Podcasts about cha2ds2 vasc

Niraj Sharma, MD, FHRS, Northside Hospital is joined by Rhea Pimentel, BChir, MD, FHRS, University of Kansas Health System and Usman Siddiqui, MD, Florida Cardiology Advent Health Systems, Orlando, to discuss how the FLUTFIB study aimed to assess the incidence, duration, timing, and symptoms of atrial fibrillation (AF) after cavotricuspid isthmus (CTI) ablation in patients with atrial flutter (AFL). The study included 100 patients with AFL, who received implantable loop recorders for continuous AF monitoring following CTI ablation. Over a median follow-up of 24 months, 77% of patients experienced AF episodes, typically occurring around 180 days post-ablation. Most AF episodes lasted over an hour, and about half of the patients reported symptoms. Baseline characteristics and risk scores (HATCH and CHA2DS2-VASc) did not predict AF development. Oral anticoagulation was discontinued in 32% of patients during follow-up but was restarted in 15% after AF detection. No strokes or transient ischemic attacks were recorded. This study, the largest of its kind, underscores the high incidence of often asymptomatic AF after AFL ablation and provides insights for anticoagulation management post-ablation.   https://www.hrsonline.org/education/TheLead Host Disclosure(s): N. Sharma: Nothing to disclose.   Contributor Disclosure(s): U. Siddiqui: Honoraria/Speaking/Teaching: Abbott Medical, Acutus Medical Inc., Impulse Dynamics USA R. Pimentel: Honoraria/Speaking/Consulting: American College of Cardiology Foundation, Honoraria/Speaking/Teaching: Medtronic, Boston Scientific, Abbott Medical, Membership on Advisory Boards: Biosense Webster This episode has .25 ACE credits associated with it. If you want credit for listening to this episode, please visit the episode page on HRS365 https://www.heartrhythm365.org/URL/TheLeadEpisode74

Audio Commentary by Dr. Valentin Fuster, Emeritus Editor in Chief

In less than 15 minutes, Medmastery's Cardiology Digest will give you the low-down on some of the most compelling studies in cardiology that clinicians with an interest in cardiovascular health need to know about. STUDY #1: We kick things off by exploring exactly where the CHA2DS2-VASc score fits into anticoagulation decisions in patients with silent atrial fibrillation. Building on the main findings from the ARTESiA and NOAH-AFNET 6 trials, this study sparks a thought-provoking discussion on the future of risk stratification. Tune in to hear insights that could shape your clinical practice.  Lopes, RD, Granger, CB, Wojdyla, DM, et al. 2024. Apixaban versus aspirin according to CHA2DS2-VASc score in subclinical atrial fibrillation: Insights from ARTESiA. J Am Coll Cardiol. In Press, Journal Pre-proof. (https://doi.org/10.1016/j.jacc.2024.05.002) STUDY #2: Next, we break down misconceptions surrounding race and treatment efficacy in heart failure with reduced ejection fraction. This study shines a light on the impacts of renin-angiotensin system inhibition across different racial groups. See how these findings challenge the outdated genetic constructs of race, and what they mean for your approach to patient care. Shen, L, Lee, MM, Jhund, PS, et al. 2024. Revisiting race and the benefit of RAS blockade in heart failure: A meta-analysis of randomized clinical trials. JAMA. 24: 2094–2104. (https://doi.org/10.1001/jama.2024.6774) STUDY #3: Finally, we turn our focus to the V142I transthyretin gene variant, to evaluate its impacts on cardiovascular health within the U.S. Black population. This research not only highlights the need for targeted genetic screening but also raises important questions about the accessibility of costly treatments for transthyretin amyloidosis. Selvaraj, S, Claggett, B, Shah, SH,  et al. 2024. Cardiovascular burden of the V142I transthyretin variant. JAMA. 21: 1824–1833. (https://doi.org/10.1001/jama.2024.4467) Maurer, MS, Miller, EJ, Ruberg, FL, et al. 2024. Addressing health disparities—The case for variant transthyretin cardiac amyloidosis grows stronger. JAMA. 21: 1809–1811. (https://doi.org/10.1001/jama.2024.2868) Yancy, CW. 2024. Heart failure in African American individuals, Version 2.0. JJAMA. 21: 1807–1808. (https://doi.org/10.1001/jama.2024.5217) Don't miss out on this rich discussion that promises to enhance your understanding and expertise!  Learn more with these courses: Medical Treatment of Heart Failure (2 CME) Atrial Fibrillation Management Essentials (1 CME) Get a Basic or Pro account, or, get a Trial account. Show notes: Visit us at  https://www.medmastery.com/podcasts/cardiology-podcast.

