mike Rosenberg from University of Colorado, and Nick Mills from University of Edinburgh for really providing us with a wonderful discussion regarding the use of machine learning applications in one study to predict the QTC interval from two leads that may be applicable to wearable devices. And in the second study, predicting the future occurrence of atrial fibrillation and even stroke as an adverse event in people at risk. Dr. Greg Hundley: On behalf of both Carolyn and myself, I 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, 2021.  

#167 - O que mudou recentemente na análise do CHADS-Vasc? by Cardiopapers

In this episode we take a look at the CHADS-VASc score for atrial fibrillation.  This scoring assessment tool is used to guide clinical decision making for anti-coagulation to prevent thromboembolism in patients with non-valvular atrial fibrillation.  References:MD Calc CHADS-VASc Calculator ToolAHA/ACC/HRS Update to the 2019 Atrial Fibrillation Guidelines"Music from https://filmmusic.io"Acid Trumpet" by Kevin MacLeod (https://incompetech.com)License: CC BY (http://creativecommons.org/licenses/by/4.0/)”

Confira explicação do Dr. Jonathan Souza de duas questões sobre CHADS2, CHADSVASc e anticoagulantes.

Listen to the episode for the answers!MC site infection for an IV drug userFirst line treatment for Non-sustained ventricular tachycardia (NSVT)MC organism in osteomyelitisDiagnosis of HemophiliaHow is a stress fracture diagnosedHow often does the USPSTF recommend screening for abdominal aortic aneurysmsAt what CHADSVASC score is it recommended to start anti coagulation in patients with afibWhat is the diagnostic study of choice for duodenal ulcersFirst line treatment for cluster headachesAntidote for heparin overdoseWhat would you see on PE for an orbital blow-out fractureWhat are two physical exam signs associated with acute pancreatitisWhat is the dosing schedule for HPV vaccineHow do you titrate the treatment for chronic Hepatic encephalopathyWhat are the 6 P’s of compartment syndrome

#49 - sabia dessa dica do Chadsvasc? by Cardiopapers

Qual paciente portador de fibrilação atrial devemos inciar a anticoagulação oral? Confira no podcast. Não esqueça de nos seguir e avaliar o podcast. Música de fundo: Quando as coisas mudam de lugar. Banda Demodee (Reprodução autorizada).

Show Notes Jeff: Welcome back to EMplify the podcast corollary to EB Medicine’s Emergency medicine Practice. I’m Jeff Nusbaum and I’m back with Nachi Gupta. This month, we are tackling a topic for which the literature continues to rapidly change - we’re talking about the ED management of patients taking direct oral anticoagulants or DOACs, previously called novel oral anticoagulants or NOACs. Nachi: Specifically, we’ll be focusing on the use of DOACs for the indications of stroke prevention in atrial fibrillation and the treatment and prevention of recurrent venous thromboembolisms. Jeff: This month’s article was authored by Dr. Patrick Maher and Dr. Emily Taub of the Icahn School of Medicine at Mount Sinai, and it was peer reviewed by Dr. Dowin Boatright from Yale, Dr. Natalie Kreitzer from the University of Cincinnati, and Dr. Isaac Tawil from the University of New Mexico. Nachi: In their quest to update the last Emergency Medicine Practice issue on this topic which was published in 2013, they reviewed over 200 articles from 2000 to present in addition to 5 systematic reviews in the cochrane database, as well as guidelines from the American Heart Association, European society of cardiology, and the american college of cardiology. Jeff: Thanks to a strong literature base, Dr’s Maher and Taub found good quality evidence regarding safety and efficacy of the DOACs in relation to warfarin and the heparin-based anticoagulants. Nachi: But do note that the literature directly comparing the DOACs is far more limited and mostly of poor quality. Show More v Jeff: Fair enough, we’ll take what we can get. Nachi: Well, I’m sure more of those studies are still coming. Jeff: Agree. Let’s get started with some basics. Not surprisingly, DOACs now account for a similar proportion of office visits for anticoagulant use as warfarin. Nachi: With huge benefits including reduced need for monitoring and a potential for reduced bleeding complications, this certainly isn’t surprising. Jeff: Though those benefits are not without challenges - most notably the lack of an effective reversal agent and the risk of unintentional overdose in patients with altered drug metabolism. Nachi: Like all things in medicine, it’s about balancing and finding an acceptable risk/benefit profile. Jeff: True. Let’s talk pathophysiology for a minute - the control of coagulation in the human body is a balance between hemorrhage and thrombosis, mediated by an extensive number of procoagulant and anticoagulant proteins. Nachi: Before the development of the DOACs, vitamin K antagonists controlled the brunt of the market. As their name suggests, they work by inhibiting the action of vitamin K, and thus reducing the production of clotting factors 2, 7, 9, and 10, and the anticoagulant proteins C and S. Jeff: Unfortunately, these agents have a narrow therapeutic window and many drug-drug interactions, and they require frequent monitoring - making them less desirable to many. Nachi: However, in 2010, the FDA approved the first DOAC, a real game-changer. The DOACs currently on the market work by one of two mechanisms - direct thrombin inhibition or factor Xa inhibition. Jeff: DOACs are currently approved for stroke prevention in nonvalvular afib, treatment of VTE, VTE prophylaxis, and reduction of major cardiovascular events in stable cardiovascular disease. Studies are underway to test their safety and efficacy in arterial and venous thromboembolism, prevention of embolic stroke in afib, ACS, cancer-associated thrombosis, upper extremity DVT, and mesenteric thrombosis. Nachi: Direct thrombin inhibitors like Dabigatran, tradename Pradaxa, was the first FDA approved DOAC. It works by directly inhibiting thrombin, or factor IIa, which is a serine protease that converts soluble fibrinogen into fibrin for clot formation. Jeff: Dabigatran comes in doses of 75 and 150 mg. The dose depends on your renal function, and, with a half-life of 12-15 hours, is taken twice daily. Note the drastically reduced half-life as compared to warfarin, which has a half-life of up to 60 hours. Nachi: The RE-LY trial for afib found that taking 150 mg of Dabigatran BID had a lower rate of stroke and systemic embolism than warfarin with a similar rate of major hemorrhage. Dabigatran also had lower rates of fatal and traumatic intracerebral hemorrhage than warfarin. Jeff: A separate RCT found similar efficacy in treating acute VTE and preventing recurrence compared with warfarin, with reduced rates of hemorrhage! Nachi: Less monitoring, less hemorrhage, similar efficacy, I’m sold!!! Jeff: Slow down, there’s lots of other great agents out there, let’s get through them all first... Nachi: Ok, so next up we have the Factor Xa inhibitors, Rivaroxaban, apixaban, edoxaban, and betrixaban.As the name suggests, these medications work by directly inhibiting the clotting of factor Xa, which works in the clotting cascade to convert prothrombin to thrombin. Jeff: Rivaroxaban, trade name Xarelto, the second FDA approved DOAC, is used for stroke prevention in those with nonvalvular afib and VTE treatment. After taking 15 mg BID for the first 21 days, rivaroxaban is typically dosed at 20 mg daily with adjustments for reduced renal function. Nachi: The Rocket AF trial found that rivaroxaban is noninferior to warfarin for stroke and systemic embolism prevention without a significant difference in risk of major bleeding. Interestingly, GI bleeding may be higher in the rivaroxaban group, though the overall incidence was very low in both groups at about 0.4% of patients per year. Jeff: In the Einstein trial, patients with VTE were randomized to rivaroxaban or standard therapy. In the end, they reported similar rates of recurrence and bleeding outcomes for acute treatment. Continuing therapy beyond the acute period resulted in similar rates of VTE recurrence and bleeding episodes to treatment with aspirin alone. Nachi: Next we have apixaban, tradename Eliquis. Apixaban is approved for afib and the treatment of venous thromboembolism. It’s typically dosed as 10 mg BID for 7 days followed by 5 mg BID with dose reductions for the elderly and those with renal failure. Jeff: In the Aristotle trial, when compared to warfarin, apixaban was superior in preventing stroke and systemic embolism with lower mortality and bleeding. Rates of major hemorrhage-related mortality were also nearly cut in half at 30 days when compared to warfarin. Nachi: For the treatment of venous thromboembolism, the literature shows that apixaban has a similar efficacy to warfarin in preventing recurrence with less bleeding complications. Jeff: Unfortunately, with polypharmacy, there is increased risk of thromboembolic and hemorrhage risks, but this risk is similar to what is seen with warfarin. Nachi: And as compared to low molecular weight heparin, apixaban had higher bleeding rates without reducing venous thromboembolism events when used for thromboprophylaxis. It’s also been studied in acute ACS, with increased bleeding and no decrease in ischemic events. Jeff: Edoxaban is up next, approved by the FDA in 2015 for similar indications as the other Factor Xa inhibitors. It’s recommended that edoxaban be given parenterally for 5-10 days prior to starting oral treatment for VTE, which is actually similar to dabigatran. It has similar levels of VTE recurrence with fewer major bleeding episodes compared to warfarin. It has also been used with similar effects and less major bleeding for stroke prevention in afib. In the setting of cancer related DVTs specifically, as compared to low molecular weight heparin, one RCT showed lower rates of VTE but higher rates of major bleeding when compared to dalteparin. Nachi: Next we have Betrixaban, the latest Factor Xa inhibitor to be approved, back in 2017. Because it’s utility is limited to venous thromboembolism prophylaxis in mostly medically ill inpatients, it’s unlikely to be encountered by emergency physicians very frequently. Jeff: As a one sentence FYI though - note that in recent trials, betrixaban reduced the rate of VTE with equivalent rates of bleeding and reduced the rate of stroke with an increased rate of major and clinically relevant non-major bleeding as compared to enoxaparin. Nachi: Well that was a ton of information and background on the DOACs. Let’s move on to your favorite section - prehospital medicine. Jeff: Not a ton to add here this month. Perhaps, most importantly, prehospital providers should specifically ask about DOAC usage, especially in trauma, given increased rates of complications and potential need for surgery. This can help with destination selection when relevant. Interestingly, one retrospective study found limited agreement between EMS records and hospital documentation on current DOAC usage. Nachi: Extremely important to identify DOAC use early. Once the patient arrives in the ED, you can begin your focused history and physical. Make sure to get the name, dose, and time of last administration of any DOAC. Pay particular attention to the med list and the presence of CKD which could point to altered DOAC metabolism. Jeff: In terms of the physical and initial work up - let the sites of bleeding or potential sites of bleeding guide your work up. And don’t forget about the rectal exam, which potentially has some added value here - since DOACs increase the risk of GI bleeding. Nachi: Pretty straight forward history and physical, let’s talk diagnostic studies. Jeff: First up is CT. There are no clear cut guidelines here, so Drs. Maher and Taub had to rely on observational studies and expert opinion. Remember, most standard guidelines and tools, like the canadian and nexus criteria, are less accurate in anticoagulated patients, so they shouldn’t be applied. Instead, most studies recommend a low threshold for head imaging, even with minor trauma, in the setting of DOAC use. Nachi: That is so important that it’s worth repeating. Definitely have a low threshold to CT the head for even minor head trauma patients on DOACs. Basically, if you’re on anticoagulation, and you made it to the ED for anything remotely related to your head, you probably win a spin. Jeff: I suspect you are not alone with that stance... There is, however, much more debate about the utility of follow up imaging and admission after a NEGATIVE scan. Nachi: Wait, is that a thing I should routinely be doing? Jeff: Well there’s not great data here, but in one observational study of 1180 patients on either antiplatelet or anticoagulant therapy, a half a percent of them had positive findings 12 hours later, and importantly none required surgical intervention. Nachi: Certainly reassuring. And for those with positive initial imaging, the authors recommend repeat imaging within 4-6 hours in consultation with neurosurgical services or even earlier in cases of unexpected clinical decline. Jeff: Interestingly, though only a small retrospective study of 156 patients, one study found markedly reduced mortality, 4.9% vs 20.8% in those on DOACs vs warfarin with traumatic intracranial hemorrhage. Nachi: Hmm that actually surprises me a bit with the ease of reversibility of warfarin. Jeff: And we’ll get to that in a few minutes. But next we should talk about ultrasound. As always with trauma, guidelines recommend a FAST exam in the setting of blunt abdominal trauma. The only thing to be aware of here is that you should have an increased index of suspicion for bleeding, especially in hidden sites like the retroperitoneum. Nachi: And just as with traumatic head bleeds, a small observational study of those with blunt abdominal trauma found 8% vs 30% mortality for those on DOACs vs warfarin, respectively. Jeff: That is simply shocking! Let’s also talk lab studies. Hemoglobin and platelet counts should be obtained as part of the standard trauma work up. Assessing renal function via creatinine is also important, especially for those on agents which are renally excreted. Nachi: Though you can, in theory, test for plasma DOAC concentrations, such tests are not routinely indicated as levels don’t correspond to bleeding outcomes. DOAC levels may be indicated in certain specific situations, such as while treating life-threatening bleeding, development of venous thromboembolism despite compliance with DOAC therapy, and treating patients at risk for bleeding because of an overdose. Jeff: In terms of those who require surgery while on a DOAC - if urgent or emergent, the DOAC will need to be empirically reversed. For all others, the recommendation is to wait a half life or even multiple half-lives, if possible, in lieu of level testing. Nachi: Coagulation tests are up next. Routine PT and PTT levels do not help assess DOACs, as abnormalities on either test can suggest the presence of a DOAC, but the values should not be interpreted as reliable measures of either therapeutic or supratherapeutic clinical anticoagulant effect. Jeff: Dabigatran may cause prolongation of both the PT and the PTT, but the overall correlation is poor. In addition, FXa inhibitors may elevate PT in a weakly concentration dependent manner, but this may only be helpful if anti-fXa levels are unavailable. Nachi: Which is a perfect segway into our next test - anti-factor Xa level activity. Direct measurements of the anti-Fxa effect demonstrates a strong linear correlation with plasma concentrations of these agents, but the anticoagulant effect does not necessarily follow the same linear fashion. Jeff: Some labs may even have an anti-FXa effect measurement calibrated specifically to the factor 10a inhibitors. Nachi: While measuring thrombin time is not routinely recommended, the result of thrombin time or dilute thrombin time does correlate well with dabigatran concentrations across normal ranges. Jeff: And lastly, we have the Ecarin clotting time. Ecarin is an enzyme that cleaves prothrombin to an active intermediate that can be inhibited by dabigatran in the same way as thrombin. The ECT is useful for measuring dabigatran concentration - it’s not useful for testing for FXa inhibitors. A normal ECT value could be used to exclude the presence of dabigatran. Nachi: So I think that rounds out testing. Let’s move into the treatment section. Jeff: For all agents, regardless of the DOAC, the initial resuscitation follows the standard principles of hemorrhage control and trauma resuscitation. Tourniquet application, direct pressure, endoscopy for GI bleeds, etc... should all be used as needed. And most importantly, for airway bleeding, pericardial bleeding, CNS bleeding, and those with hemodynamic instability or overt bleeding, those with a 2 point drop in their hemoglobin, and those requiring 2 or more units of pRBC - they all should be considered to have serious, life threatening bleeds. This patient population definitely requires reversal agents, which we’re getting to in a minute. Nachi: A type and screen should also be sent with the plan to follow standard transfusion guidelines, with the goal of a hemoglobin level of 7, understanding that in the setting of an active bleed, the hemoglobin level will not truly be representative. Jeff: Interestingly, in the overdose literature that’s out there, bleeding episodes appear to be rare - occurring in just 5% of DOAC overdose cases. Nachi: Finally, onto the section we’ve all been waiting for. Let’s talk specific reversal agents. Praxbind is up first. Jeff: Idarucizumab or Praxbind, is the reversal agent of choice for dabigatran (which is also called pradaxa). According to data from the RE-LY trial, it reverses dabigatran up to the 99th percentile of levels measured in the trial. Nachi: And praxbind should be given in two 2.5 g IV boluses 15 minutes apart to completely reverse the effects of dabigatran. Jeff: As you would expect given this data, guidelines for DOAC reversal recommend it in major life-threatening bleeding events for patients on dabigatran. Nachi: Next up is recombinant coagulation factor Xa (brand name Andexxa), which was approved in 2018 for the FXa inhibitors. This recombinant factor has a decoy receptor for the FXa agents, thus eliminating their anticoagulant effects. Jeff: Recombinant factor Xa is given in either high or low dose infusions. High dose infusions for those on rivaroxaban doses of >10 mg or apixaban doses >5 mg within the last 8 hours and for unknown doses and unknown time of administration. Low dose infusions should be used for those with smaller doses within the last 8 hours or for last doses taken beyond 8 hours. Nachi: In one trial of 352 patients, recombinant factor Xa given as an IV bolus and 2 hour infusion was highly effective at normalizing anti-FXa levels. 82% of the assessed patients at 12 hours achieved hemostasis, but there were also thrombotic events in 10% of the patients at 30 days. Jeff: And reported thrombotic events aren’t the only downside. Though the literature isn’t clear, there may be limited use of recombinant factor Xa outside of the time of the continuous infusion, and even worse, there may be rebound of anti-Fxa levels and anticoagulant effect. And lastly, the cost is SUBSTANTIAL. Nachi: Is there really a cost threshold for stopping life threatening bleeding…? Jeff: Touche, but that means we need to save it for specific times and consider other options out there. Since this has only been around for a year or so, let’s let the literature play out on this too... Nachi: And that perfectly takes us into our next topic, which is nonspecific reversal agents, starting with prothrombin complex concentrate, also called PCC. Jeff: PCC is FDA approved for rapid reversal of vitamin K antagonist-related hemorrhagic events and is now being used off label for DOAC reversal. Nachi: PCC comes in 3 and 4 factor varieties. 3-factor PCC contains factors 2, 9, 10 and trace amounts of factor 7. 4 factor PCC contains factors 2, 9 10, as well as purified factor 7 and proteins C and S. Jeff: Both also contain trace amounts of heparin so can’t be given to someone with a history of HIT. Nachi: PCC works by overwhelming the inhibitor agent by increasing the concentration of upstream clotting factors. It has been shown, in healthy volunteers, to normalize PT abnormalities and bleeding times, and to achieve effective bleeding control in patients on rivaroxaban, apixaban, and edoxaban with major bleeding events. Jeff: In small studies looking at various end points, 4 factor PCC has been shown to be superior to 3 factor PCC. Nachi: Currently it’s given via weight-based dosing, but there is interest in studying a fixed-dose to decrease both time to medication administration and cost of reversal. Jeff: Guidelines currently recommend 4F PCC over 3F PCC, if available, for the management of factor Xa inhibitor induced bleeding, with studies showing an effectiveness of nearly 70%. As a result, 4F PCC has become an agent of choice for rapid reversal of FXa inhibitors during major bleeding events. Nachi: Next we have activated PCC (trade name FEIBA). This is essentially 4Factor PCC with a modified factor 7. Though traditionally saved for bleeding reversal in hemophiliacs, aPCC is now being studied in DOAC induced bleeding. Though early studies are promising, aPCC should not be used over 4factor PCC routinely as of now but may be used if 4Factor PCC is not available. Jeff: Next we have recombinant factor 7a (trade name novoseven). This works by activating factors 9 and 10 resulting in rapid increase in thrombin. Studies have shown that it may reverse the effect of dabigatran, at the expense of increased risk of thrombosis. As such, it should not be used as long as other agents are available. Nachi: Fresh Frozen Plasma is the last agent to discuss in this section. Not a lot to say here - FFP is not recommended for reversal of any of the DOACs. It may be given as a part of of a balanced massive transfusion resuscitation, but otherwise, at this time, there doesn’t seem to be a clear role. Jeff: Let’s move on to adjunct therapies, of which we have 3 to discuss. Nachi: First is activated charcoal. Only weak evidence exists here - but, according to expert recommendations, there may be a role for DOAC ingestions within 2 hours of presentations. Jeff: Perhaps more useful than charcoal is our next adjunct - tranexamic acid or TXA. TXA is a synthetic lysine analogue with antifibrinolytic activity through reversible binding of plasmin. CRASH-2 is the main trial to know here. CRASH-2 demonstrated reduced mortality if given within 3 hours in trauma patients. There is very limited data with respect to TXA and DOACs specifically, so continue to administer TXA as part of your standard trauma protocol without modification if the patient is on a DOAC, as it’s likely helpful based on what data we have. Nachi: Next is vitamin K - there is no data to support routine use of vitamin K in those taking DOACs - save that for those on vitamin K antagonists. Jeff: Also, worth mentioning here is the importance of hematology input in developing hospital-wide protocols for reversal agents, especially if availability of certain agents is limited. Nachi: Let’s talk about some special circumstances and populations as they relate to DOACs. Patients with mechanical heart valves were excluded from the major DOAC trials. And of note, a trial of dabigatran in mechanical valve patients was stopped early because of bleeding and thromboembolic events. As such, the American College of Cardiology state that DOACs are reasonable for afib with native valve disease. Jeff: DOACs should be used with caution for pregnant, breastfeeding, and pediatric patients. A case series of 233 pregnancies that occurred among patients on a DOAC reported high rates of miscarriage. Nachi: Patients with renal impairment are particularly concerning as all DOACs are dependent to some degree on renal elimination. Current guidelines from the Anticoagulation Forum recommend avoiding dabigatran and rivaroxaban for patients with CrCL < 30 and avoiding edoxaban and betrixaban for patients with CrCl < 15. Jeff: A 2017 Cochrane review noted similar efficacy without increased risk of major bleeding when using DOACs in those with egfr > 30 (that’s ckd3b or better) when compared to patients with normal renal function and limited evidence for safety below this estimated GFR. Nachi: Of course, dosing with renal impairment will be different. We won’t go into the details of that here as you will probably discuss this directly with your pharmacist. Jeff: We should mention, however, that reversal of the anticoagulant in the setting of renal impairment for your major bleeding patient is exactly the same as we already outlined. Nachi: Let’s move on to some controversies and cutting-edge topics. The first one is a pretty big topic and that is treatment for ischemic stroke patients taking DOACs. Jeff: Safety and efficacy of tPA or endovascular therapy for patients on DOACs continues to be debated. Current guidelines do not recommend tPA if the last DOAC dose was within the past 48 hours, unless lab testing specific to these agents shows normal results. Nachi: Specifically, the American Heart Association suggests that INR and PTT be normal in all cases. ECT and TT should be tested for dabigatran. And calibrated anti-FXa level testing be normal for FXa inhibitors. Jeff: The AHA registry actually included 251 patients who received tpa while on DOACs, which along with cohort analysis of 26 ROCKET-AF trial patients, suggest the risk of intracranial hemorrhage is similar to patients on warfarin with INR < 1.7 and to patients not on any anticoagulation who received tpa. However, given the retrospective nature of this data, we cannot exclude the possibility of increased risk of adverse events with tpa given to patients on DOACs. Nachi: Endovascular thrombectomy also has not been studied in large numbers for patients on DOACs. Current recommendations are to discuss with your stroke team. IV lysis or endovascular thrombectomy may be considered for select patients on DOACs. Always include the patient and family in shared decision making here. Jeff: There are also some scoring systems for bleeding risk to discuss briefly. The HAS-BLED has been used to determine bleeding risk in afib patients taking warfarin. The ORBIT score was validated in a cohort that included patients on DOACs and is similarly easy to use, and notably does not require INR values. Nachi: There is also the ABC score which has demonstrated slightly better prediction characteristics for bleeding risk, but it requires high-sensitivity troponin, limiting its practical use. Jeff: We won’t say more about the scoring tools here, but would recommend that you head over to MD Calc, where you can find them and use them in your practice. Nachi: Let’s also comment on the practicality of hemodialysis for removal of the DOACs. Multiple small case series have shown successful removal of dabigatran, given its small size and low protein binding. On the other hand, the FXa inhibitors are less amenable to removal in this way because of their higher protein binding. Jeff: Worth mentioning here also - dialysis catheters if placed should be in compressible areas in case bleeding occurs. The role of hemodialysis for overdose may be limited now that the specific reversal agent, praxbind, exists. Nachi: In terms of cutting-edge tests, we have viscoelastic testing like thromboelastography and rotational thromboelastometry. Several studies have examined the utility of viscoelastic testing to detect presence of DOACs with varying results. Prolongation of clotting times here does appear to correlate with concentration, but these tests haven’t emerged as a gold standard yet. Jeff: Also, for cutting edge, we should mention ciraparantag. And if you’ve been listening patiently and just thinking to yourself why can’t there be one reversal agent to reverse everything, this may be the solution. Ciraparantag (or aripazine) is a universal anticoagulant reversal agent that may have a role in all DOACs and heparins. It binds and inactivates all of these agents and it doesn’t appear to have a procoagulant effect. Nachi: Clinical trials for ciraparantag have shown rapid and durable reversal of edoxaban, but further trials and FDA approval are still needed. Jeff: We’ve covered a ton of material so far. As we near the end of this episode, let’s talk disposition. Nachi: First, we have those already on DOACs - I think it goes without saying that any patient who receives pharmacological reversal of coagulopathy for major bleeding needs to be admitted, likely to the ICU. Jeff: Next we have those that we are considering starting a DOAC, for example in someone with newly diagnosed VTE, or patients with an appropriate CHADS-VASC with newly diagnosed non-valvular afib. Nachi: With respect to venous thromboembolism, both dabigatran and edoxaban require a 5 day bridge with heparin, whereas apixaban and rivaroxaban do not. The latter is not only easier on the patient but also offers potential cost savings with low risk of hemorrhagic complications. Jeff: For patients with newly diagnosed DVT / PE, both the American and British Thoracic Society, as well as ACEP, recommend using either the pulmonary embolism severity index, aka PESI, or the simplified PESI or the Hestia criteria to risk stratify patients with PE. The low risk group is potentially appropriate for discharge home on anticoagulation. This strategy reduces hospital days and costs with otherwise similar outcomes - total win all around. Nachi: Definitely a great opportunity for some shared decision making since data here is fairly sparse. This is also a great place to have institutional policies, which could support this practice and also ensure rapid outpatient follow up. Jeff: If you are going to consider ED discharge after starting a DOAC - there isn’t great data supporting one over another. You’ll have to consider patient insurance, cost, dosing schedules, and patient / caregiver preferences. Vitamin K antagonists should also be discussed as there is lots of data to support their safety outcomes, not to mention that they are often far cheaper…. As an interesting aside - I recently diagnosed a DVT/PE in an Amish gentleman who came to the ED by horse - that was some complicated decision making with respect to balancing the potentially prohibitive cost of DOACs with the massive inconvenience of frequently checking INRs after a 5 mile horseback ride into town... Nachi: Nice opportunity for shared decision making… Jeff: Lastly, we have those patients who are higher risk for bleeding. Though I’d personally be quite uneasy in this population, if you are to start a DOAC, consider apixaban or edoxaban, which likely have lower risk of major bleeding. Nachi: So that’s it for the new material for this month’s issue. Certainly, an important topic as the frequency of DOAC use continues to rise given their clear advantages for both patients and providers. However, despite their outpatient ease of use, it definitely complicates our lives in the ED with no easy way to evaluate their anticoagulant effect and costly reversal options. Hopefully all our hospitals have developed or will soon develop guidelines for both managing ongoing bleeding with reversal agents and for collaborative discharges with appropriate follow up resources for those we send home on a DOAC. Jeff: Absolutely. Let’s wrap up with some the highest yield points and clinical pearls Nachi: Dabigatran works by direct thrombin inhibition, whereas rivaroxaban, apixaban, edoxaban, and betrixaban all work by Factor Xa inhibition. Jeff: The DOACs have a much shorter half-life than warfarin. Nachi: Prehospital care providers should ask all patients about their use of anticoagulants. Jeff: Have a low threshold to order a head CT in patients with mild head trauma if they are on DOACs. Nachi: For positive head CT findings or high suspicion of significant injury, order a repeat head CT in 4 to 6 hours and discuss with neurosurgery. Jeff: Have a lower threshold to conduct a FAST exam for blunt abdominal trauma patients on DOACs. Nachi: Assessment of renal function is important with regards to all DOACs. Jeff: While actual plasma concentrations of DOACs can be measured, these do not correspond to bleeding outcomes and should not be ordered routinely. Nachi: The DOACs may cause mild prolongation of PT and PTT. Jeff: Idarucizumab (Praxbind®) is an antibody to dabigatran. For dabigatran reversal, administer two 2.5g IV boluses 15 minutes apart. Reversal is rapid and does not cause prothrombotic effects. Nachi: Recombinant FXa can be used to reverse the FXa inhibitors. This works as a decoy receptor for the FXa agents. Jeff: Vitamin K and FFP are not recommended for reversal of DOACs. Nachi: Consider activated charcoal to remove DOACs ingested within the last two hours in the setting of life-threatening hemorrhages in patient’s on DOACs. Jeff: Hemodialysis can effectively remove dabigatran, but this is not true for the FXa inhibitors. Nachi: 4F-PCC has been shown to be effective in reversing the effects of the FXa inhibitors. This is thought to be due to overwhelming the inhibitor agent by increased concentrations of upstream clotting factors. Jeff: tPA is contraindicated in acute ischemic stroke if a DOAC dose was administered within the last 48 hours, unless certain laboratory testing criteria are met. Nachi: Emergency clinicians should consider initiating DOACs in the ED for patients with new onset nonvalvular atrial fibrillation, DVT, or PE that is in a low-risk group. Jeff: So that wraps up Episode 31! Nachi: As always, additional materials are available on our website for Emergency Medicine Practice subscribers. If you’re not a subscriber, consider joining today. You can find out more at ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credit. You’ll also get enhanced access to the podcast, including any images and tables mentioned. PA’s and NP’s - make sure to use the code APP4 at checkout to save 50%. Jeff: And the address for this month’s cme credit is www.ebmedicine.net/E0819, so head over there to get your CME credit. As always, the [DING SOUND] you heard throughout the episode corresponds to the answers to the CME questions. Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at EMplify@ebmedicine.net with any comments or suggestions. Talk to you next month!

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first. Dr Greg Hundley:             You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.                                                 This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals. Dr Carolyn Lam:                And what did the study show? Dr Greg Hundley:             So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.                                                 So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.                                                 Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.                                                 What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia. Dr Carolyn Lam:                So how did they show or find this fourth category? Dr Greg Hundley:             Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.                                                 During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.                                                 So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients. Dr Carolyn Lam:                Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are? Dr Greg Hundley:             Aren't cilia on prokaryotes? I mean, I think of bacteria. Dr Carolyn Lam:                All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.                                                 Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling. Dr Greg Hundley:             Carolyn, this is so interesting. I had no idea about these cilia. So what did they find? Dr Carolyn Lam:                So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response. Dr Greg Hundley:             So how do we use this clinically, and what does it mean for us? Dr Carolyn Lam:                These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance. Dr Greg Hundley:             Wow, very interesting! Dr Carolyn Lam:                Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.                                                 So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.                                                 They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases. Dr Greg Hundley:             Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart? Dr Carolyn Lam:                Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.                                                 Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.                                                 So, that wraps up our summaries Greg. Shall we move to our feature discussion? Dr Greg Hundley:             Absolutely. Dr Greg Hundley:             Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.                                                 Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience? Dr Renato Lopes:              The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.                                                 We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.                                                 What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.                                                 So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect. Dr Greg Hundley:             Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race? Dr Renato Lopes:              That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex. Dr Greg Hundley:             Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight? Dr Renato Lopes:              This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.                                                 I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.                                                 It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients. Dr Greg Hundley:             Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation? Dr Brian Olshansky:         It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.                                                 One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.                                                 Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.                                                 We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.                                                 Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight. Dr Greg Hundley:             On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week. Dr Carolyn Lam                  This program is Copyright American Heart Association 2019.  