FDA approves PFA, breakthrough in PAH, residual leaks after percutaneous LAAO, OAC in low to intermediate risk people are the topics John Mandrola, MD, discusses 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. FDA Approves PFA FDA Approves First Pulsed Field Ablation System for AF https://www.medscape.com/viewarticle/fda-approves-first-pulsed-field-ablation-system-af-2023a1000vit - PULSED AF https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.064329 - ADVENT Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2307291 - MANIFEST https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.064959 II. Pulmonary HTN Positive Topline Data for Sotatercept in PAH: STELLAR https://www.medscape.com/viewarticle/982407 - STELLAR https://www.nejm.org/doi/10.1056/NEJMoa2213558 - Editorial on STELLAR https://www.nejm.org/doi/full/10.1056/NEJMe2300324 III. Peri-Device Leaks - Greek Meta-analysis https://doi.org/10.1093/eurheartj/ehad828 IV. Intermediate Risk AF – Norwegian Study - Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study AFNOR Study https://doi.org/10.1093/eurheartj/ehad659 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 the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

CardioNerds (Dr. Daniel Ambinder, Dr. Giselle Suero Abreu, Dr. Kahtan Fadah, and Dr. Colin Blumenthal) discuss arrhythmias in CardioOncology with Dr. Michael Fradley. In this episode, Dr. Michael Fradley joins us in the CardioNerds CardioOncology clinic where he uses his unique dual training in cardio-oncology and electrophysiology to walk us through the complex interplay and management of these disorders. We discuss the incidence and pathophysiology of these arrhythmias, including the link with various cancer treatments, screening and detection, and complex management including rate vs rhythm control in atrial fibrillation, need for anticoagulation, effects on the QTc and so much more. Given the unique challenges with this population we also delve into how this affects their oncology care and how to approach changes to their cancer treatment. Show notes were drafted by Dr. Kahtan Fadah and episode audio was edited by student Dr. Tina Reddy. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Arrhythmias in CardioOncology Arrhythmias are common in cancer patients due to shared risk factors and bi-directional risk between cardiac and oncologic disorders. Many cancer therapeutics can be directly arrhythmogenic or lead to cardiotoxicities that pre-dispose to arrhythmias. Though incidence of arrhythmia can be significant increased with some cancer therapeutics (e.g. ibrutinib), there is not specific data to support proactive ambulatory monitoring for arrhythmia without evidence of clear symptoms. Atrial fibrillation is the most common arrhythmia in cancer patients and management of atrial fibrillation, as well as other tachyarrhythmias, is unchanged from management in non-cancer patients. General principles of when to start anticoagulation or rate vs rhythm control are not significantly different (e.g. still use CHA2DS2-VAsC, monitor for symptoms etc), but providers should be more mindful of drug-drug interactions with cancer therapeutics. Cancer therapeutics as well as common medications used to treat side effects or complications (e.g. antiemetics, antibiotics, etc) can prolong the QT interval and increase risk of Torsades de pointes (TdP). The QTc should be monitored with an ECG for patients on these medications. If a patient does develop a serious arrhythmia like TdP, management is similar to that in non-cancer patients. The goal of arrhythmia management in cardio-oncology is to prevent cardiovascular disease from becoming a barrier to appropriate cancer therapy. Though cancer therapeutics should be temporarily or permanently discontinued in potentially fatal events (e.g TdP from QTc prolonging meds), the overall goal is to manage the arrhythmias appropriately to allow cancer therapeutics to be continued or restarted. Show notes - Arrhythmias in CardioOncology What is the prevalence of arrhythmias in patients with cancer? Arrhythmias are common in patients with cancer due to a multitude of factors. Atrial fibrillation is the most common arrhythmia in this population and occurs in approximately 5% of patients with cancer. The driving forces are multifactorial and include the direct arrhythmogenic effects of cancer therapeutics and cardiotoxicities of cancer therapeutics that make arrhythmogenesis more likely. Additionally, there is a bi-directional link between cancer and cardiac disorders. For example, not only is atrial fibrillation more common in patien...

CardioNerds cofounder Dr. Daniel Ambinder, series co-chair Dr. Dinu Balanescu (FIT, Mayo Clinic), and episode lead Dr. Anjali Rao (FIT, UTSW) discuss training in cardio-oncology with Dr. Stephanie Feldman from Rutgers University. In this episode, the group discusses some of the most burning questions about educating the next wave of cardio-oncologists. As Dr. Feldman mentions, the projected number of cancer survivors is predicted to be around 24 million by 2024, underscoring the growing importance of cardio-oncology in our practice. We highlight some of the challenges facing trainees and training programs alike, including how to integrate cardio-oncology education into general cardiology training, the optimal structure for an advanced cardio-oncology fellowship, and the role of cardio-oncology in the inpatient setting. We also talk about the takeaways from the ACC Cardio-Oncology Leadership Council document. Dr. Feldman reflects on the importance of flexibility in education in the current landscape, drawing on her personal experience as a cardio-oncologist during the COVID-19 era. Notes were drafted by Dr. Anjali Rao. Audio editing was performed by student doctor, Shivani Reddy. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  Pearls • Notes • References • Production Team CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Cardio-Oncology: Training and Future Directions It may be possible to achieve “COCATS level 2” cardio-oncology training during general cardiology fellowship. A dedicated cardio-oncology year may appeal to trainees who want to achieve “COCATS level 3”, i.e., dedicate their practice to caring for patients with complex cardio-oncology needs, become involved in clinical trials, and lead cardio-oncology clinical and training programs. Supplemental learning opportunities for general fellows can include: Rotating in a cardio-oncology clinic, ideally attached to a National Cancer Institute-designated cancer center Multi-modality cardiac imaging Participating in cardio-oncology research Some currently available educational opportunities include:The International Cardio-Oncology Society (ICOS) weekly webinarsThe American Society of Echocardiography (ASE) webinars on global longitudinal strainThe American Society of Nuclear Cardiology lecture series on cardiac amyloidosis Cardio-oncology focused conferences, such as the American College of Cardiology's (ACC) Advancing the Cardiovascular Care of the Oncology Patient and Memorial Sloan Kettering's Cardio-Oncology Symposium. Each institution may have different inpatient cardio-oncology needs depending on whether there is a stand-alone cancer hospital or another format. Examples of inpatient consults that may benefit from having a cardio-oncologist involved include:Cardiovascular risk assessment prior to bone marrow transplant or cancer related surgery in a patient with known coronary artery diseaseImmune checkpoint inhibitor myocarditisChemotherapy-related cardiac dysfunction Management of systemic anticoagulation in a patient with high CHA2DS2-VASc and chemotherapy related thrombocytopenia. Show notes - Cardio-Oncology: Training and Future Directions The need for cardio-oncology experience is undeniable given the growing population of patients with cancer and cardiovascular disease, particularly given the number of anti-neoplastic therapies with potential cardiovascular side effects. There are several strategies for incorporating cardio-oncolo...