Welcome to the 8th episode in the series of "What we have learnt this week...". Tonight Vicky, Emma and Christina talk about UTI guidelines in the over 65s, AF and anticoagulation risk calculators, DOLs and antibiotics in the older patient.  Useful links this week:  PHE UTI in >65s:   https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/755890/PHE_UTI_flowchart_-_Under_65_women.pdf CHADsVASc and HASBLED scoring systems: https://www.chadsvasc.org Anticoagulation risk in falls:  Risk of Falls and Major Bleeds in Patients on Oral Anticoagulation Therapy; Donze, J; Clair, Carole; The American Journal of Medicine; Volume 125, Issue 8; August 2012,Pages 773-778   BMA guidance on DOLS: https://www.bma.org.uk/advice/employment/ethics/mental-capacity/deprivation-of-liberty-safeguards E-LFH learning module on DOLS: https://www.e-lfh.org.uk/programmes/deprivation-of-liberty-safeguards/

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, from National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor for circulation from VCU Health Systems in Richmond, Virginia. Dr Carolyn Lam:                What does cardiac autoimmunity, glycemic control, and cardiovascular disease risk and Type I diabetes have in common? Well, you've got to wait for our feature discussion. This one's such a hot one, don't you agree, Greg? We could hardly finish talking. Dr Greg Hundley:             Absolutely, and Myra, you're just going to love listening to her. Dr Carolyn Lam:                Yep, but stay tuned. First, we're going to discuss a couple of papers each. Greg. Dr Greg Hundley:             Thanks Carolyn. So, the first paper I've got is from Professor Van Rein at Leiden University Medical Center. And basically he's getting at the issue of bleeding in patients with atrial fibrillation. So this is a retrospective cohort that evaluates different anticoagulation strategies for atrial fibrillation. They examined 272,315 patients that had a median age of 75 years and followed them longitudinally over time. These individuals experience 31,459 major bleeding events, and what he did is he evaluated whether they were not taking anticoagulant therapy, whether they were on a vitamin K antagonist, a DOAC, antiplatelet therapies, and then all combinations of the above, including single, double and triple therapy.                                                 What he observed is relative to taking a vitamin K antagonist alone. The hazard ratios range from 1.13 to 3.73 in those that were receiving dual antiplatelet therapy of vitamin K antagonist plus antiplatelet therapy, a DOAC plus antiplatelet therapy, and then of course triple therapy, which had that highest hazard ratio. Dr Carolyn Lam:                But were there particular combinations within these groups that had particularly high bleeding risk? Dr Greg Hundley:             Well, yeah, Carolyn. As we might expect, triple therapy was the worst, but those that were receiving triple therapy, there were two subgroups that were particularly susceptible to having a bleeding episode. First, those that were greater than 90 years of age, and second, those that had CHADS-VASc 2 scores greater than six. Of course, these are very complicated patients, often particularly that latter group. So there are clinical implications. I mean, clearly, this isn't a randomized trial, but what we should take away from this is that if we have one of those two patient groups, age greater than 90, CHADS-VASc score greater than six, that we ought to minimize the time that those individuals are on that triple therapy. Dr Carolyn Lam:                Talk about and bleeding, I've got a paper, and it's on the performance of the ABC scores for assessing the risk of stroke and systemic embolism or bleeding in patients with atrial fibrillation. This is a study that actually looked at the performance of these scores in an external cohort, which actually hasn't really been done. Now, as a reminder, the ABC score is actually the age biomarker clinical history stroke score, which helps to estimate the risk of stroke or systemic embolism. The ABC bleeding risk score incorporates biomarkers along with the clinical variables to estimate the risk of bleeding.                                                 All of these were tested in the ENGAGE AF-TIMI 48 trial, which was that multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS-VASc 2 score of two and above. Now, this was from Dr Morrow and the TIMI study group in the Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts. Basically what they found was that the ABC stroke and ABC bleeding risk scores performed well in stratifying the risk for stroke or systemic embolic events or major bleeding in this multinational trial.                                                 Compared to the CHADS-VASc score, the ABC stroke score provided both correct upward and downward reclassification of the stroke systemic embolism risk. Compared with the HAS-BLED score, the ABC bleeding score resulted in a predominantly correct downward reclassification of the bleeding risk. Dr Greg Hundley:             So, this new ABC score, do we integrate it with HAS-BLED? Do we integrate it with CHADS-VASc 2? How do we use this clinically? Dr Carolyn Lam:                So first of all, there are some important remaining unanswered questions, and this was really nicely discussed in an accompanying editorial by Dr Hylek from Boston University School of Medicine. Among this, first of all, the ABC scores need to be validated in patients outside of a clinical trial. Remember, this was a clinical trial cohort. Then there are questions about the timing of measurements of the score, the different settings, hospital and otherwise. Do these scores perform equally well across different vascular beds and in diverse patient populations at the same thresholds used?                                                 So, all these things still need to be addressed. And really, in Dr Hylek's words, the work has just begun. Dr Greg Hundley:             This is an issue with the theme that might be bleeding, and I'm going to talk about a study from Professor Huisman from Leiden University again, and this is the RE-VERSE AD study. Again, patients that are receiving dabigatran and that may have a GI bleed or patients that are on this therapy and unexpectedly need an emergent surgical procedure, this investigative team evaluated the utility of idarucizumab on reversing that anticoagulant dabigatran. So what did they do? They administered 2.5 milligrams of idarucizumab twice separated by 15 minutes.                                                 And again, the study population was uncontrolled GI bleeding or those in need of an emergent procedure. The types of GI bleeds that were involved in this study, a third were upper GI bleeds, a third lower, and then a third, it was either unknown, or there was a mixture of both upper GI or lower GI bleeding. So how do we know that dabigatran is effective? We use a DTT time, and 98% of those with an elevated diluted thrombin time had that reduced after receiving these two twin 2.5 milligram doses at a time point of four hours after administration. Dr Carolyn Lam:                Okay, but were there any complications? Dr Greg Hundley:             Yeah, there were. So first of all, something to think about is that this is a high-risk group. In this study, 14.6% of the cohort actually later died either from the bleeding or what have you. Then another thing we need to be thinking about is when we reversed this anticoagulant, do patients experience thrombotic events? So what this group reported is 4.4% did within 30 days. What were those? Myocardial infarction, deep venous thrombosis, and subsequent PE. Then also at the 30-day time point, one patient experienced an ischemic event.                                                 Another question is once you've administered this, you've gone through the procedure. You stopped the GI bleeding, or you've had the surgery. In this particular study, 66% of those individuals had restarted their DOAC. Those events occurred on top of that. So, interesting information. Looking at administration of idarucizumab, and we'll be using this I think frequently as DOACs are used more frequently in the population, particularly dabigatran, so some important data in guiding us on what we might expect when we administer this therapy. Dr Carolyn Lam:                I think going back to atrial fibrillation though, this is my other selected paper, and it's actually results from the GARFIELD-AF Registry. It's from Dr Bassand from University of Besançon in France, and colleagues, and basically, they looked at the early risks of death, stroke, systemic embolism and major bleeding in patients with newly diagnosed atrial fibrillation in the GARFIELD-AF Registry. They basically found that the rates of all three major clinical events was significantly higher during the first month than in the subsequent period set following up to 12 months.                                                 The leading causes of early death were heart failure, sudden death, acute coronary syndromes, infection or sepsis, and respiratory failure. Dr Greg Hundley:             So, what's the take-home message here? Dr Carolyn Lam:                This is observational, so the key thing to understand here, it's a registry. It's observational. We can't really tell chicken from egg with regards to its newly diagnosed AF verses events, which comes first, which causes what. But nonetheless, the increased hazards of an early event and especially cardiovascular mortality in these newly diagnosed AF patients really point to the importance of comprehensive care for such patients and really should alert physicians to detect warning signs of possible early mortality in these newly diagnosed patients. Dr Greg Hundley:             Very good, Carolyn. Dr Carolyn Lam:                I think that wraps it up. Let's hop to our feature discussion, shall we? I'm so super excited about today's feature paper because it may explain that strong link between hyperglycemia and cardiovascular disease in type one diabetes and all by revealing a potential novel pathway that may have been hiding in plain sight. And yes, I'm stealing the words of editorialists and our associate editor, Dr Naveed Sattar from University of Glasgow, and we're all so pleased to have with us the corresponding author of today's feature paper, Dr Myra Lipes from Joslin Diabetes Center in Boston, Massachusetts. Myra, start us off by telling us a little bit about your study please. Dr Myra Lipes:                   Sure. So we were interested in examining the role of whether chronic hyperglycemia could trigger cardiac autoimmunity in type one diabetes, because chronic hyperglycemia is associated with subclinical myocardial damage, and we had actually previously observed just unexpectedly in a young adult cohort that ... Actually from Italy, where unexpectedly, we noticed that patients with the poorest glycemic control expressed cardiac antibodies. There's a lot of interesting people who are autoimmune-proned may overreact to injury of certain tissues.                                                 So, type one diabetes, it's a classical autoimmune disorder. So we examined, really tested this hypothesis, in stored samples from the DCCT/EDIC study, and this is a very landmark study where patients were randomized to tight glycemic control, intensive glycemic control. Then another group had just conventional control, and this was done over an average of six and a half years. So during this time, the samples were stored. Every year samples were stored from participants, and this was quite a rich data set that is publicly available. So we studied the development of autoimmunity in two groups that had very distinct separations of the A1C level.                                                 We specifically excluded people who developed kidney disease or cardiovascular disease events during the study. So this is a cohort that had relatively recent onset type one diabetes. They're relatively healthy, and again, groups were matched with cardiovascular risk factors at the beginning and the end of this DCCT period. And of course with our studies, we've also looked genetically because your HLA immune response genes can influence susceptibility to autoimmunity.                                                 These patients were actually matched in HLA genotypes. So what we found was that patients with poor glycemic control, there was expression over time. You could see a time course relationship between expression of antibodies over time on the levels of the antibodies that were different in the two A1C groups. The number of antibodies were different in that with the high group expressing more antibodies, more different types of antibodies. These are antibodies ... might say antibodies as like proteins in the blood, and they're actually directed against parts of the myocytes, the myofibrillar complex, and a major target is cardiac myosin heavy chain.                                                 We saw the different parts of the myosin heavy chain retarded, and the presence of two or more antibodies, different types of antibodies, different regions of the myosin to different isoforms. Also, we saw antibodies, the troponin, troponin I. So the number of antibodies with different ... with almost a complete absence of antibodies in a tightly controlled group. I might mention the A1C average was 6.5%, so this is a very tightly controlled group whereas the poorly controlled group is at the opposite extreme, the average A1C during DCCT. The mean updated A1C was about 10%.                                                 So, it was a very clean group, two different groups, and we could see that the number of the types, the number over time, very different in the two groups. In fact the profiles of these antibodies were almost very similar to patients with Chagas cardiomyopathy. That was our positive control group. Chagas cardiomyopathy is possibility to be a form of chronic myocarditis directed against cardiac myosin. So the profiles are almost indistinguishable. So on one hand, you have relatively healthy patients with type one before glycemic control, and that was very unexpected that this would look pretty similar.                                                 But very interestingly, and I might say unexpectedly, we saw ... It was very clear that the people with the highest titers of antibody and the most different types of antibodies, particularly two or more, were subsequently ... We noticed that those patients were at high risk for developing CVD events. And that's while the number of events was slow, we noticed that all the patients, some 60%, had two or more antibodies and developed cardiovascular events. Perhaps one more striking example is a single patient in the study could die of cardiovascular death, had a positivity for all five antibodies at highest titer.                                                 Then we looked at coronary calcification just to measure subclinical atherosclerosis. We noticed that the same numbers, two or more, and also the same antibody specificities that were the highest predictors of CVD events were also predictive of coronary ... had detectable coronary calcification. In addition, we looked at the levels trying to find mechanistically what could explain the link between cardiac autoimmunity and an increased risk for atherosclerosis. We looked at CRP, high sensitivity CRP levels.                                                 Again, these were measured about a decade after the antibody samples were obtained, and we saw that the positivity for multiple antibodies was also associated with markedly elevated ... subsequently elevated high sensitivity CRP levels with levels of six versus something like 1.4 in a group with one or less antibody. So these were very intriguing findings, suggesting a role for autoimmune pathways as a susceptibility to cardiovascular disease in type one diabetes. Dr Greg Hundley:             Myra, that was absolutely incredible description of the study and all the particulars of the findings. I wonder if I could ask both you and Naveed, where do you see the next steps moving forward with this research in the future? Number one. And number two, is this in any way can be used to segregate patients that may need, for example, really aggressive glucose control with an insulin pump or something of that nature? Naveed Sattar:                  I think we left this study as beautifully described as you see by Dr Lipes. I think the context ... We looked at this from editorial perspective ... is that most people don't realize if you have a middle-aged person with type one, their hazard ratio for cardiovascular risk is about somewhere between four to six fold for men and women respectively, which is much higher than type two. It's often thought that it's the area under the curve for hyperglycemia. But what this paper throws up is actually maybe there's another pathway, which we just didn't understand that this wasn't a permanent autoimmunity closing subclinical myocardial disease and inflammations.                                                 But potentially, for me though, there's a saying in British that one swallow does not make a summer. So, it would be nice for other groups to replicate this. I think the findings are, as they stand in isolation, fantastically well done. But it would be lovely if other groups had accessible samples, and I knew of several groups that have up towards tens of thousands of samples, maybe even not 10,000. Certainly 10,000 or so plus or minus samples for type and prospective outcomes to potentially validate the findings and extend them.                                                 And really, if the antibodies do help protect people at higher risk in a meaningful way and improve beyond what we can already do, then you're right. Absolutely. If we can pick up early people who are going to have substantially higher risk, you would want to potentially improve glycemic control, potentially pumps, CGM, closed-loop systems or more intensive statins or lower blood pressure targets or other types of antihyperglycemic agents, which seem to be being tested in type one as well. So that's really one example.                                                 And for me, the other thing would be really nice is to pull up any inflammation. Is this high systemic inflammation? Is it IL-6 level? Is it something else? What about troponin and BNP levels, et cetera. I'd be interested to hear what Dr Lipes thinks and how do you think to take it forward as well. Dr Myra Lipes:                   So, this is something Dr Sattar said and I completely agree. Actually, right now, we're looking at the DCCT cohort as a whole for already. It's relatively small compared to the population-based studies. But there's 1,400 patients, and the subjects had CMR studies that were published in Circulation. So we're going to actually study next whether we see CMR evidence of systolic dysfunction and looking at the broader DCCT cohort. So, those studies are underway. But of course the ultimate test would be looking at if there were samples available from the Swedish NDRs, Scottish registry.                                                 I think it's something that's not often done prospectively. So that would be incredibly exciting, and that's the important thing. I'd say with type one diabetes, for screening for type one diabetes, the use of autoantibodies and particularly two or more different types of islet autoantibodies, and this is just putting things in a broader context, is the entry criteria for type one diabetes prevention trials and something cardiologists wouldn't be aware of but this particular thing. So in decades, people, researchers, in the field has spent decades optimizing islet antibody assays.                                                 So by analogy, it would be really important to standardize assays so that they can be done in Sweden and Scotland and so that other groups could confirm this, and I'm confident that this could be done, since the setting up of our assays was really built on the experience of people of developing standardized assays and rigorous cutoff points for antibody positivity. So it would be really important to work internationally to try to tap into this. Dr Carolyn Lam:                Oh, my goodness. Myra, Naveed, these are such insightful comments. I think as Greg said earlier, I think we could go on forever discussing this paper, but I'm so sorry. Our time is up. Before we go though, I must point all readers to look at figure five of this marvelous paper. It puts together the whole schema of how autoantibodies can play a role both in myocardial and atherosclerotic cardiovascular disease and type one diabetes.                                                 Thank you so much. Greg and I loved having you. Listeners, don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Caroline Lam, associate editor from the National Heart Center and Duke National University of Singapore. Greg Hundley:                   And I'm Greg Hundley, Professor at the Pauley Heart Center of Virginia Commonwealth University Health Sciences in Richmond, Virginia. Dr Carolyn Lam:                In case you guys missed us last week, this is how our new podcast is gonna work. Greg and I are going to invite you for coffee with us, almost with a journal in hand, and we're gonna chat about the week's issue, highlighting two original papers each, that we thought were awesome. And don't you worry, the feature discussion is still there, authors will join us for a feature discussion right after our coffee.                                                 And for this week, the feature paper speaks about the MOMENTUM 3 trial, and talks about the important analysis of stroke outcomes in this trial. But before that, I think Greg, you've got a couple of papers don't you? Greg Hundley:                   Absolutely Carolyn. So the whole issue, I think we're gonna pick out several stroke papers, really a stroke theme. The first paper is Ankit Maheshwari. He looked at the utility of P-wave morphology on the 12-lead electrocardiogram, to help predict ischemic stroke in patients with atrial fibrillation.                                                 Now, how did he do this? Basically, they looked at a large cohort of individuals from the ARIC study, and these were patients that developed atrial fibrillation. And electrocardiograms had been recorded prior to their Afib episode.                                                 So, what were they looking for in P-wave morphology? Well, they were looking for changes in Lead three. They were looking for changes in V1. They were also looking for extension of that P-wave. So a prolonged duration. And what they observed, is that that abnormal P-wave, could forecast abnormal atrial remodeling, that might be an indicator of future stroke. Dr Carolyn Lam:                Huh, interesting. But is it really reproducible? Did they validate it somehow? Greg Hundley:                   Yeah, so that's great Carolyn. You know, in papers like this, you like to take a finding in one large cohort, but then you've got to reproduce it. So they went to the MESA Study. Remember now, Mesa are individuals without cardiovascular disease. ARIC are patients with cardiovascular disease. And the finding was reproducible in MESA. Also, what the authors did, is they looked at the relevance of this EKG finding to our existing CHADS-VASc2 scoring system.                                                 And what was really smart by these investigators, is that if you added the information from the abnormal P-wave morphology to the CHADS-VASc2 score, you could forecast stroke. Now you say, well CHADS-VASc2 is already pretty reliable, but what about those patients that have a CHADS-VASc score of one right? We're always kind of wondering, do we anticoagulate them? Do we give them aspirin, et cetera. Well if the P-wave morphology was abnormal and they were at higher risk for stroke, that could sway you as a clinician, to go ahead and prescribe anticoagulation for that group of patients.                                                 And something very simple, just from the 12-lead EKG before the patients went into atrial fibrillation. You've got a paper that also is sort of focusing on stroke. You want to tell us about that? Dr Carolyn Lam:                Yeah, one big data to another big data series. This time, it's Get With The Guidelines Stroke series, and this paper is from Dr Menon from University of Calgary in Canada. Where they described the door to treatment times for endovascular therapy in acute stroke. What is that? Well that's a time interval from when the patient arrives in the emergency department or the door, to the first pass of the treatment initiation and endovascular therapy. And basically they found that the median door to first pass time was 130 minutes. Only 3% of patients achieved a door to first pass time of less than 60 minutes.                                                 In multivariable analyses, older age arrival during nonregular hours and a history of diabetes, were all associated with the longer door to first pass time. And finally, among hospitals with an annual endovascular therapy case volume of 40 or less, every five unit increase in that volume was associated with a 3% reduction in this door to first pass time. Greg Hundley:                   It sounds like that could be really useful information for stroke centers, you know, that are managing these patients acutely. How do you think these results are going to impact that Carolyn? Dr Carolyn Lam:                Great question. So first thing is, I think it provides some benchmark times for this in hospital workflow, and it obviously shows areas of improvement. For example, improving workflow during nonregular hours, or increasing the experience of a center, and basically emphasizes the point that efforts on streamlining workflow and saving time, need to continue so that the full potential of endovascular therapy is realized. Greg Hundley:                   Oh wow, that's outstanding. I'm gonna transition sort of to a basic science paper, also trying to help manage patients with stroke. This one is looking at the safety of all of the dehydrogenased right stem cells. Well, what the world is that. In animals, what has been shown previously, is this particular cells type, that's harvested from your bone marrow, can be infused into the carotid artery, and those animals experience smaller neurologic deficits after stroke. And so with that encouraging result in animals, these investigators sought to test the efficacy of this type of therapy, well not really the efficacy, but the safety of this type of approach in those patients that have sustained actually quite a large stroke.                                                 You had to have a relatively large neurologic deficit to qualify for this study. And just quickly, the way this works is these cells enter up through the bloodstream and they modulate inflammation. By modulating inflammation, that facilitates healing in the stroke patient. Dr Carolyn Lam:                Yeah, but wow. I mean bone marrow, biopsy and isolating the cells and so on. How is the study done? Greg Hundley:                   So, the key here is you've had your stroke, you're still in the hospital with a large neurologic deficit. And so day 11 to 17, you undergo a bone marrow biopsy. Then the cells are purified, and they're reinfused into your carotid artery by the way.                                                 And so, what was the study trying to do? Well, it was actually looking at the safety off all this. And what would the concern be? You're infusing these cells into the carotid artery. They go into the cerebral microcirculation, and those that are working in this field, are concerned is that going to promote more emboli? Is that going to promote thrombus? Extend the size of the infarct in the brain, et cetera?                                                 So, the investigators performed MRI's and neurologic exams. And what they found is the neurologic findings in the patients really didn't change, so there was no benefit. But the study wasn't set up to look for a benefit. And there were four patients that had a little bit of an enlargement of the stroke observed on MRI. So, a lot more to come in this basic science realm, but it's interesting to see investigators thinking about this in a whole different way, where we're harvesting one cell type from your body, and then infusing it up into the brain to sort of help rescue the situation. Dr Carolyn Lam:                Well, another paper dealing with stroke. This time, a Mendelian randomization study to explore whether genetically determined circulating levels of cytokines and growth factors, may be associated with stroke. And this was done in the mega stroke GWA data set and validated in the UK biobank, and it’s by Dr Dichgans and colleagues from the university hospital, Ludwig Maximilian University of Munich. They basically found, that a genetic predisposition to higher circulating levels of monocyte chemoattractant protein one, was associated with a higher risk of stroke. The associations also found for the etiology of the stroke subtypes, and especially for large artery stroke and cardioembolic stroke. In fact the genetically determined levels of this monocyte chemoattractant protein one, was also associated with higher risk of the related phenotypes of coronary artery disease and myocardial infarction. Greg Hundley:                   So, how do you bring this to practice in the clinic Carolyn? Dr Carolyn Lam:                So, this is still some steps away, but I do think that it very nicely supports the idea that inflammation as part of the pathogenesis of stroke, and of course additional work is needed to determine whether targeting the specific monocyte chemoattractant protein one, or it's downstream effectors, may be a meaningful strategy to lower stroke risk. So, terribly interesting. Greg Hundley:                   Yeah, you know it sounds like hitting inflammation or targeting that, is a real theme here from the basic science group. Well this is great Carolyn.                                                 And now, I guess we'll transition over to our feature article. Dr Carolyn Lam:                Absolutely. So, we're here to discuss the long-term results of the MOMENTUM 3 Trial, and that was a randomized controlled trial of the HeartMate 3 versus the Heartmate II left ventricular assist device. And this time, with a focus on stroke. The outcomes that's just so important to our patients. Greg and I are incredibly pleased to have with us, the authors, Dr Mandeep Mehra from Brigham and Women's Hospital, as well as our senior associate editor, Dr Biykem Bozkurt, to discuss this paper.                                                 Mandeep, perhaps just set the scene by telling us what this secondary analysis found? Dr Mandeep Mehra:       This analysis is really focused on the issue of stroke, as you pointed out. I'd like to just lace into context what this is important. Ever since the advent of left ventricular assist device therapy from the 80s and early 90s, to now, one of the major Achilles' heels, whether we have used pulsatile flow devices or non-pulsatile flow devices, has been the very constant occurrence of a high incidence of stroke, beyond the stroke rates were predominantly as compared to ischemic strokes. Then with the newer devices, we actually saw a reversal, where we began to see more ischemic strokes as opposed to hemorrhagic strokes, almost an equal parts at this time point.                                                 And this has been one of the critical reasons why we have not been able to expand the therapy beyond the very, very sick patient. Greg Hundley:                   Very nice. And another particular in the results here is, you didn't really see a difference in stroke rates, either hemorrhagic or ischemic strokes early, but you did start to see a difference after 180 days. Why do you think that's the case? Dr Mandeep Mehra:       That's a great point Greg. We really saw no difference in the first 30 days. When we analyzed this data, we divided it into a perioperative, a first 30-day time point. Then, we looked at the short-term time point up to 180 days or six months, and then beyond that to the two year end point. What became very clear is that most of the gains that we saw in the stroke rate, began to appear after the first 30 days, did not quite reach statistical significance at six months, but really the differences became heavily pronounced after six months, all the way out to two years.                                                 So, first point that I would make Greg, is that we did see differences beyond 30 days, it's just that they didn't reach conventional statistical significance. The second thing is, the more important point that you make, asking why that was the case. We actually think that the reason behind that, is that the first three months or so after that implant, really is a period of chaos in these patients, where the hemocompatibility, which is essentially the interface between the device as well as the patient, is attempting to be established. And it's very similar in a way as we see in heart transplantation Greg, where the real challenge in heart transplantation is between rejection and infection.                                                 And in the case of left ventricular assist device is the challenges between bleeding and thrombosis. It turns out that three months, whether it be transplantation or whether it be left ventricular assist devices, seems to be this period of chaos and adjustment, during which the patient and the device are starting to get to know each other.                                                 And this is why we think that most of the gains occurred after this period of chaos was overcome. Greg Hundley:                   No, it's really interesting that after accounting or adjusting for all the anticoagulant drugs, antiplatelet drugs, even the other medical therapies that were applied, you found these results. I mean, maybe also bring in Biykem here to answer the question, what is this machine doing that's providing such a benefit? Dr Biykem Bozkurt:         The two-year results being quite impressive for the HeartMate 3 are truly encouraging. Because I think we truly see a concordance benefit beyond 180 days, especially the nondisabling strokes, giving the hope to the providers that we can further perhaps enhance the field by focusing on optimization of anticoagulation strategies, prevention of atrial fibrillation, and maybe even consider our algorithms or pathways for stroke. Because, in this protocol, even though the stroke management was not standardized, and I'm sure that the data will not yield that information as to which centers were able to approach the stroke management in a perhaps evidence based approach, the sobering facts are regardless of the device, at two years, approximately half of the patients died. Even the non-disabling stroke patients had increased mortality compared to no-stroke patients.                                                 And if you examine evidence-based approaches, only one-third of the hemorrhagic stroke patients had reversal of anticoagulation, and a very small percentage ... actually, none of the patients had device intervention for the ischemic stroke. That raises the question of yes at two years the HeartMate 3 results are very promising. But, can we further even advance the field by doing evidence based standardized pathway driven stroke treatment approaches.                                                 The other very interesting finding from this trial is, in ENDURANCE trial, which was another trial with centrifugal device, HVAD device, there was an association of the stroke rates with inadequate control of blood pressure and anticoagulation, which was not noted in this trial. Maybe Mandeep can comment on do we truly have the adequate power to be able to infer whether blood pressure control and/or appropriate anticoagulation management strategies will matter? Dr Mandeep Mehra:       Biykem you've said it really well, and I'd like to just make some additional points with respect to the question. So, first of all Greg you're absolutely correct, that we tried to search for anything that would predict this reduction in stroke with the HeartMate 3, and it turned out that all we were left with is the device itself. So, it really begs the question, what is it about the device or it's interface that may have resulted in this.                                                 And of course, some of what I'm about to tell you will be speculation, but it may actually carry some water. So, for example, the HeartMate 3 is very unique in one other aspect, and that is that, even though it's a small profile device, it's engineering principles are such that it allows for very wide blood flow pathways. And in fact, despite its small profile, the blood flow pathways allow for 20 times more red blood cells to travel through the primary and secondary pathway, than other devices.                                                 What it means is that as blood is going through this device, it is exposed to very low sheer stress. And in return, the benefit that we see very clearly with this device in a very, very important way, is the fact that we see almost no denovo pump thrombosis developing with this device. Certainly, if the device doesn't carry some small quad risks in it, that cause problems with the device, it's probably also not causing the production of smaller non-device malfunction producing thrombi, which may with other devices, actually develop and cause strokes.                                                 So, we think that particular engineering enhancement, may play a very important role in reducing this stroke rate that we have observed.                                                 The second very important point that Biykem brought up, is this notion about the management of ... whether it be with anticoagulants or with blood pressure management. And for a moment let's dwell on the blood pressure issue. One of the striking things with the other centrifugal device, the HVAD device, is that the ENDURANCE Trial showed a significantly higher stroke rate with that device. And in fact, in a subsequent study, the ENDURANCE Supplemental Trial, when blood pressure was tightly, tightly controlled in the device, there appeared to be a small signal in reduction in strokes, although it still did not meet the non-inferiority endpoint, compared to the HeartMate II in the second supplementary trial that was done with that device.                                                 So, what's unique about this? Well, we can very clearly say maybe we just didn't have enough ability to show a difference in this particular trial, we didn't analyze it the right way, because we didn't have a blood pressure intervention or low or higher permissive blood pressures in this trial. But I would say that there's one other issue that I think may have played a very important role in this, and that is the HeartMate 3 is intrinsically developed with a fixed pulse algorithm. And in fact, the HeartMate 3 has a capacity where the magnetically levitated rotor upregulates itself and then downregulates itself every two seconds, and creates an internal pulsatility.                                                 Now, engineers developed that pulsatility to really decrease stasis, so that the pump wouldn't thrombose. But we often see that it provides sufficient peripheral pulsatility, not to the pulse pressures that we would normally like to see, but certainly to some degree, where the vasculature can perceive or transduce some degree of pulsatility. Why that may be important is, that it may actually allow for preservation of baroreceptor function in these patients, which tends to be lost in continuous flow pumps.                                                 And how important that is for blood pressure regulation and its vascular effect, may be something that needs to be looked at into the future. But it's certainly a very, very intriguing issue for us to examine. Dr Biykem Bozkurt:         Mandeep, one final question or comment. Do want to comment on the stroke rates of HeartMate II compared to former trials. Because that comes as a common query as to why in MOMENTUM 3 the stroke rate in HeartMate II, appear to be higher than the former trials. Dr Mandeep Mehra:       So very quickly, I'll tell you they're not. So, if you look at the 2009 randomized trials, randomized patients with a HeartMate II versus the HeartMate XVE trial, the two-year stroke rates with the HeartMate II in that trial were 19%, exactly what we observed at two years in this trial.                                                 Other trials have shown exactly that same number. The only trial in which there appeared to be a difference in those numbers, was in the ENDURANCE Trial, where the two-year rate of any stroke was 12%, and was a little lower in the HeartMate II than what we observed. However, I will caution you that if someone dies before having a stroke, then they die without a stroke. And so, stroke can sometimes we underestimated if the population that is enrolled, such as a transplant ineligible population at very high risk, is dying more often than having the chance of a stroke.                                                 So, I actually do not think at all that there was any difference whatsoever compared to prior trials. And even when you look at the ENDURANCE Supplement Trial, which is probably the most contemporary comparison of HeartMate II stroke rates, with MOMENTUM 3, the ENDURANCE Supplement Trial was only a one year trial, and the stroke rates even at one year were right on target with what we observed at the HeartMate II group in MOMENTUM 3. So, frankly that criticism is probably an unfounded criticism. Dr Biykem Bozkurt:         Thank you. Dr Carolyn Lam:                Wow, thank you Mandeep and Biykem, for really helping us go under the hood with this paper. I'm heart failure trained as well, but I learned so much, I'm sure our listeners did as well, and I'm sure you agree too Greg.                                                 Thank you so much for joining us today. Don't forget to tune in again next week.                                                 This program is Copyright American Heart Association 2019.  