Dr. Daniel Ambinder (CardioNerds Co-Founder), Dr. Kelly Arps (Series Co-Chair and EP fellow at Duke University), Dr. Stephanie Fuentes Rojas (FIT Lead and EP fellow at Houston Methodist), and Dr. Ingrid Hsiung (Cardiology Fellow at Baylor Scott & White Health) discuss situational assessment of stroke and bleeding risk with expert faculty Dr. Hafiza Khan (Electrophysiologist at Baylor Scott & White Health). In this episode, we discuss stroke and bleeding risk in specific situations such as prior to cardioversion, triggered episodes, and perioperatively. These are scenarios that are commonly encountered and pose specific challenges. Episode notes were drafted by Dr. Stephanie Fuentes. Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian. This CardioNerds Atrial Fibrillation series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Kelly Arps and Dr. Colin Blumenthal. This series is supported by an educational grant from the Bristol Myers Squibb and Pfizer Alliance. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. We have collaborated with VCU Health to provide CME. Claim free CME here! Disclosures: Dr. Ellis discloses grant or research support from Boston Scientific, Abbott-St Jude, advisor for Atricure and Medtronic. CardioNerds Atrial Fibrillation PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Atrial Fibrillation: Situational Assessment of Stroke and Bleeding Risk In patients with persistent atrial fibrillation with tachycardia induced cardiomyopathy, timely restoration of normal rhythm is important. In patients not on established oral anticoagulation one option is to wait 3 weeks on oral anticoagulation prior to considering cardioversion. Another option is to pursue TEE prior to cardioversion as TEE is currently the gold standard imaging modality to exclude a LAA thrombus. Following cardioversion (chemical or electrical), anticoagulation must not be interrupted for 4 weeks due to atrial stunning. This is especially true for patients who have been in atrial fibrillation for an extended period of time. Individualizing assessment of stroke and bleeding risk is imperative when determining perioperative anticoagulation (AC) management. ACC has a helpful app (ManageAnticoag App) to make this easier. When considering AC in triggered atrial fibrillation (e.g., pneumonia, sepsis), it is important to consider the substrate that made the patient susceptible to developing atrial fibrillation. AC is favored in patients with high CHA2DS2-VAsC score and many traditional risk factors for atrial fibrillation as they are at high risk for future development of atrial fibrillation. Atrial fibrillation is a marker of poor outcomes in patients who have undergone coronary artery bypass graft (CABG) surgery. It is unclear if patients should be started on long-term AC for new onset atrial fibrillation after CABG regardless of risk factors. This is currently being investigated in the PACES trial. Notes - Atrial Fibrillation: Situational Assessment of Stroke and Bleeding Risk How do we choose an imaging modality for excluding LAA thrombus exclusion prior to cardioversion? TEE is the gold standard. It also provides other information that is important for management of atrial fibrillation (e.g. LA size/volume, presence/degree of mitral regurgitation/stenosis, ejection fraction). Gated cardiac CTA may have a growing role for evaluation of LAA thrombus. What is the data behind the recommendation for uninterrupted AC following cardioversion and what is atrial stunning? All patients should be anticoagulated for four weeks after cardioversion,

Commentary by Dr. Teresa Lopez Fernandez

The following question refers to Section 7.7 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by St. George's University medical student and CardioNerds Intern Chelsea Tweneboah, answered first by Baylor College of Medicine Cardiology Fellow and CardioNerds Ambassador Dr. Jamal Mahar, and then by expert faculty Dr. Michelle Kittleson. Dr. Kittleson is Director of Education in Heart Failure and Transplantation, Director of Heart Failure Research, and Professor of Medicine at the Smidt Heart Institute, Cedars-Sinai. She is Deputy Editor of the Journal of Heart and Lung Transplantation, on Guideline Writing Committees for the American College of Cardiology (ACC)/American Heart Association, is the Co Editor-in-Chief for the ACC Heart Failure Self-Assessment Program, and on the Board of Directors for the Heart Failure Society of America. Her Clinician's Guide to the 2022 Heart Failure guidelines, published in the Journal of Cardiac Failure, are a must-read for everyone! The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #10 Ms. Heffpefner is a 54-year-old woman who comes to your office for a routine visit. She does report increased fatigue and dyspnea on exertion without new orthopnea or extremity edema. She was previously diagnosed with type 2 diabetes, morbid obesity, obstructive sleep apnea, and TIA. She is currently prescribed metformin 1000mg twice daily, aspirin 81mg daily, rosuvastatin 40mg nightly, and furosemide 40mg daily. In clinic, her BP is 140/85 mmHg, HR is 110/min (rhythm irregularly irregular, found to be atrial fibrillation on ECG), and BMI is 43 kg/m2. Transthoracic echo shows an LVEF of 60%, moderate LV hypertrophy, moderate LA enlargement, and grade 2 diastolic dysfunction with no significant valvulopathy. What is the best next step? A Provide reassurance B Refer for gastric bypass C Refer for atrial fibrillation ablation D Start metoprolol and apixaban Answer #10 Explanation The correct answer is D – start metoprolol and apixaban. Ms. Hefpeffner has a new diagnosis of atrial fibrillation (AF) and has a significantly elevated risk for embolic stroke based on her CHA2DS2-VASc score of 6 (hypertension, diabetes, heart failure, prior TIA, and female sex). The relationship between AF and HF is complex and they the presence of either worsens the status of the other. Managing AF in patients with HFpEF can lead to symptom improvement (Class 2a, LOR C-EO). However, large, randomized trial data are unavailable to specifically guide therapy in patients with AF and HFpEF. Generally, management of AF involves stroke prevention, rate and/or rhythm control, and lifestyle / risk-factor modification. With regards to stroke prevention, patients with chronic HF with permanent-persistent-paroxysmal AF and a CHA2DS2-VASc score of ≥2 (for men) and ≥3 (for women) should receive chronic anticoagulant therapy (Class 1, LOE A). When anticoagulation is used in chronic HF patients with AF, DOAC is recommended over warfarin in eligible patients (Class 1, LOE A). The decision for rate versus rhythm control should be individualized and reflects both patient symptoms and the likelihood of better ventricular function with sinus rhythm. For patients with HF and symptoms caused by AF, AF ablation is reasonable to improve symptoms and QOL (Class 2a,

On Episode 24 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2023 issue of Stroke: “Covert Brain Infarction as a Risk Factor for Stroke Recurrence in Patients With Atrial Fibrillation” and “Subarachnoid Hemorrhage During Pregnancy and Puerperium.” She also interviews Dr. Georgios Tsivgoulis about his article “Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis.” Dr. Negar Asdaghi:         Let's start with some questions. 1) When during pregnancy is an intracranial aneurysm at the highest risk of rupture? 2) What does the presence of covert brain infarcts mean in the setting of atrial fibrillation? 3) And, finally, how is the inflammatory form of cerebral amyloid angiopathy different from the classic CAA form, and why is it important to differentiate between the two? We'll be answering these questions and much more in today's podcast. We're covering the latest in cerebrovascular disorders, and this is the best in Stroke. Stay with us. Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. Together with my co-editors, Drs. Nastajjia Krementz and Eric Goldstein, here's our article selection for the month of January. Symptomatic intracerebral hemorrhage is a feared complication of reperfusion therapies in acute stroke, so there's a lot of interest in looking for predictors of development of this complication, especially when you're making decisions for pursuing endovascular therapy. For many years now, we've known about some of these predictors, such as presence of a large infarct core and high blood glucose levels. But in the recent years, other radiographic markers of tissue viability, such as a poor collateral status and unfavorable venous outflow profile, have been shown to be predictors of post-reperfusion hemorrhagic transformation. In this issue of the journal, we learn about another imaging marker that can potentially predict parenchymal hemorrhage occurrence post-endovascular therapy, which is high hypoperfusion intensity ratio, or HIR, as measured by perfusion imaging. What is HIR? It's a long name for a simple ratio that can easily be measured by dividing the volume of tissue with Tmax delay of over 10 seconds to the volume of tissue with Tmax delays of over 6 seconds. Simply put, Tmax 10 divided by Tmax 6. These volumes, as you know, are typically provided to us by almost all post-processing perfusion softwares, and so this ratio can be easily calculated in the acute setting. So, in this paper led by Dr. Tobias Faizy from University Medical Center in Hamburg and colleagues, we learned that higher hypoperfusion intensity ratios are strongly associated with parenchymal hemorrhage occurrence after endovascular therapy. So, in summary, HIR, that is a quantitative ratio, can be used as a marker to risk stratify patients that are undergoing endovascular therapy in terms of helping us predicting the risk of development of intracerebral hemorrhage after reperfusion therapies. In a separate study in this issue of the journal, we read a very interesting paper titled "Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk." How are intracranial aneurysms even related to anti-epileptic drugs? Well, first of all, it's been known for a long time based on genome-wide association studies that there are multiple common genes that are associated with increased risk of intracranial aneurysm development. Now, some of the largest genetic studies to date have shown pleiotropy between genetic causes of development of intracranial aneurysms and genes encoding targets for anti-epileptic drugs. Now that's a fascinating finding because finding commonalities between these genes may help find new treatment targets for intracranial aneurysms. So, in this paper in this issue of the journal, the investigators from the University Medical Center in Utrecht found an association in the expression of anti-epileptic drug target gene CNNM2 and intracranial aneurysm risk. They found that certain anti-epileptic drugs, such as phenytoin, valproic acid, and carbamazepine, that are expected to lower CNNM2 levels in the blood may subsequently lead to a lower risk of development of intracranial aneurysms. And, of course, a reasonable follow-up study to this would be to investigate whether persons exposed to these anti-epileptic drugs have indeed a lower risk of unruptured intracranial aneurysms and subarachnoid hemorrhage, and how variation in CNNM2 expression can lead to development of aneurysms. Bottom line, CNNM2 may be a relevant drug target for treatment of cerebral aneurysms. As always, I encourage you to review these papers in detail in addition to listening to our podcast today. My guest on the podcast today is the Chairman of Neurology at the University of Athens, Dr. Georgios Tsivgoulis. He joins me all the way from Greece to talk about cerebral amyloid angiopathy-related inflammation, or CAA-ri. He's a remarkable researcher, and I can say with absolute confidence that we cannot find a better summary of this very tough topic elsewhere. He ends the interview with an intriguing account of the early description of dementia in Greek mythology. But first, with these two articles. What are covert brain infarcts, or CBIs? Are these the John Wick or the James Bond of the stroke world? After all, they operate undercover. They're ominous and attack without warning. That's probably why they're also called silent infarcts. Now, whatever we call them, we need to know how prevalent they are and what does their presence actually mean. Let's dive into this topic. For at least two centuries, if not longer, we've known about covert brain infarcts. Early description of these lesions is credited to Amédée Dechambre, a medical intern at Salpêtrière Hospital in Paris who noted that there are strokes that can cause symptoms like hemiplegia, but also strokes that are asymptomatic, or so he thought at the time. In the modern times, while we agree with our pathology forefathers that CBIs are different from symptomatic strokes, we also know that they are not entirely asymptomatic. The symptoms can be subtle and tend to sneak up on the patient, but what is clear is that amassing of covert brain infarcts results in an overall decline in cerebrovascular reserve of the brain. With the advent of neuroimaging, we now know that CBIs are age-dependent and prevalent, seen in almost 10 to 30% of even healthy adults, but much more prevalent in those with vascular risk factors, and they can be caused by nearly the entire spectrum of neurovascular disease, including large vessel, small vessel disorders, cardioembolism, and others. Now, how do these covert infarcts catch up in those with atrial fibrillation? Neuroimaging studies have shown that patients with A-fib, especially those untreated, have a higher percentage of embolic-appearing CBIs, and conversely, those with embolic formed pattern of CBIs are more likely to have undiagnosed A-fib. So the question is, what's the significance of CBI in those with confirmed A-fib? In this issue of the journal, Dr. Do Yeon Kim from Seoul National University and colleagues help us answer this question using the EAST-AF, which stands for East Asian Ischemic Stroke Patients With Atrial Fibrillation Study. So, the paper included over 1300 patients with A-fib and first-ever stroke without a prior history of TIA or stroke. And then they categorized these patients into those who had evidence of CBI on neuroimaging and those who didn't. So, what did they find? Forty-two percent of patients with A-fib and first-ever stroke had evidence of covert brain infarcts on