Dr Wong:             Welcome to the monthly podcast, "On The Beat, for Circulation: Arrhythmia, and Electrophysiology." I'm doctor Paul Wong, editor in chief, with some of the key highlights from this month's issue. We'll also here from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field.                                 In our first article, Mathew Daly and associates examine whether a high-resolution, 9 French, infrared thermography catheter can continuously image esophageal temperatures during atrial fibrillation catheter ablation. The infrared temperature catheter was inserted nasally or orally into the esophagus, adjacent to the left atrium. Endoscopy was performed within 24 hours to document esophageal injury. Thermal imaging showed that 10 out of 16 patients experienced one or more events where the peak esophageal temperature was greater than 40 degrees centigrade. Three patients experienced temperatures greater than 50 degrees centigrade and one experienced greater than 60 degrees centigrade. Analysis of temperature data from each subject's maximal thermal event revealed high radius, 2.3 degrees centigrade per millimeter and rates of change 1.5 degrees centigrade per second, with an average length of esophageal involvement of 11.0 millimeters.                                 Endoscopy identified three distinct thermal lesions, all in patients with temperatures greater than 50 degrees centigrade, all resolving within two weeks. The authors concluded that infrared thermography, high-resolution mapping of esophageal temperatures during catheter ablation may be performed. Esophageal thermal injury occurs with temperatures greater than 50 degrees centigrade, and was associated with large spacial-temporal gradients.                                 In our next article, Nitesh Sood and associates reported on the real-world incidence and predictors of perioperative complications in transvenous lead extractions involving ICD leads in the NCDR ICD registry. Lead extraction was defined as removal of leads implanted for greater than one year. Predictors of major perioperative complication for all extraction procedures, 11,304, and for high voltage leads, 8,362, or 74% across 762 centers were analyzed, using univariate and multivariate logistic regression. Major complications occurred in 258, or 2.3% of the extraction procedures. Of these, 258 procedures with a complication, 41 or 16% required urgent cardiac surgery. Of these, 14 or 34% died during surgery. Among the total 98, or 0.9% deaths reported, 18 or 0.16% of the total occurred during extraction.                                 In multivariate, logistic regression analysis of all extractions, female sex, admission other than electively for the procedure, three or more leads extracted, longer implant duration, dislodgement of other leads, patients' clinical status, requiring lead extraction, such as infection or perforation, were associated with increased risk of complications. For high voltage leads, smaller lead diameter, a flat versus round coil shape, in greater proximal surface coil area, were multivariate predictors of major perioperative complications.                                 The rate of major complications and mortality with transvenous lead extraction is similar in the real world compared to single center studies from high volume centers. There remains a significant risk of urgent cardiac surgery with a very high mortality, and planning for appropriate cardiothoracic surgical backup is imperative.                                 In our next paper, Bence Hegyi and associates, have reported on the repolarization reserve in failing rabbit ventricular myocytes, and the role of calcium and beta-adrenergic effects on delayed and inward rectifier potassium currents. The authors measured the major potassium currents, IKr, IKs, IK1, and their calcium and beta-adrenergic dependence in rabbit ventricular myocytes, in chronic pressure, in volume overload, induced heart failure, and compared them to age-matched controls.                                 The authors made a number of observations. One, action potential duration was significantly prolonged only at lower pacing rates, 0.2 to 1 Hertz, in heart failure under physiological ionic conditions and temperature. Two, beat to beat variability of action potential duration was also significantly increased in heart failure. Three, both IKr and IKs were significantly regulated in heart failure under action potential clamp but only when cytosolic calcium was not buffered. Four, CaMKII inhibition abolished IKs upregulation in heart failure, but did not affect IKr. Five, IKs response to beta-adrenergic stimulation was also significantly diminished in heart failure, and, six, IK1 was also decreased in heart failure regardless of calcium buffering, CaMKII inhibition or beta-adrenergic stimulation.                                 These observations changed when cytosolic calcium was buffered. The action potential prolongation in heart failure was also significant in higher pacing rates. The authors concluded that in heart failure, calcium dependent up regulation of IKr and IKs counter-balances the reduced IK1, maintaining the repolarization reserve, especially at higher heart rates. In physiologic conditions, unlike conditions of strong cytosolic calcium buffering. Under beta-adrenergic stimulation, reduced IKs responsiveness, severely limits the integrated repolarizing potassium current in repolarization reserve in heart failure, increasing the arrhythmia propensity.                                 In the next paper, Christopher Piorkowski and associates report on the feasibility of a combined endo-epicardial catheter approach for mapping the ablation of atrial fibrillation. The authors studied 59 patients with permanents pulmonary veins isolation and had further symptomatic recurrences of paroxysmal atrial fibrillation, persistent atrial fibrillation, or atrial tachycardia. These patients underwent repeat ablation using bi-atrial endo- and epicardial mapping and ablation. Identification of arrhythmia substrates and selection of ablation strategy were based on sinus rhythm voltage mapping. In all patients, endo-epicardial mapping ablation were feasible using standard technologies of catheter access, three dimensional mapping, and radiofrequency ablation.                                 Epicardial mapping and ablation did not add procedural risk. Exclusively, epicardial low voltage substrate were found in 14% of patients. For the first time, novel epicardial conduction abnormalities located in the epicardial fiber network were described in human patients, 19% of the cohort. Epicardial ablation was needed in 80% of the patients. Over 23 months of follow up, freedom from arrhythmia recurrence was 73%. The authors used continuous monitoring and three months blanking period. Freedom from ATR of greater than two minutes was defined as the primary end-point.                                 The authors concluded that endo-epicardial mapping ablation was feasible and safe. Epicardial ablation increases transient mortality of ablation lesions. Further studies will be needed to demonstrate reproducibility and long-term outcomes, and how the technique compares to other methods.                                 In the next article, Michael Wolf and associates examined the long-term results of substrate modification for ablation of ventricular tachycardia using substrate elimination, targeting local, abnormal ventricular activities, or LAVA, post-myocardial infarction. They reported on 159 consecutive patients undergoing first ablation, age 65, 92% with ICDs, 54% with storms, and 73% with appropriate shocks. LAVA were identified in 92% and VT was inducible in 73%. Complete LAVA elimination after ablation was achieved in 64% and non-inducibility was achieved in 85%. During a median follow-up of 47 months, single procedure, ventricular free survival was 55%, 10% storms, and 19% shocks. The ventricular arrhythmia free survival was 73% after one year and 49% after five years.                                 Complete LAVA elimination was associated with improved outcomes, ventricular arrhythmia free survival of 82% at one year and 61% at five years. The subgroup treated with multi-electrode mapping and real-time image integration had improved ventricular arrhythmia free survival, 86% at one year and 65% at four years. Repeat procedures were also performed in 18% of patients. The outcomes improved, 69% ventricular arrhythmia free survival during a median follow-up of 46 months.                                 In a single center study, substrate modification, targeting LAVA for post myocardial infarction ventricular tachycardia resulted in a substantial reduction in ventricular tachycardia storm and ICDs shocks with up to 49% of patients free of arrhythmias at five years after a single procedure. Complete LAVA elimination, multi-electrode mapping, and real-time integration were associated with improved ventricular arrhythmia free survival.                                 In the next paper, Jean-Baptiste Gourraud and associates examined the safety and feasibility of transvenous lead extraction in adults with congenital heart disease over a 20 year period at a single center. The authors reported on 71 transvenous lead extraction procedures in 49 patients with adult congenital heart disease, mean age 38 years in which a total of 121 leads were extracted. The primary indication for extraction were infection in 48%, lead failure in 31%. A laser sheath was required in 46% and a femoral approach in 8%. Complete transvenous lead extraction was achieved in 92% of the leads. 49% of the patients had transposition of the great arteries. In multivariate analysis, lead duration was predictive of transvenous lead extraction failure. No perioperative death or pericardial effusion was observed. Subpulmonary, atrioventricular valve regurgitation increased in eight patients, five of whom had TGA and were independently associated with ICD leak or valvular vegetation.                                 After a median of 54 months of follow up after the first lead extraction, three deaths occurred independently from lead management. The authors concluded that despite complex anatomical issues, transvenous lead extraction can be achieved successfully in most adult congenital heart disease patients using advanced extraction techniques. Subpulmonary AV valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries.                                 In the next paper, Gabriela Orgeron and associates examined the incidence of ventricular arrhythmias and follow-up in ARVC patients grouped by the level of indication for ICD placement, based on the 2015 International Task Force Consensus Statement Risk Stratification Algorithms for ICD Placement in arrhythmogenic right ventricular dysplasia/cardiomyopathy. In 365 of arrhythmogenic right ventricular dysplasia/cardiomyopathy patients, the authors found that the algorithm accurately differentiates survival from any sustained VT/VF among the four risk groups, p < 0.001. Patients with a Class I indication had significantly worst survival from VT/VF than patients with a Class IIa indication or a Class IIb. However, the algorithm did not differentiate survival free from VF or V flutter between patients with Class I and Class II indications. Adding Colter results, less than 100 PVCs per 24 hours to the classification, helps differentiate the risk.                                 Patients with a high PVCs burden, greater than 1000 PCVs per 24 hours had a poor survival from both VT/VF and VF and V flutter.                                 In the next paper, Takeshi Kitamura and associates studied eight patients that had bi-atrial tachycardia, a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit and were mapped using an automatic, high resolution, mapping system. 708 patients had a history of persistent atrial fibrillation, including septal or anterior left atrial ablation before developing bi-atrial tachycardia. One of the patients had a history of atrial septal path closure with a massively enlarged right atrium. The authors found that 9 atrial tachycardias, with a median cycle length of 334 milliseconds had three different types. Three were peri-mitral and peri-tricuspid reentrant circuit, three utilized the right atrial septum in a peri-mitral circuit, and three utilized only the left atrium and the left right atrial septum.                                 Catheter ablation successfully terminated eight of the nine bi-atrial tachycardias. The authors found that all patients who developed bi-atrial tachycardia had an electrical obstacle on the intraseptal left atrium, primarily from prior ablation lesions.                                 In our next paper, Kwang-No Lee and associates randomized 500 patients with paroxysmal atrial fibrillation to one of two strategies after pulmonary vein isolation. One, elimination of non-PV triggers in 250 patients, group A, or, two, step-wise substrate modification using complex fractionated atrial electrogram or linear ablation until non-inducibility of atrial tachyarrhythmias was achieved, 250 patients in group B. Recurrence of atrial tachyarrhythmias was higher in group B compared to group A. 32% of patients in group A experienced at least one episode of recurrent atrial tachyarrhythmia after the single procedure, compared to 43.8% in group B. P-value of 0.012 after a median follow-up of 26 months. Competing risk analysis showed that the cumulative incidence of atrial tachycardia was significantly higher in group B compared to group A (p= 0.007).                                 The authors concluded that elimination triggers as the end-point of ablation in paroxysmal atrial fibrillation patients decreased long-term recurrence of atrial tachyarrhythmias compare to non-inducibility approach achieved by additional empiric ablation.                                 In our final paper of the month, Roland Tilz and associates reported on 10 year outcome after circumferential pulmonary vein isolation using a double lasso and three dimensional electro anatomic mapping technique. From 2003 to 2004, 161 patients with symptomatic drug refractory paroxysmal atrial fibrillation underwent electro-anatomical mapping guided circumferential pulmonary vein isolation. The procedure end-point was absence of pulmonary vein spikes thirty minutes after isolation, after a single procedure and a median follow up of 129 months, stable sinus rhythm was present in 32.9% of patients based on Holter-ECGs and telephonic interviews. After multiple procedures, mean 1.73 and median follow up of 123.4 months, stable sinus rhythm was seen in 62.7% of patients. Progression towards persistent atrial fibrillation was observed in 6.2%.                                 The authors concluded that although the 10-year single procedure outcome in patients with paroxysmal atrial fibrillation was low, 32.9%, it increased to 62.7% after multiple procedures and the progression rate to persistent atrial fibrillation was remarkably low.                                 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. Dr Kapa:               Thank you Paul, and welcome back everybody to Circulation’s “On the Beat”, where we'll be discussing hard hitting articles across the electrophysiology literature.                                 Today, we'll be reviewing 22 separate articles of particular interest, published in January 2018. The new year saw plenty of articles that are of particular interest either for the future of our field of for present management of our patients. First, within the realm of atrial fibrillation, we'll review several articles within the realm of anticoagulation and left atrial appendage occlusion.                                 The first article we'll review is by Yong et al in the American Heart Journal, volume 195, entitled "Association of insurance type with receipt of oral anticoagulation in insured patients with atrial fibrillation: A report from the American College of Cardiology NCDR PINNACLE registry." In this publication, the author sought to evaluate the effect of insurance type on the appropriate receipt of anticoagulant therapy, specifically looking at warfarin versus NOACs. They reviewed retrospectively over 360,000 patients and found significant differences in appropriate prescription of anticoagulants, irrespective of which anticoagulant was considered. Medicaid patients received less appropriate anticoagulant prescription than those who were privately insured on Medicare or military insured. Furthermore, those on military or private insurances had a higher rate of NOAC prescription than those with Medicare.                                 Furthermore, there was an even wider disparity in NOAC use than warfarin use amongst differently insured patients. These data are important in that they highlight potential variability in appropriate management of patients based on insurance type. Of course, there are many issues that might impact this, such as health care access or available pharmacy coverage of specific medications. Furthermore, the authors do not dive into the impact on outcomes based on the therapy availability.                                 The next article we'll review is by Jazayeri et al, entitled "Safety profiles of percutaneous left atrial appendage closure and lysis: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016" published in the Journal of Cardiovascular Electrophysiology in volume 29 issue 1. Here, the authors sought to evaluate the overall safety profiles of procedures performed with different percutaneous left atrial appendage occlusion devices, including LARIAT and WATCHMAN. They review 356 unique reports and compared outcomes pre- and post- approval of the WATCHMAN device. The look at the specific composite outcome of stroke, TIA, pericardiocentesis, cardiac surgery, and death. They noted that this composite outcome occurred more frequently with WATCHMAN than with LARIATs, and this is irrespective of pre- or post- approval status.                                 These findings highlight the importance of postoperative monitoring in evaluation of overall outcomes. The reason by which there was more frequent negative outcomes in the WATCHMAN than LARIATs need to be considered. Obviously there's several limitations in the MAUDE database, similar with all large databases. However, it does highlight the importance of considering the mechanisms or sure decision making necessary, not just amongst patients and their providers but amongst operators of the staff or amongst physicians and industry executives. To determine how to optimize devices going forward.                                 Speak of left atrial appendage occlusion devices and the potential future of these, we next review an article by Robinson et al, entitled "Patient-specific design of a soft occluder for the left atrial appendage" published in nature biomedical engineering, in volume two in the year 2018. Robinson et al used 3D printing to create a soft, immunocompatible, biocompatible, endocardial implant to occlude the left atrial appendage. They use the individual CT of an in vivo pig to three D print using a specialized material, a left atrial appendage occlusion device, and demonstrated feasibility of achieving adequate occlusion. This paper is important and is one of the initial [inaudible 00:22:03] to how three D printing may be used to optimize patient care. In fact, three D printing has the potential to overturn medical manufacturing and device development.                                 Anatomy tends to be more often patient-specific than not. That's one size fits all implant designs may not be optimal, and resulting exclusion or inadequate occlusion amongst many patients. Decide of three D printable patient specific rapidly prototype soft devices that are biocompatible and hemocompatible, holds the potential to revolutionize the occlusion.                                 Staying in the field of left atrial appendage occlusion, we next review an article by Lakkireddy et al entitled "left atrial appendage closure and systemic homeostasis: The LAA homeostasis study" published in JACC. The authors sought to evaluate the effect of epicardial-versus endocardial left atrial appendage occlusion on systemic homeostasis, including effects on neuro-hormonal profiles of patients. They performed a prospective, single center, observational study, including 77 patients, about half of whom received endocardial versus epicardial device. Interestingly, they noted that the epicardial left atrial appendage occlusion cohort exhibited significant decrease in blood adrenaline, noradrenaline and aldosterone levels. Those are not seen with endocardial devices. Internal epicardial devices are associated with increases in adiponectin and insulin levels as well as a decrease in free fatty acids and consistently lower systemic blood pressure.                                 These data suggest a significant difference in the effect of epicardial versus endocardial closure left atrial appendage on neurohormonal profile. The authors propose several mechanisms for these findings but not the exact mechanisms as yet unclear. Several factors potentially could lead to these findings. One is that epicardial ligation may result in more total ischemia of the left atrial appendage than endocardial closure. Another potential mechanism maybe that the presence for material in the pericardial space versus in the bloodstream may have different effects on neuro-hormonal profile. However, these significant differences in outcomes highlight the importance of considering whether all approaches of left atrial appendage occlusion are considered equal. Many flaws of this study is that it's observational and not randomized. Does it possible those receiving epicardial closure may have been perceived to be lower risk for epicardial puncture, in this, as result, had better long-term outcomes.                                 Changing gears now but staying within the realm of atrial fibrillation, we next review elements for cardiac mapping and ablation. The first article we review is one that has received significant press, published by Marrouche et al entitled "Catheter ablation for atrial fibrillation with heart failure" in the New England Journal of Medicine, volume 378. It is well recognized that morbidity and mortality are higher in heart failure patients who also have atrial fibrillation. Marrouche et al published the results of the CASTLE-AF trial, which attempted to determine if catheter ablation [inaudible 00:24:46] better outcomes among patients with heart failure and atrial fibrillation. They randomized 179 patients to ablation and 184 to medical therapy, which consisted of either rate or rhythm control. Inclusion criteria were those with NYHA class II to IV heart failure, LVEF of 35% or less, and an ICD.                                 The primary endpoint was a composite where the death from many causes or hospitalizations for worsening heart failure. They noted over a median of three as a follow up, the end-point was reached in 28.5% of the ablation group and 44.6% of the medical therapy group, accounting for a significant hazard ratio of 0.62. Furthermore, fewer patients that in the ablation group died from any cause, were hospitalized for worsening heart failure, or died from cardiac causes. These data made a big splash because they're highly supportive of the premise that catheter ablation may be beneficial in some patients with atrial fibrillation and heart failure, often beyond that of medical therapy alone.                                 One major strength of this paper is that the actual AF burden was tracked by the ICD, so we know for sure whether or not the procedure was successful and how controlled the atrial fibrillation was. One thing to note however, is that subgroup analysis suggest that those with more symptomatic heart failure, namely NYHA class III to IV, not benefit as much from ablation. Furthermore, it's also important to note that the five years expected mortality in patients was higher than predicted in the CASTLE-AF trial, however overall these trials highly suggest that the potential benefit that ablation may hold over conventional medical therapy. Extrapolation to comparison with the utility of interventions such as biventricular pace with AV node ablation, however, remains to be considered.                                 Next, we review an article by Chugh et al entitled "Spectrum of atrial arrhythmias using ligament of Marshall in patients with atrial fibrillation" published in Heart Rhythm volume 15, issue 1. They reviewed the spectrum of presentations associated with arrhythmogenesis attributed to the ligament of Marshall, amongst patients with atrial fibrillation. They demonstrate that nearly a third of those patients, ligament of Marshall associated arrhythmias had a pulmonary vein ligament connection, that variously required ablation, the left lateral ridge, the mitral annulus, or alcohol ablation. In addition, they noted about a quarter of patients had atrial tachycardia attributable to the ligament, and the remaining had periatrial reentry requiring either ablation or alcohol injection of the ligament to attain a conduction block.                                 The relevance of this publication, albeit it is of a small number of patients and a small center, lies in highlighting on the right mechanisms by which the ligament of Marshall may contribute to arrhythmogenesis. Namely, can include direct venous connections, inhibition to inaudibility to attain mitral block, and directly attributed atrial arrhythmias. Recognition of the various ways and situations under which the ligament of Marshall may play a role in arrhythmogenesis in atrial fibrillation patients, may optimize physician decisions to look for identify and target the ligaments. What is not as well understood however is the frequency with which ligament of Marshall plays a significant role in arrhythmogenesis in atrial fibrillation.                                 Moving gears, we next review an article by Pathik et al entitled "Transient rotor activity during prolonged three-dimensional phase mapping in human persistent atrial fibrillation" published in a special issue of JACC Clinical Electrophysiology, that focus on atrial fibrillation specifically, in volume 4 issue 1. Pathik et al sought to validate three-dimensional phase mapping system for persistent atrial fibrillation. Commercially available rotor mapping systems project the heart into two dimensions based on a three-dimensional catheter. Instead, Pathik et al used a combination of basket catheters along with the non-left atrial surface geometry to construct three D representations of phase progression. Amongst 9 out of 14 patients, they identified 34 rotors, with all these rotors being transients. Of particular interest, the rotors were only seen in areas of high electric density, where internal electric distances were shorter. They also noted the single wave front is also the most common propagation pattern. The importance of this publication lies in considering two things. First is the three dimensional representation of rotor position and the feasibility of this, and the second is really the high electro-density necessary to observe for others.                                 This has been one of the main problems in rotor analysis, namely what the spacial and temporal density is, that is required to identify rotors, especially given how transient they often are. The presence of rotors does not necessarily mean they're ablation targets in all patients. However, the question still remains regarding the optimal approach to mapping rotors, it needs to be remembered that rotors actually are meant to represent three dimensional scrollway phenomena, that cannot necessarily always be reflected in traditional two D mapping schema. Furthermore, to be remembered that when we claim three-dimensional mapping, this just reflects a two-dimensional surface being wrapped in three dimensions to reflect overall internal surface geometry but it does not take into account transmural activation.                                 Thus, taking into account all these elements it should be remembered as sometimes, it is possible that a rotor might exist but it's just not evident based on the two-dimensional representation or a two-dimensional representation that looks like a rotor may in fact not be a rotor when you consider it in a three-dimensional media.                                 Our last article within the realm of cardiac mapping and ablation we will consider is by Zghaib et al, entitled "Multimodal examination of atrial fibrillation substrate: Correlation of left atrial bipolar voltage using multielectrode fast automated mapping, point by point mapping, and magnetic resonance imaging intensity ratio", published in JACC Clinical Electrophysiology, in the same volume as the previous article. The authors sought to compare fast automated mapping with multiple electrodes versus point by point mapping and correlate with weighed gadolinium enhancement as seen by MRI, termed the image intensity ratio.                                 