neuroimaging. Let's think about it for a moment. These patients presented with what was thought to be their first-ever stroke, not knowing they already had some in their brain. Now, what makes things really worse is that over a quarter of these subjects had more than just one covert infarct. Not surprisingly, those with CBI tended to be older, had higher blood pressure, and had worse white matter hyperintensity burden. This is kind of expected and also not expected was the fact that most of these covert infarcts were actually embolic in pattern. Over 60% of them were embolic. Another 14% of cases had combined embolic and non-embolic-appearing CBIs. Now, overall, the one-year incidence of ischemic stroke and all-cause mortality was higher in those that had CBIs at baseline. When they started looking at the specific patterns of CBIs, those embolic-appearing CBIs had a threefold higher risk of recurrent ischemic stroke, whereas those with non-embolic-appearing covert infarcts had oddly a higher all-cause mortality rate but not recurrent ischemic stroke. And finally, just briefly, the authors noted that the addition of CBIs to the classic CHA2DS2-VASc score didn't meaningfully otherwise statistically improve the scoring metrics, so they left it at that. So, the take-home message is that 42% of A-fib patients presenting with first-ever stroke actually had prior strokes without even knowing based on this study. And most of these strokes were embolic-appearing, and these covert brain infarcts can be used as predictors of future clinical strokes in this population. Strokes should be the last thing to worry about when we think of pregnancy. In the United States, around 30 in 100,000 women, unfortunately, experienced a stroke during pregnancy, and between 6 to 8 in 100,000 deliveries are complicated by subarachnoid hemorrhage. What's the most common cause of pregnancy-associated subarachnoid hemorrhage? In the general population, close to 80% of subarachnoid hemorrhage cases are aneurysmal. Is this true for the pregnant population as well? And importantly, what's the contemporary incidence trend, risk factors, and outcomes of pregnancy-related subarachnoid hemorrhage? In this issue of the journal, Dr. Korhonen and Petra [Ijäs] and their colleagues from the Departments of Neurology and Obstetrics and Gynecology at Helsinki University Hospital will give us the answers to some of these questions through a nationwide population-based study in Finland. So, they looked at over one and a half million pregnant women who gave birth during a 30-year time period between 1987 to 2016. Subarachnoid hemorrhage was identified through appropriate ICD codes and then further adjudicated based on confirmatory information, including neuroimaging and data from lumbar puncture. A total of 57 cases of pregnancy-related subarachnoid hemorrhage was identified in this paper. The mean age of women was 33, ranging from 23 to 45, and the clinical presentation was typical for subarachnoid hemorrhage, including thunderclap headache and mild neurological symptoms. So, what did they find? So, first off, in terms of general observations, the overall incidence rate of pregnancy-related subarachnoid hemorrhage in this study was 3 over 100,000 deliveries. This is almost half the incidence rate reported from the nationwide registries in the United States. Seventy-seven percent of pregnancy-related subarachnoid hemorrhage cases were aneurysmal, so very similar to the general population. The other 23% were non-aneurysmal cases, but it's important to note that 40% of those non-aneurysmal cases also had vascular etiologies, so etiologies such as moyamoya syndrome, postpartum angiopathy, AVM, to name a few. Like non-pregnant patients with subarachnoid hemorrhage, the aneurysmal cases were sicker patients in general. They had a lower GCS at presentation, higher Hunt and Hess scores, and required more ICU admissions. The next finding is very important because it actually shows that development of subarachnoid hemorrhage during pregnancy significantly impacted obstetrical care. A total of 66% of women with subarachnoid hemorrhage during pregnancy ended up having a C-section and a high percentage of these cesarean sections were actually elective. This is in contrast with subarachnoid hemorrhages in the postpartum period where 67% of women had spontaneous vaginal deliveries. The other important finding of the paper was really highlighting the differences between pregnancy-related aneurysmal versus non-aneurysmal subarachnoid hemorrhages. We already talked about how, in general, aneurysmal cases had more severe neurological presentations, so, not surprisingly, they also had worse outcomes with a mortality rate of 16% for the aneurysmal subarachnoid hemorrhage cases, and only 68% of women with pregnancy-related aneurysmal subarachnoid hemorrhage reached a favorable outcome, which was defined in this study as modified Rankin Scale of 0 to 2. Other important differences included the fact that the incidence of aneurysmal subarachnoid hemorrhage increased towards the end of pregnancy and was highest in the third trimester. This ties in with the findings from prior studies all indicating that rupture of an aneurysm is most common in the third trimester. By contrast, the incidence of non-aneurysmal subarachnoid hemorrhage peaked in the second trimester in this study. And finally, in terms of risk factors, first let's talk about age. The incidence rate of pregnancy-associated subarachnoid hemorrhage increased with age of the mother. So, in this study, there were no cases noted amongst women aged below 20 years of age to an incident rate of 12 per 100,000 deliveries among women aged 40 years or over. So that's a fourfold increase from the overall incidence rate of pregnancy-related subarachnoid hemorrhage, and very important point that we learned from this paper. Apart from age, smoking beyond 12 weeks of gestation and hypertension were also independent factors associated with pregnancy-related subarachnoid hemorrhage. So, overall, hypertension, smoking are bad and are significant risk factors for pregnancy-related subarachnoid hemorrhage. And if we have to remember just one thing from this paper, let it be this one: The rupture of an aneurysm is most common in the third trimester of pregnancy. Cerebral amyloid angiopathy, or CAA, is an important cause of intracranial hemorrhage and refers to deposition of β-amyloid fibrils in the wall of the small- and medium-sized cerebral blood vessels, mostly involving cortical and leptomeningeal arteries. It is believed that the deposition of β-amyloid results in architectural disruption of the blood vessels, which then leads to perivascular leakage. That's the pathophysiological mechanism behind the development of cerebral microbleeds. And this process, of course, can cause frank vascular rupture resulting in cortical intracerebral hemorrhage or development of high-convexity subarachnoid hemorrhages. It is important to note that varying amounts of perivascular inflammation, that is inflammation surrounding β-amyloid-laden blood vessels, may be present in some CAA cases, rendering them the designation of inflammation-related CAA. However, frank vasculitic destruction of the vessel wall, such as what is found in amyloid-β-related angiitis, or ABRA, and primary angiitis of the central nervous system, is usually absent in most CAA-related inflammation cases. How these entities are best defined, diagnosed, and treated is subject of intense research. In this issue of the journal, in the study titled "Clinical, Neuroimaging, and Genetic Markers in CAA-Related Inflammation," Dr. Georgios Tsivgoulis and colleagues take us through a systematic review and meta-analysis of published studies of patients with CAA-related inflammation. I am joined today by Dr. Tsivgoulis himself to discuss this paper. He's a Professor of Neurology and Chairman of the Second Department of Neurology at the University of Athens School of Medicine. Dr. Tsivgoulis is the residency program director and the director of cerebrovascular fellowship program with extensive research and expertise in the field of stroke. Good morning, Georgios, and welcome to our podcast. Dr. Georgios Tsivgoulis: Good morning, Negar. I'm delighted to be here and delighted to present our findings, on behalf of all our co-authors. Dr. Negar Asdaghi:         Thank you very much for being here and congrats again on the paper. So, Georgios, let's start with this interest that's going on with using clinical and radiographic features to make the diagnosis of CAA-related inflammation in contrast to moving ahead and performing brain biopsy. Can you please start us off with a brief review of the newly proposed clinico-radiographic criteria for this condition, please? Dr. Georgios Tsivgoulis: Yes. As you mentioned, Negar, CAA-ri is a distinct, however, rare subset of cerebral amyloid angiopathy. Firstly, Greenberg and the Boston group published in Neurology in 2007 a paper highlighting that a diagnosis of a probable CAA-ri patient could be made on the basis of characteristic clinical and neuroimaging findings without requiring a biopsy. Following this observation, Chung and colleagues in 2010, in a seminal paper in JNNP, proposed the first diagnostic criteria for probable and definite CAA-ri. For the definite diagnosis, besides the typical clinical presentation with headache, encephalopathy, focal neurological signs and seizures, and the characteristic neuroimaging findings with T2 or FLAIR hyperintense asymmetric white matter lesions complicated with microbleeds and leptomeningeal or parenchymal gadolinium enhancement, and histopathological confirmation with amyloid deposition within cortical leptomeningeal vessels associated with perivascular, transmural or intramural inflammation was also required. The latest criteria developed in 2015 by Auriel and colleagues that were published in JAMA Neurology using a validation study modified the current criteria for the diagnosis of CAA-ri. In this paper, the author supported the use of empirical immunosuppressive therapy, avoiding brain biopsy, for patients meeting the criteria proposed for probable CAA-ri. They suggested that a brain biopsy should be considered in empirically treated patients who failed to respond to corticosteroid therapy within three weeks. The criteria by Auriel and colleagues are widely applicable in everyday clinical practice, and we also use this criteria for the inclusion of studies in our current meta-analysis. I would like to highlight for our audience that the latest criteria for CAA-ri were published in 2015 by Auriel and colleagues. However, these are different for the criteria for cerebral amyloid angiopathy than the latest criteria were published in 2022 in Lancet Neurology, OK? Dr. Negar Asdaghi:         Georgios, that was a great start for this interview. You had mentioned a lot of information here. I just want to highlight what you just said. So, we are using for this meta-analysis, the latest criteria in CAA-related inflammation published in JAMA by Auriel and colleagues. That's slightly different than, we're not referring to the 2022 criteria of cerebral amyloid angiopathy. It's an important distinction. We're going to talk about this a little more as we go through the interview, but I want to come back to your current paper and start from there. Can you please tell us about the importance of this paper, why doing a meta-analysis was important in your view, and tell us a little bit about the studies that were included in your paper? Dr. Georgios Tsivgoulis: Yes, thank you for that question. CAA-ri is an increasingly recognized entity since the recent diagnostic criteria by Auriel and colleagues published in 2015. In collaboration with the greater availability of the high-resolution MR, we can have now a reliable non-invasive diagnosis of possible or probable CAA-ri, avoiding the risk of brain biopsy. However, I need to highlight that the early diagnosis remains a great challenge for the clinicians and neurologists. Searching the literature, we observe that there is scarce data regarding the prevalence of the distinct clinical, neuroimaging, and genetic markers among patients diagnosed with CAA-ri. We believe that pooling all this information in the current meta-analysis would be very helpful for every clinician, increasing a comprehensive understanding of this rare cerebrovascular disorder. Consequently, we conducted this meta-analysis including 21 studies that recruited a total of 378 patients with CAA-ri. Our study involved only 4 prospective and 17 retrospective hospital-based cohorts of patients diagnosed with CAA-ri based on autopsy or biopsy or on the recent Auriel diagnostic criteria that do not require autopsy or biopsy. Due to limited data in the literature regarding this entity, we had to include only small cohort studies with at least five patients in our meta-analysis. We excluded case reports and case series with less than five patients. This is, by far, the largest available sample of CAA-ri patients in the literature. Dr. Negar Asdaghi:         OK, great. So, let me just recap this, more so for myself. So, we have 21 studies, and you excluded studies that included less than 5 patients. So, practically speaking, case reports. Dr. Georgios Tsivgoulis: Yes, and single-case reports. Dr. Negar Asdaghi:         Yes. And practically speaking, of the total number of patients that are included in this meta-analysis, you have 378 cases, and basically the diagnosis of CAA-related inflammation was either based on the newly proposed criteria or based on biopsy-confirmed or autopsy cases. Dr. Georgios Tsivgoulis: Which is the standard criteria. Dr. Negar Asdaghi:         So, now, I'm dying to ask you about these clinical and radiographic characteristics of patients with CAA-related inflammation in this meta-analysis. Dr. Georgios Tsivgoulis: The mean age of patients in the included studies was approximately 72 years old, and there was no obvious gender predominance. Fifty-two percent of the patients were of female sex. In our study, 70% of the included patients presented with cognitive decline, which was the most common neurological manifestation, while 50% of the total sample had focal neurological signs and 54% encephalopathy presentation. Symptoms such as headache and seizures were less common, 37 and 31% respectively. With regard to the radiological findings, hyperintense