We all recognize that bipolar voltage is critical to recognizing and evaluating substrate. It's traditionally used in decay regions of substrate in both the atrium and ventricles. However, whether a newer automated approach used to characterize substrate perform equally well in comparison with traditional point to point mapping is still unknown. Thus, the authors in 26 patients perform cardiac MRI and mapping endocardial using both voltage mapping techniques. They noted that for each unit increase in image intensity ratio on MRI, in other words, increasing late enhancement, there was 57% reduction of bipolar voltage. They also noted that the bipolar voltage using other fast elevating mapping or point by point was significantly related with actual differences in calculated voltage, becoming more dissimilar in the extreme of high and low voltage areas.                                 The relevance of this publication is highlight in the potential utility of fast automated mapping in creating accurate voltage maps. The correlation of voltage values with image-intensity ratios suggest the utility of either approach. In turn, correlation with MRI suggest a pathologic correlate for all of these findings. However, whether substrate characterization guide ablation carries incremental benefit remains to be seen.                                 Changing gears but staying in the realm of atrial fibrillation, we next review elements of risk stratification and management. The first article we review is by Friedman et al, entitled "Association of left atrial appendage occlusion and readmission for thromboembolism amongst patients with atrial fibrillation undergoing concomitant cardiac surgery", published in JAMA, volume 319, issue four. Friedman et al sought to evaluate whether surgical left atrial appendage occlusion let to a reduction in long-term thromboembolic risk in a large database of Medicare recipients. They included the primary outcome as readmission for thromboembolism, including stroke, TIA, or systemic embolism, in up to three years of follow-up. With secondary end-points including hemorrhagic stroke, all-cause mortality, and a composite end-point of all outcomes.                                 Amongst more than 10,000 patients, there were almost 4,000 patients receiving surgical occlusion of left atrial appendage. Surgical occlusion was associated with a reduction in thromboembolic risk, OR of 6%, all cause mortality, 17 versus 24%, and the composite end-point, 21 versus 29%. However, interestingly, surgical occlusion was only associated with reduction in thromboembolic risk compared with no occlusion amongst those discharged without anticoagulation and those discharge with it. Namely, the thromboembolic risk reduction was primarily seen in those where the surgical occlusion, those who were sent home without any sort of anticoagulation. These data suggest that surgical occlusion leads to reduction of thromboembolic risk overall. As any large database based study, there are massive flaws in the database itself. Namely, we're relying on the coding of hospitals and operators. To know exactly what was done and what happens latter.                                 However, these data are hypothesis generating. One key element is the fact that surgical left atrial appendage occlusion was only superior in reducing thromboembolic risk amongst those discharged without anticoagulation. This raises the question as why. Was left atrial appendage completely closed in these patients? In which case, they may be at further increased risk or that the operators felt that there is a high risk for other reasons that cannot be cleaned from an administrative datasets? While the data support consideration of the benefit of left atrial appendage occlusion in a surgical manner, a kin to what has been seen in papers on WATCHMEN and other approaches, and how is the critical nature of randomized trials in this regard.                                 We next review an article published in JAMA Cardiology, volume three issue one by Inohara et al, entitled "Association of atrial fibrillation clinical phenotypes with treatment patterns and outcomes: A multicenter registry study." Traditionally classification of AF has depended largely on factors such as the nature of AF, paroxysmal versus persistent, LA size, and other factors such as extend of the late enhancement. Inohara et al sought to evaluate whether cluster analysis could better define heterogeneity of AF in the population. They included an observational cohort of almost 10,000 patients admitted to 124 sites in the United States in the ORBIT-AF registry.                                 Outcome was a composite major address cardiovascular and neurological events or major bleeding. Amongst these patients, they identified four clusters, including one those with lower rates of risk factors and comorbidities than other clusters, two, those with AF at younger ages and with comorbid behavior disorders. Three, those with AF with tachycardia-bradycardia type syndromes and had devices for sinus node dysfunction, and four, those with AF with other risk factors such as a coronary disease. Those in the first cluster had significantly lower risks of major events. All clusters were noted to have symptom dissociation to specific clinical outcomes.                                 These data are interesting and highlight the highly heterogeneous nature of classifying risk attributable to atrial fibrillation. When broad datasets associated atrial fibrillation with specific outcomes. Maybe suggest an attribution to all patients with atrial fibrillation. However, this single relationship was specific to the outcomes suggest the limitation of applying outcome as approach to understand atrial fibrillation impacts and outcomes, namely depending on clusters that may take into account patient age or comorbidities, it may be irrelevant in discriminating patient outcomes than the traditional paradigm in the same paroxysmal versus persistent or depending on the left atrial size.                                 These data also highlight the importance of considering the inclusion criteria in randomized trials of atrial fibrillation before stripling real world outcomes to patients who don't fit within that trial.                                 Next, we will be reviewing an article by Chou et al entitled "Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation," published in JACC, volume 71 issue two. Chou et al sought to evaluate the effect of aging and evolving instant comorbidities to stroke risk in patients with atrial fibrillation. Many large database studies or trials where added baseline CHADSVASC score and the then ensuing follow up period to define risk over time of ischemic stroke.                                 The authors hypothesized that as patients age, develop new comorbidities that would change the score, may be more predictable of long-term outcomes than the score itself. They included over 31,000 patients who do not have comorbidities to CHADSVASC aside from age and sex but had atrial fibrillation. They didn't calculate a delta score defined as the difference between the baseline and follow up scores. The mean baseline score was 1.29 with an increase in 2.3 during follow up, with an average delta of one. The score may not change over follow up in 41% of patients. Interestingly, significantly more patients had a delta CHADSVASC of one or more and develop ischemic stroke than non-ischemic stroke. The delta CHADSVASC was shown to better predictor of ischemic stroke than either baseline or follow up CHADSVASC score. This data suggest that additive shifts in the CHADSVASC score over time may be more predictive of stroke risk than the actual score itself.                                 These findings are thoughtful and logical. They indicate the potential impact of continued aging or acquisition identification of new comorbidities. In some patients, potential discovery or new comorbidities or follow-up; for example, hypertension and coronary artery disease may lead to reclassification of stroke risk. That is important to maintain close follow up of atrial fibrillation patients, and not to show a continued need or lack of need of anticoagulation on the basis of a baseline evaluation. This also holds relevance single center long-term outcomes in patients specific scores. Whether is acquisition of new comorbidities or presence of baseline comorbidities or predict a long-term score, should we consider when assessing the need for anticoagulation, particularly in perceived initially low risk cohorts who go on to develop ischemic stroke.                                 Lastly, within the realm of atrial fibrillation, we review an article by Hussain et al, entitled "Impact of cardiorespiratory fitness on frequency of atrial fibrillation, stroke, and all-cause mortality" published in the American Journal of Cardiology, volume 121 issue one. Hussain et al review the effect of cardiorespiratory fitness on overall outcomes and incidence of atrial fibrillation and outcomes amongst patients with atrial fibrillation. Amongst over 12,000 individuals prospectively followed up after treadmill exercise test, they noted 1,222 had a incidence of AF, 1,128 developed stroke, and 1,580 died. For every 10% increase in functional layover capacity, there was a 7% decrease in risk of incident AF, stroke, or death.                                 Similarly, in those who developed AF, stroke was lower in those with higher functional aerobic capacity. These findings support the notion known to other areas of cardiovascular disease that better cardiorespiratory fitness is associated with better outcomes, in this case to stroke, incident AF, or mortality. Furthermore, even on the presence of AF, those with better functional capacity had a lower risk of stroke. These data highlight the continued importance of counseling patients on the benefits of physical fitness even in the setting of already present AF.                                 Moving on to a different area of electrophysiology, we review the realm of ICD pacemakers and the CRT.                                 The first article review is by Sze et al entitled "Impaired recovery of left ventricular function in patients with cardiomyopathy and left bundle branch block" published in JACC volume 71 issue 3. Patients with left bundle branch block and cardiomyopathy are known to respond to CRT therapy. Thus the investigators sought to evaluate whether guideline medical therapy in patients with reduced LVEF and left bundle branch block, afford a beneficial first line approach therapy. The reason for this currently guidelines suggest waiting at least three months before consideration of CRT has had as some patients may recover on guideline directed medical therapy without the need for device implantation.                                 They review patients with a LVEF of less or equal than 35% and baseline ECG showing left bundle branch block. In evaluating left ventricular ejection fraction at follow up of three to six months. They excluded patients with severe valvular disease, and already present cardiac device, an LVAD, or heart transplant. Among 659 patients meeting criteria, they notice 74% had a narrow QRS duration of less than 120 whereas 17% had QRS duration greater than 120, and the remainder had a QRS duration greater 120 but was not left bundle branch block. The mean increase in the left ventricular ejection fraction on guideline directed medical therapy was in those with a narrow QRS duration and least in those with left bundle branch block, 8.2%.                                 Furthermore, when comparing mean LVEF improvement, those with on versus non-on guideline directed medical therapy, there was virtually no difference in rates of recovery. Furthermore, composite end-point of heart failure hospitalization mortality was highest in those with left bundle branch block. These data suggest that those with bundle branch block and cardiomyopathy received less overall benefit from guideline directed medical therapy over the three to six months follow up period. Whether this is due to already more severe myopathic process to start with or due to the CRT is unclear. However, it may suggest that in some patients, left bundle branch block may benefit from inclusion of CRT early in their disease course as known the significant number of patients up to three to six months guideline directed medical therapy with insufficient DF recovery may then benefit from CRT. As well as intervening earlier may result in better outcomes, especially knowing the high and term raise mortality in heart failure hospitalization remains to be seen.                                 A trial studying early implantation of CRT on these patients may be relevant.                                 The next article review is by Gierula et al entitle "Rate-response programming tailored to the force-frequency relationship improves exercise tolerance in chronic heart failure" published in JACC Heart Failure, in volume six, issue two. The authors sought to evaluate whether tailored rate-response programming improved exercise tolerance in chronic heart failure. The double blinded, randomized, control, crossover study, they compared the effects of tailored programming on the basis of calculated force-frequency relationship, defined as including critical heart rate, peak contractility, and the slope, multidimensional programming and exercise time and maximal oxygen consumption. They demonstrate amongst 98 enrolled patients that rate-response settings limiting heart rate raise to below the critical heart rate led to create exercise timing and higher peak oxygen consumption.                                 These data suggest that personalizing rate-response therapies may improve exercise time and oxygen consumption values in patients with heart failure and pacing devices. The main limitation of the study is that the number of patients was small, 90, and then the number of patients crossing over was even smaller, 52. However, highlights the potential of working closely between device programmers and consideration of individual's characteristics and their exercise needs in determining optimal programming strategy.                                 Finally, within the realm of devices, we review an article by Hawkins et al, entitled "Long-term complications, reoperations, and survival following cardioverter defibrillator implant" published in Heart, volume 104 issue three. Hawkins et al sought to evaluate the long-term complications and risk of reoperation associated with defibrillator implantations in a large [inaudible 00:41:56] population of 300,410 patients, they noted over a 30-month follow up period there was a 12% reoperation rate within the year of implant. This is most prominent for CRT devices, with a risk of 18% in one year post-implant. Furthermore, CRT had the highest rate of early complications, with device complexity, age, or the presence of atrial fibrillation being significantly associated with complication risk.                                 Mortality also increased over time from 5% within the first year to nearly a third after five years. However, younger patients exhibited five years survival similar to the general population with a progressive decline of this as older patients were considered. These findings highlight several critical issues. First, they report a high one year reoperation rate for a variety of reasons. This finding highlights the importance of considering protocols to minimize the need for reoperation. Furthermore, they note the higher rate amongst CRT patients, with seems logical given the likely longer associated procedural risk and need for more leads. Finally, the impact of age on expectant survival are to be taken into consideration with the device and the life-saving potential of the defibrillator.                                 Moving on to cellular electrophysiology, review one article by Zhang et al, entitled "Reduced N-type calcium channels in atrioventricular ganglion neuron are involved in ventricular arrhythmogenesis" published at the journal of the American Heart Association, in volume seven issue two. Zhang et al reported a rat model of ventricular arrhythmogenesis and characterized the role of atrioventricular ganglion neurons in risk of arrhythmogenesis as well as the mechanism for this risk this model relates in humans to the attenuated cardiac vagal activity in heart failure patients, which is known to relate to their arrhythmic risk. The demonstrated reduced N-type calcium channel in these AV ganglion neurons, which project innervating systems to the myocardium, resulting in increased risk of PVCs, and increased susceptibility to induction of ventricular arrhythmias with programmed stimulation.                                 The relevance of the intrinsic cardiac nervous system arrhythmogenesis has become increasingly prominent as methods to study it have improved. Understanding the direct and most relevant inputs may facilitate better understanding of risk of arrhythmias in patients. In the case of this study by Zhang et al, the critical finding is that disorder of the atrioventricular ganglion neurons may lead to increased susceptibility for ventricular arrhythmogenesis. Clinical relevance includes consideration of effects on this specific ganglion when performing ablation on for other conditions, and potential long-term effect on arrhythmogenic risk, as well as potentially relevant functional explanations for arrhythmogenesis.                                 Moving on to the genetic channelop, these are considered two separate articles. The first one by Bilmayer et al, entitled "ExomeChip-Wide analysis of 95,626 individuals identified ten novel loci associated QT and JT intervals" published in Circulation: Genomic and Precision Medicine, in volume 11 issue 1. This whole exome study reviewed several novel loci that modified the QT and JT intervals. They include over 100,000 individuals and identified ten novel loci not previously reported in the literature. This increases the number of known loci that impact from ventricular portal adjacent by nearly one third. These loci appear to be responsible for myocyte and channel structure and interconnections that internally impact the ventricular repolarization.                                 While long QT syndrome be characterized amongst the known genes in 75% of affected individuals, that also means one fourth long QT syndrome cannot be characterized based on known genes impacting ventricular repolarization. The identification of novel loci or novel that may be affect repolarization kinetics to unique means are critical to define novel therapies as well as in genetic counseling the patients in potential effects on family members when screening them for potential disease risk. These findings should assess an opportunity for further studying the mechanisms by which these loci modulate QT and JT intervals and the potential contribution to phenotypic risk.                                 The second paper within this realm we review is by Zumhagen et al, entitled "Impact of presynaptic sympathetic imbalance on long QT syndrome by positron emission tomography" published in Heart, volume 104. The authors sought to evaluate by a PET scan the impact of sympathetic heterogeneity on long-QT syndrome risk. Amongst 25 patients with long-QT syndrome, including long-QT type I and II, and 20 ostensibly healthy controls, they noted that regional retention in disease were similar between affected patients and controls. However, regional washout rates were higher in the lateral left ventricles in patients with long-QT syndrome. Internal global washout rates were associated with greater frequency of clinical symptoms. That's there seem to be some relationship between regional and global sympathetic heterogeneity, particularly during washout, with overall risk in long-QT syndrome patients.                                 These findings report the notion for sympathetic imbalance, partly mediating the risk attributable to long-QT syndrome. The findings on PET suggest regional imbalance of presynaptic cathecholamine and reuptake and release, being one mechanisms. This was most prominent in long-QT I patients who also often drive most benefit from left sided sympathectomy. The novelty of these findings is in the potential role of imaging to determine basic contributors to congenital long-QT syndrome in given patients. The larger prospect of size would really need to be evaluated this further.                                 Moving on to the realm of ventricular arrhythmias, we review three different articles. The first one, by Hamon et al, entitled "Circadian variability patterns predict and guide premature ventricular contraction ablation, procedural disability, and outcomes" published in Heart Rhythm, volume 15 issue one. Hamon et al sought to evaluate whether circadian variability of PVC frequency can predict optimal drug response intraprocedurally during PVC ablation. One of the main problems of PVC ablation is when PVC are infrequent and tend to disappear during the procedure, achieving procedural success or attaining sufficient frequencies of PVCs to map becomes very difficult. Next, they use Holter monitoring in the ambulatory stripe to define three groups. Those of higher PVC burden during faster heart rates, those with higher PVC burden during slower heart rates, and those with no correlation between their PVCs burden and their heart rate.                                 More than half the one hundred and one patients included a high burden of PVCs at fast rate while 40% had no correlation between the two and 10% had higher burden in slower heart rates. Almost one third of patients taken for ablation have infrequent PVCs during a procedure, while the best predictor of this being a low ambulatory PVC burden of less than 120 per hour. Isoproterenol infusion was only useful in lessening PVCs in those with PVCs associated with fast heart rates. The isoproterenol washout or phenylephrine where used with those associated with slower heart rates.                                 Interestingly, not a single drug was effective in inducing PVCs in those with infrequent PVCs that have not heart rate correlation in the ambulatory stages. They noted that outcomes ablates were similar amongst those with higher heart rate associated PVCs and non-heart rate correlated PVCs previously responded to a drug. But, [inaudible 00:48:08] noted only a 15% success rate from ablation in infrequent PVCs in patients who lacked correlation between PVC burden and heart rate and who were unresponsive to drug previously. These data are important highlighting the potential for further defining idiopathic PVC ablation needs and likelihood of success based on ambulatory data, by correlating PVC burden with heart rate and their circadian variability, it's possible to predict likelihood specific intraoperative drugs working when dealing with infrequent intraprocedural PVCs.                                 Furthermore, the finding of lack of correlation with slower or fast heart rate in terms of PVC burden is associated with the poor success rate unless those PVCs are drug responsive. Highlights the potential benefit of performing preoperative antiarrhythmic drug testing to get likelihood of ablation success in this patients.                                 The next article we review is by Lee et al, entitled "Incidence and significance of the lesions encountered during epicardial mapping and ablation of ventricular tachycardia in patients with no history of prior cardiac surgery or pericarditis" published in Heart Rhythm, volume 15 issue one. Lee et al sought to determine the frequency of pericardial lesions, impeding mapping in patients without prior surgery, operative procedure, or pericarditis, in other words virgin hearts. Amongst 155 first time attempts of access, 8% had pericardial lesions. The only clinical predictor was the presence of severe renal impairment.                                 In addition, no patients with supposedly normal hearts had a lesions. Notably, those with a lesion had more frequent impairment in mapping and lower overall success rates; there were similar complication rates as those without the lesions. These data are relevant in highlighting the ease of mapping of pericardial access may not always be present, even when dealing with inversion of pericardial space. A lesion may be present in patients, particularly with severe renal disease. Advising patients of this possibility prior to the procedure and considering that epicardial access may be impaired in a fair number of patients, even the absence of prior history of surgery, epicardial access or pericarditis isn't important.                                 The final article we'll review within the realm of ventricular arrhythmias is by Kumar et al, published in Journal of Cardiovascular Electrophysiology, volume 29 issue one, entitled "Right ventricular scar-related ventricular tachycardia in nonischemic cardiomyopathy: Electrophysiological characteristics, mapping, and ablation underlying heart disease." Kumar et al sought to evaluate the substrate and outcomes associated with right ventricle scar related ventricular tachycardia ablation in nonischemic patients at large, but particularly in those with neither stroke or coronary artery disease as potential explanations for this scar. They reviewed 100 patients consecutively over half of whom had ARVC and the remainder was sarcoid or RV scar of unclear origin. Those with RV scar of unknown origin tend to be older compared to the ARVC patients, and had more severe LV dysfunction compared with saroid patients.                                 However, the scar distribution extend was similar within all these groups. Furthermore VT/VF survival was higher in those with RV scar of unknown origin. The velocity of survival free or death or cardiac transplant and VT/VF survival seen in sarcoid patients. These data suggest that close to one third of patients, RV scar related VT may have VT of unknown cause. Total outcome was superior overall to those with defined myopathic processes. What's most interesting is, over follow up, none of those with RV scar of unknown origin develop any further findings to reclassify them as sarcoid or ARVC. It is possible this group reflects some mild form of either disease however. Again, the exact pathophysiologic process remains unclear. These findings may help in counseling patients who are in long-term expected outcomes from ablation intervention.                                 The final article we'll review this month is within the realm of other EP concepts that may be broadly applicable, published by van Es et al, entitled "Novel methods for electrotissue contact measurement with multielectrode catheters", published in Europace, volume 20 issue one. In this publication, the authors sought to evaluate the potential utility of a novel measure on evaluating electro tissue contact. With multielectrode catheters it is known that one of the problems with assessing contact is a contact force that cannot be used. Electro with coupling index is often used but even this has fragile problems, especially when you get into high impedance areas, that can be affected by surrounding ion impedance structures. Due to the fact that measuring contacts forces challenging in such multielectrode catheters, the authors measure electric interface resistance by applying a low level electrical field, pushing neighboring electrodes. They compared the effectiveness of assessing contact by this approach without using contact force in a poor side model.                                 They know that this measure was directly correlated with contact force in measuring tissue contacts. These findings support a role for aversion of an active electrode location and determining tissue proximity and contact-based on the coupling between the electrodes on multipolar catheters in the tissue. These findings may be highly useful when there is a variety of catheters where contact force cannot be implemented. Further studies on the methods and cutoff to establish tissue proximity on the end of contact will be also needed.                                 To summarize, however, as a term was brilliant here that was not well explained, active electrical location is actually a phenomenon that occurs in nature. This is seen in deep sea fish, which actually have multiple electrodes oriented around its body. They emit a small electrical field that results in a general impedance field surrounding the fish. This essentially is the way of visualizing the world around them. Perturbations based on proximity to different structures, whether they are live or death, and based on whether they are live or death, results in changes in the perturbations of this resistive fields, resulting in proximity determination by the fish. Several individuals are looking into potential applications of this to understanding tissue proximity when using catheters in the body. This consideration of impedance is fundamentally different than the traditional measure impedance were used by traditional generator.                                 I appreciate everyone's attention to this key and hardening articles that we've just focus on or this past month of cardiac electrophysiology across literature. Thanks for listening. Now back to Paul. Dr Wong:             Thanks Suraj, you did a terrific job surveying all journals for the latest articles on topics of interesting in our field. There's not an easier way of staying in touch with the latest advances. These summaries and the list of all major articles in our field for month can be downloaded from the Circulation: Arrhythmia and Electrophysiology website. We hope that you 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.                                       