T2 FLAIR white matter lesions were very, very common in 98% of our patients, and they were also complicated with lobar cerebral microbleeds, with a prevalence of 96%, and these two were, by far, the most prevalent neuroimaging findings, that white matter hyperintensities coupled with a cerebral microbleed. The pooled prevalence rates of gadolinium-enhanced lesions was 54%, and also the prevalence of cortical superficial siderosis was 51%, which is also very high in this cohort of patients with CAA-ri. Dr. Negar Asdaghi:         OK. So many of the features Georgios said, you mentioned, from presence of white matter hyperintense lesions on T2 FLAIR to presence of cortical microbleeds or superficial siderosis, these features are also seen in patients with cerebral amyloid angiopathy. What are some of the important differentiating features between the two conditions? Dr. Georgios Tsivgoulis: Yes, this is an excellent clinical question. First of all, the lower age threshold for CAA-ri is 40 years old, whereas in cerebral amyloid angiopathy, the lower age threshold is 50 years. So, patients who are younger than 50 years can be diagnosed with CAA-ri, but they cannot be diagnosed with CAA. Another issue is that comparing the result of this meta-analysis with another recent meta-analysis focusing on CAA, on cerebral amyloid angiopathy, that our international multi-collaborative group published in Stroke in 2002, we also evaluated the presence of clinical phenotypes and radiological markers among patients with cerebral amyloid angiopathy. We have documented that transient focal neurological episodes are much more common in patients with cerebral amyloid angiopathy in contrast to patients with CAA-ri. These episodes, which are called TFNEs, transient focal neurological episodes, are attributed to cortical subarachnoid hemorrhage or cortical superficial siderosis. So, I think this is another important clinical distinction. The most important, however, differentiating features between the two entities are neuroimaging markers, in specific, in particular, T2 FLAIR hyperintense unifocal or multifocal lesions with mass effect. These are the most prevalent neuroimaging features among patients with CAA-ri, but they're very seldomly described in patients with cerebral amyloid angiopathy, in patients with CAA. Another characteristic neuroimaging finding very indicative of the inflammation is the leptomeningeal or parenchymal gadolinium enhancement. This finding has been very rarely described in patients with non-inflammatory cerebral amyloid angiopathy. So, the clinical distinction is not so solid. However, the neuroimaging distinction would provide us with very strong information that can help us differentiate these two conditions. Dr. Negar Asdaghi:         Excellent points, I have to say, golden points, not just excellent points. I'm going to try to recap this and see if I understood it correctly. So, for our listeners, we have two conditions that potentially have many common points. One is the cerebral amyloid angiopathy, and the second one, which is obviously the subject of this interview, is cerebral amyloid angiopathy-related inflammation. The most important differentiating factors between the two are actually the neuroimaging features, as Georgios mentioned. So, the first feature that was mentioned is presence of T2 FLAIR hyperintense lesions. Some of them are large and have actually mass effects. This feature is rarely seen in patients with CAA, and it's an important radiographic factor that is seen in patients with CAA-related inflammation. The second distinguishing feature was leptomeningeal enhancement, again, rarely seen in non-inflammatory CAA, but was seen in a significant proportion of patients with CAA-related inflammation. These were the neuroimaging features. You also mentioned two other factors. The median age of CAA-related inflammation was lower than CAA. That can be helpful. And also the entity of transient focal neurological episodes, or TFNE, is rarely seen in inflammatory cases of CAA, whereas it is described in cases with cerebral amyloid angiopathy and mostly related to development of either cortical subarachnoid hemorrhage or cortical superficial siderosis. I think I got this all, correct? Dr. Georgios Tsivgoulis: Excellent. Dr. Negar Asdaghi:         All right, so let's come now to the genetics of CAA. The apolipoprotein E gene is associated with the presence of amyloid angiopathy and development of lobar intracerebral hemorrhage, and we've learned about this in cases with cerebral amyloid angiopathy. Is there an association with ApoE, and did you find anything in this meta-analysis? Dr. Georgios Tsivgoulis: Another very exciting question. In 2007, there was a first report that the apolipoprotein ε4 homozygosity may be considered a risk factor for CAA-ri, and there was a strong correlation reporting a high prevalence of 77% of this apolipoprotein ε4 alleles among patients with CAA-ri. To justify this correlation, the hypothesis was that an underlying pathogenic mechanism, which increases the amyloid-β deposition and has a pro-inflammatory effect, may be suspected as the cause of this disorder. The largest, however, prospective cohort of CAA-ri patients conducted by Antolini and colleagues and was published in 2021 in Neurology, reported a much lower prevalence of apolipoprotein ε4 carriers accounting for 37%, 23% heterozygotes and 14% homozygotes. So, we also documented a pool prevalence of apolipoprotein ε4 homozygosity of 34%. So, we did not confirm the initial finding of 77%. However, in our meta-analysis, the homozygosity was 34%, and we need to have a cautious interpretation of these results because data is limited, and we need larger future population-based studies and in larger cohorts to evaluate the prevalence rate of these specific genetic markers. So, we can confirm an association between apolipoprotein ε4 homozygosity, however not as strong as originally reported in 2007. Dr. Negar Asdaghi:         OK. So, Georgios, thank you. And again, very important factor to keep in mind for our clinicians listening in. Unfortunately, based on what you mentioned, we don't have yet a genetic marker to, for sure, tell us if we're dealing with CAA-related inflammation, yes or no, as you mentioned. Just to recap, earlier on, there was studies to suggest a very strong association between apolipoprotein ε4 homozygosity and CAA-related inflammation. But later on, this was not confirmed by subsequent studies, and in your meta-analysis, you found 34% ApoE ε4 homozygosity amongst patients with CAA-related inflammation and could not confirm that original high association. OK, so with all of that, it's a lot of information. I have to go to the next question regarding controversies involving the levels of Aβ40, Aβ42, and P-tau proteins in CSF in the setting of CAA-related inflammation. Can you please tell us more about these biomarkers? Dr. Georgios Tsivgoulis: Yes. The overlap of Alzheimer's disease and CAA can be attributed to the coexistence of some degree of cerebrovascular amyloid deposition and amyloid plaque pathology, which is very common. And, of course, the evaluation of amyloid and tau proteins in CSF is of high