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.                                                 Today's issue features striking results from the ASSERT 2 trial of the prevalence of subclinical atrial fibrillation detected with implantable monitors in a group of high-risk older individuals. Much more soon, right after these summaries.                                                 The first original paper in this weeks' journal shows for the first time that myocardial edema, in the week after STEMI in humans, is a bimodal phenomenon. First off, there is Dr. Fernandez Jimenez and Barreiro-Perez, corresponding author Dr. Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that the time course of edema reaction in 16 patients with anterior STEMIs successfully treated by primary angioplasty compared to 16 matched controls using cardiac magnetic resonance and assessing its implications for myocardium at risk quantification. The STEMI patients were scanned serially within the first three hours after reperfusion and at, one, four, seven and 40 days, while controls were scanned once. Furthermore, they performed an experimental study of 20 pigs undergoing 40 minute ischemia reperfusion, followed by serial cardiac magnetic residence exams at 120 minutes, one, four and seven days after reperfusion.                                                 The authors found that am initial wave of edema appeared abruptly at reperfusion, but it was significantly attenuated by 24 hours. The initial wave of edema was followed by a second or differed healing related wave of edema several days after reperfusion, reaching a plateau around four to seven days after myocardial infarction. Of note, cardiac magnetic resonance myocardium at risk quantification at 24 hours post-reperfusion severely underestimated the infarct size.                                                 In summary, post-MI edema in patients follows a bimodal pattern, which affects cardiac magnetic resonance in estimates of myocardium at risk. The dynamic changes in post-STEMI edema, highlight the need for standardization of cardiac magnetic resonance timing to retrospectively delineate myocardium at risk and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day four and seven, post-MI, seems a good compromise for standardization. However, further studies are needed to study the effect of other factors on these variables.                                                 The next paper sheds light on molecular mechanisms underline the progression of atherosclerosis, involving multiple inflammatory events, as well as the counteraction by inflammatory responses in cells such as the endothelium, circulating monocytes and resident macrophages in the arterial wall.                                                 Co-first authors, Dr. Li and Martin, corresponding author Dr. Shyy from Xi'an Jiaotong University Health Science Center and University Health Science Center and University of California, San Diego and colleagues, analyzed RNA seek data to identify cholesterol oxidation and e-flux genes regulated by Kruppel-like factor 4, which is a key anti-inflammatory transcription factor. They found that Kruppel-like factor 4 upregulates cholesterol 25 hydroxylase and liver X receptor in vascular endothelial cells and macrophages. In further in vitro and in vivo experiments, they show that access enhanced reverse cholesterol transport from the vascular wall, mitigated inflammation through suppression of sterile regulatory binding protein two and NOD-like receptor family hiring pyrin domain containing protein three inflammasome in endothelial cells and also promoted cholesterol e-flux in M1 to M2 transition in macrophages.                                                 In summary, Kruppel-like factor 4 trans-activates cholesterol 25 hydroxylase and liver X receptor, promoting the synergistic effects between individual cells and macrophages to protect against atherosclerosis susceptibility, and this may therefore be a therapeutic target for cardiovascular disease.                                                 The next study provides data on the safety and efficacy of a novel cobalt alloy-based coronary stent eluting the antiproliferative agent, ridaforolimus, for treatment of patients with coronary artery disease.                                                 Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia and colleagues, reported the primary results of the bionics trial, which was a prospective international, one-to-one randomized trial conducted to evaluate in a noninferiority design, the relative safety and efficacy of ridaforolimus-eluting stents compared to slow release zotarolimus-eluting stents among 1,919 patients at 76 centers undergoing PCI. At 12 months, the primary endpoint of target lesion failure was 5.4% for both devices, thus meeting the prespecified criteria of noninferiority of ridaforolimus stent compared to the zotarolimus stent.                                                 Angiographic and intravascular ultrasound measures of restenosis, late lumen loss and nepintimal hyperplasia measured at 13 months, were similar in both devices. Treatment with the ridaforolimus-eluting stent resulted in low rates of myocardial infarction, repeat revascularization and stent thrombosis, and results were consistent in predefined patients and lesion groups. The authors therefore concluded that these results support the safety and efficacy of ridaforolimus-eluting stents in patients representative of every day clinical practice.                                                 Well, that wraps it up for your summaries. Now, for our future discussion.                                                 Today for our future discussion, we are going to talk about a true global public health problem. It's a condition that affects 33 million people worldwide, a number that is expected to double by 2050, and what we're talking about is atrial fibrillation. Those are the numbers of just what we know of detected atrial fibrillation, but today's paper deals with silent subclinical atrial fibrillation and the results of the ASSERT 2 trial. I'm so pleased I have the first and corresponding author with us today, Dr. Jeff Healey from Population Health Research Institute at McMaster University in Hamilton, Ontario. Welcome, Jeff. Dr. Jeff Healey:                 Good morning. Dr. Carolyn Lam:               Also on the show today is Dr. Sami Viskin, associate editor from Tel Aviv Medical Center. Hi, Sami. Dr. Sami Viskin:                 Hi. Hello, everybody. Dr. Carolyn Lam:               Jeff, from ASSERT to ASSERT 2, could you give us a bit of the picture of what made you do ASSERT 2 and what have we learned? Dr. Jeff Healey:                 The ASSERT trial was a large 2,500 patient trial in patients in with pacemakers and also implantable defibrillators and it was really an easy first place to study this entity of sub-clinical atrial fibrillation because, of course all of these patient had implanted devices with electrodes in their atrial where they could report all of the internal activity continuously for many years at a time. This was done with really no incremental costs or inconvenience to the patient, the data were already being collected, so in ASSERT we asked the question, how common is atrial fibrillation as it is not detected clinically and is it associated with stroke? What we found was that over time, somewhere between 30% and 40% of patients with an implemented device developed atrial fibrillation, which we termed subclinical atrial fibrillation, because this was not detected by the usual clinical mean. Great results, very interesting, but begged the question, is this a unique entity that we see only in pacemaker patients or if you just took older individuals in the more general population, would you see subclinical atrial fibrillation as well? That was really the impetus for doing that ASSERT 2 trial in patients who are over the age of 65, had cardiovascular condition, placed them at increased risk or stroke in atrial fibrillation, but did not have implanted devices. Dr. Carolyn Lam:               Indeed, Jeff. That's a beautiful set up. The ASSERT was really quite a landmark study suggesting that what we know as clinical may be just the tip of the iceberg, isn't it? Now you've extended it, and I think it'd be really important for the audience to understand that ASSERT 2 was really a high risk cohort. Could you maybe tell us a little bit more of what you did and what more we learned? Dr. Jeff Healey:                 Sure. These were typical patients who might be attending a cardiology clinic, an outpatient general medicine clinic who did not have pacemakers and did not have any history of atrial arrhythmias, but you're right, they were high-risk. These were patients over 65 who have had clinical risk factors, things like hypertension, or diabetes, but also some other marker of increased risk such as a BNP that was elevated or left atrial enlargement. Dr. Carolyn Lam:               Yeah and your findings were so striking. Tell us. Dr. Jeff Healey:                 What was quite was surprising was, indeed, we found that in the non-pacemaker, non-defibrillator population from ASSERT 2, we also found high prevalence of subclinical atrial fibrillation. This was really quite surprising. In fact, it was many times higher than we had predicted. We found that over time, the annual risk of developing atrial fibrillation in this cohort was 34.4% per year, which is truly astounding number of patients who developed atrial fibrillation. Dr. Carolyn Lam:               That's like one in three of such patients experiencing at least one of these episodes lasting at least five minutes? That's really impressive. Dr. Jeff Healey:                 It was high.  You could look into that study and find groups where the risk was even higher, so we chose to cut off left atrial volume of 58 millimeters and not correspondent with the median volume of the population series of Olmstead County for people over the age of 65 who came in for an echocardiogram, and that was the minimum left atrial size to get into the trial. If you then looked at within the ASSERT 2 trial and looked at the volumes within the trial, somewhere around 72 1/2 milliliters, if you looked at the patients who had the top of atrial size, that risk was as high 50% per year, so one in two. Dr. Carolyn Lam:               Another thing I noticed though about your results is that the frequency of these episodes, it's not that frequent, and so what we would do typically in a 24-hour monitoring or even a seven-day monitoring would have captured only a small proportion of these. Isn't that the case, Jeff? Could you give us some numbers there? Dr. Jeff Healey:                 Yes, of course. The episodes that qualified were at last five minutes in duration, we then do longer episodes in course, but these were much less frequent in the single digit percent risk, and what we found was there were, as you say, quite infrequent. So with the standard 24-hour halter monitor, for example, you would have had a very low pickup. It really goes to show that the longer you monitor, the more you will find. I think that's the key message out of this study and other studies like it.                                                 I think conversely, you also have to realize that the more you look, or the harder you look, you may be uncovering atrial fibrillation that behaves differently than atrial fibrillation you find, for example, in the single 12 lead ECG. We have found, and others have found, that the risk of stroke we find when we would have short episode picked up only with long term continuous monitoring is real but it's much lower than we see with atrial fibrillation that was picked up by ECB where patients are presenting in emergency rooms stroke with symptoms. Dr. Carolyn Lam:               That's such relevant points, and it really brings up the unanswered questions perhaps, exactly what is the correlation with stroke risk? What should we do about it? Sami, I'm sure you have other questions when you handle this paper and we had so many discussions among the editor, would you like to just start the ball rolling in some of these considerations? Dr. Sami Viskin:                 Well, actually, we understood from the beginning of the study was not powered to show any difference in outcome by intervention, by treating any of these patients that had discovered atrial fibrillation with anticoagulation, so we took this paper as what it is, a paper that shows the unexpectedly high privileges of atrial fibrillation in patients who have neither symptoms nor electrocardiographic documentation of atrial fibrillation when they undergo implantation of our recording device. So we took this paper for what it is, a very interesting finding that opens the door for new studies, testing perhaps the value of intervention with anticoagulation at an earlier stage. Dr. Carolyn Lam:               Yeah, I agree. I'd love to hear Jeff's thoughts on what those next steps may be, but just to point out to the audience, I mean, at the moment, our decisions on whether to anti-coagulate, like the CHADSVASC score and so on, doesn't really take into account the type of atrial fibrillation or the duration of atrial fibrillation? Does it? What do we do now? What do we do in the context of the fact that results, like the COMPASS trial, that maybe just based on the presence of vascular disease, we should anti-coagulate, right? Jeff, how about your thoughts? What are the next steps? Dr. Jeff Healey:                 You're right. I mean, is there a value for empirically anticoagulating individuals. That's really going to boil down to the individuals with an absolute risk of stroke and how well they do on anticoagulants. Good question.                                                 In the post-stroke world or post-cryptogenic stroke, which we now report to as [inaudible 00:16:48], these individuals are being evaluated with two large clinical trials, looking at this idea of just empiric anticoagulation with low dose, NOAC in comparison to aspirin.  These trials are ongoing, and they expect to report findings by the end of 2018.                                                 In the general population, no such large scale trial is ongoing at the present time. You mentioned COMPASS and the big COMPASS results were clearly a big result at the European Society meeting, but it must be clarified that the dose of NOAC or rivaroxaban used in COMPASS was not the typical dose that we would use in the treatment of patients with atrial fibrillation, so much lower. I think we have to be careful when we're talking about doses that may be different 5 to 10 fold and what is then coagulating a patient and what is not. I think, certainly, I would not consider the COMPASS tests right now to be an effective atrial fibrillation dose, but as we've discussed, subclinical atrial fibrillation is different and we may have further data in the future.                                                 Now, how do we get there? I think many people are aware of two ongoing trials, the ARTESIA trial, which is run by our group, the NOAH-AF Trial run by Kirchof and the group from Birmingham and the AF-NET organization, and these two ongoing trials have taken this question back again, so the pacemaker population that we are enrolling thousands of patients with pacemakers and defibrillators who have these short episodes, and they're being randomized treatment with a full dose new oral anticoagulant vs aspirin. These trials are ongoing, and I think these trials and the pacemaker population will actually give us the answer to what is the risk benefit for treating, so interesting course of event. We started in the pacemaker population to show there was risk for these short episodes, that this was hotly debated 10 - 15 years ago, and now we take ASSERT 2 and other trials into the non-pacemaker population to show that this is actually a problem for older individuals in general, and now the third step, go back into the pacemaker clinic again and to do trials to study the effectiveness in therapy. Dr. Carolyn Lam:               Great point and great takeaways. How about, Sami? What do you think would be the take-home message for clinicians at this moment based on what we know now and based on this new data? Dr. Sami Viskin:                 Well, the message is clear, the message is that atrial fibrillation is far more prevalent than what we think it is, the message is that for every event of atrial fibrillation that we feel we probably have many events that we don't feel we should be distrustful about judging the decision to anti-coagulate or not based on symptoms, and I'm referring now to patients who already have one event documented of atrial fibrillation and are waiting until they feel the next one, before they start taking anti-coagulations. This is another warning about how we should be careful about trusting symptoms when deciding to treat and when not to treat. I just said this opens a new door for a new line of studies, looking at how early to intervene with anticoagulation, what dosage should be used for these patients who probably have lower burden of atrial fibrillation. If you can see that the patients who have atrial fibrillation documented on the electric cardiogram, as patients who simply have a higher burden and therefore they are more likely to come up with documentation on a regular ACG, so perhaps those only have subclinical atrial fibrillation have a lower burden, perhaps they can benefit from lower doses of anticoagulation, but these are all fit, that need to be proven by trials. Dr. Jeff Healey:                 It is not only an issue for implanted devices but with the implantable cardiac monitors, this is now relevant for many other patients who have these devices implanted for things like syncope, but also there's been a lot of progress in the last 5 to 10 years on surface-attached based monitors or other types of monitors that can be with patients for days, weeks and even months, and we're all grappling with this in clinical medicine, what to do with a person with 25 beats of an atrial tachycardia or 37 seconds on a 30-day monitor? It's all an issue of the density, the burden of arrhythmia, and we do believe there is some gradience in the risk of stroke ... You're right, the treatment is not obvious, but we should take our treatment for patients who are in atrial fibrillation a lot or all the time, and simply apply it upstream like, that we may have very different treatment or approaches that are more tailored to individual patient risk. Dr. Carolyn Lam:               Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff. We discussed a lot of other questions that need to be answered, but you've really opened the door to look at some of these questions with your paper today and we're really very proud to be publishing your paper in this week's journal.                                                 Thank you very much, listeners for joining us this week. 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. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.                                                 The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.                                                 They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.                                                 On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence.                                                  In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.                                                 The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.                                                 This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.                                                 All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.                                                 They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.                                                 In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.                                                 In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.                                                 The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.                                                 They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.                                                 Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.                                                 Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.                                                 The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.                                                 The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.                                                 These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.                                                 After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.                                                 These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.                                                 The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.                                                 As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.                                                 The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.                                                 Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.                                                 Those were your highlights. Now, for our featured discussion.                                                 On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.                                                 This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.                                                 Welcome Daniel. Dr. Daniel Singer:             Thank you for having me. Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana. Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here. Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found? Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.                                                 There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.                                                 While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.                                                 What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper. Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation. Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.                                                 Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.                                                 Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.                                                 If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"                                                 We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores. Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static. Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.                                                 We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.                                                 One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation. Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.                                                 Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts? Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.                                                 A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.                                                 I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well. Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.                                                 The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.                                                 We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.                                                 This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.                                                 I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror. Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.                                                 As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.                                                 If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.                                                 In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that? Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.                                                 At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.                                                 We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke. Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.                                                 I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.                                                 One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients. Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.                                                 Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings. Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.                                                 The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.                                                 I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid. Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.  

In this episode Dr. Clare Atzema, Dr. Nazanin Meshkat and Dr. Bryan Au discuss the presentation, etiology, precipitants, management and disposition of Atrial Fibrillation in the Emergency Department. The pros and cons of rate and rhythm control are debated, what you need to know about rate and rhythm control medications reviewed, and the strength of the Ottawa Aggressive Protocol discussed. The importance of appropriate anticoagulation is detailed, with a review of the CHADS-VASc score and whether to use Warfarin, Dabigatran or ASA for stroke prevention for patient with Atrial Fibrillation. We end off with a discussion on how to recognize and treat Wolff-Parkinson-White syndrome in the setting of Atrial Fibrillation.

In this episode Dr. Clare Atzema, Dr. Nazanin Meshkat and Dr. Bryan Au discuss the presentation, etiology, precipitants, management and disposition of Atrial Fibrillation in the Emergency Department. The pros and cons of rate and rhythm control are debated, what you need to know about rate and rhythm control medications reviewed, and the strength of the Ottawa Aggressive Protocol discussed. The importance of appropriate anticoagulation is detailed, with a review of the CHADS-VASc score and whether to use Warfarin, Dabigatran or ASA for stroke prevention for patient with Atrial Fibrillation. We end off with a discussion on how to recognize and treat Wolff-Parkinson-White syndrome in the setting of Atrial Fibrillation. The post Episode 20: Atrial Fibrillation appeared first on Emergency Medicine Cases.

As a bonus to Episode 20 on Atrial Fibrillation, we present here, Dr. Clare Atzema, a leading EM researcher in Atrial Fibrillation, telling her Best Case Ever related to Afib. What would you do if you needed to cardiovert a patient who was too obese to fit on an ED stretcher? Dr. Atzema, along with Dr. Nazanin Meshkat and Dr. Bryan Au, discuss the presentation, etiology, precipitants, management and disposition of Atrial Fibrillation in the Emergency Department. The pros and cons of rate vs rhythm control are debated, what you need to know about Afib medications, and the value of the Ottawa Aggressive Protocol discussed. The importance of appropriate anticoagulation is detailed, with a review of the CHADS-VASc score and whether to use anticogulants or ASA for stroke prevention for patients with Afib. We end off with a discussion on how to recognize and treat Wolff-Parkinson-White syndrome in the setting of Atrial Fibrillation. [wpfilebase tag=file id=382 tpl=emc-play /] [wpfilebase tag=file id=383 tpl=emc-mp3 /]

As a bonus to Episode 20 on Atrial Fibrillation, we present here, Dr. Clare Atzema, a leading EM researcher in Atrial Fibrillation, telling her Best Case Ever related to Afib. What would you do if you needed to cardiovert a patient who was too obese to fit on an ED stretcher? Dr. Atzema, along with Dr. Nazanin Meshkat and Dr. Bryan Au, discuss the presentation, etiology, precipitants, management and disposition of Atrial Fibrillation in the Emergency Department. The pros and cons of rate vs rhythm control are debated, what you need to know about Afib medications, and the value of the Ottawa Aggressive Protocol discussed. The importance of appropriate anticoagulation is detailed, with a review of the CHADS-VASc score and whether to use anticogulants or ASA for stroke prevention for patients with Afib. We end off with a discussion on how to recognize and treat Wolff-Parkinson-White syndrome in the setting of Atrial Fibrillation. [wpfilebase tag=file id=382 tpl=emc-play /] [wpfilebase tag=file id=383 tpl=emc-mp3 /] The post Best Case Ever 7: Atrial Fibrillation appeared first on Emergency Medicine Cases.