significance for the prognosis and the evolution of CAA patients. In our previous review, we have summarized the literature and noticed that CSF concentrations of Aβ40 and, secondarily, Aβ42 were much lower in patients with cerebral amyloid angiopathy compared with Alzheimer's disease. Total tau and phospho-tau CSF levels were comparable to healthy controls in CAA and lower than patients with Alzheimer's disease. Moving now to CAA-ri, there were scarce data about these biomarkers amongst CAA-ri patients. The majority of the relevant studies have found relatively low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau. In the present meta-analysis, the pooled means of biomarker levels were based on the findings of only two studies with heterogeneity, and these limit substantially the validity of our observations. However, they confirm the previous reports indicating, as I said before, but I would like to repeat, low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau. Dr. Negar Asdaghi:         Perfect. So, thank you, Georgios. I'm going to recap what you said. So, we're talking about CSF biomarkers, and first what you mentioned is going back to the original studies concentrated on using these biomarkers as ways of differentiating between cerebral amyloid angiopathy and Alzheimer's disease. And very briefly, to recap what you said, in general, the levels of Aβ40 and, secondarily, Aβ42 was found to be much lower than the Alzheimer's levels in patients with CAA. Now coming to the inflammatory form of CAA, what you mentioned and what you found in this meta-analysis, practically speaking, confirmed that the levels of Aβ40 and Aβ42 in CSF are low and the levels of P-tau are high in this condition as well. So, one thing I want to ask as a secondary question to that is, that it sounds like these biomarkers are more or less similar in CAA and CAA -related inflammation, not that different. Is that correct? Dr. Georgios Tsivgoulis: It's absolutely correct. And I would also like to highlight a major limitation of the meta-analysis that we had available data from only two studies to pool the mean of these CSF biomarker levels. So, these results need to be acknowledged with caution, and we would love to repeat our meta-analysis after the publication of more studies and prospective cohorts measuring the CSF biomarkers in patients with CAA-ri. Dr. Negar Asdaghi:         OK. So, again, important to note, as you mentioned, that there's heterogeneity in data because of just paucity of information on this, but as we stand today, the biomarkers won't really help us in terms of differentiating between the two conditions that are CAA or CAA-related inflammation. And so, I think I've learned a lot from this interview myself, but I think we have to just talk briefly about the available therapies for CAA-related inflammation. Dr. Georgios Tsivgoulis: Yes. In our meta-analysis, we sought to summarize the available information regarding different therapeutic strategies and outcomes among CAA-ri patients. Our results supported our clinical experience indicating that corticosteroids represent the first-line treatment in these patients' outlook. Steroids have been associated with clinical and radiological improvement of the primary disease episode and decreased risk of subsequent relapses in patients with CAA-ri. Additional immunosuppressive therapies, including cyclophosphamide, mycophenolate mofetil, azathioprine, IVIG, or rituximab, have been also reported as adjunct therapies in selected cases with a more severe course of the disease. However, this is another limitation that needs to be acknowledged. That data regarding the treatment and the outcomes are limited and heterogeneous, which prevented us from drawing robust conclusions using a meta-analytical approach. And we believe that we need future cohort studies with prospective data validation in order to generate a proposal for a therapeutic algorithm management in these cases. Dr. Negar Asdaghi:         Thank you, Georgios. So, we have a condition that is now being more and more recognized. We now have criteria based on clinical and radiographic presentation features of patients that might help us with this diagnosis to differentiate it from cerebral amyloid angiopathy. And in terms of therapies, the idea is that the most studied drug is really just first-line therapy, that's corticosteroids. And then there's positive data regarding use of all other forms of immunosuppression, including, as you mentioned, cyclophosphamide, rituximab, and oral agents such as mycophenolate mofetil or azathioprine. We have limited information about those, but I want to highlight something you actually mentioned earlier on in the interview, which is the field is moving towards making these diagnoses based on clinical features and radiographic features that you had highlighted and actually giving patients immunosuppression early on and only move on to a biopsy if the patient had failed these therapies for a period of time, which you mentioned three weeks. So, I think it's important for us as clinicians to keep this evolving criterion and recommendations in mind. And before we end, I want to ask you a hypothetical question, Georgios. In your opinion, what's an ideal randomized trial for CAA-related inflammation in the future? Dr. Georgios Tsivgoulis: I think before going to the randomized, the ideal randomized trial for CAA-ri, and designing this trial, we need much more information regarding the underlying pathophysiological mechanisms. There are many unanswered questions. What is the diagnostic value of CSF biomarkers such as amyloid, we discussed earlier, and tau protein? And, of course, what is the value of CSF and the amyloid-β autoantibodies, if there is any? What is the value of genetic markers such as apolipoprotein E genotype and a correlation with the co-existing inflammation in CAA-ri? However, I don't want to defer this question. So, a typical answer would be that with regard to the ideal patients, we would want a young patient without comorbidities after the first manifestation of CAA-ri who has shown a good clinical and radiological response to corticosteroids in order to define the best second-line therapy. However, before answering all these questions in a clinical trial, if we can, I think that we need to understand the CSF and genetic biomarkers in order to uncover mechanisms regarding pathophysiology that can help us to design more targeted clinical trials studying novel disease-modifying treatments. Dr. Negar Asdaghi:         Thank you. Dr. Georgios, it's been a pleasure having you on the podcast, and I can say we've learned a lot. We look forward to having you back here and talk about that hypothetical randomized trial, and I'm sure one day hopefully will happen in our lifetime. Thank you for being here. Dr. Georgios Tsivgoulis: Thank you. Thank you for having me. It was a pleasure. Dr. Negar Asdaghi:         Thank you. Homer, the legendary Greek poet, described a case of dementia in his seminal work, The Odyssey, in the late eighth century before Christ. He described the cognitive decline of Odysseus's father, King Laertes. The detailed account of the king's mental decline, loss of short-term memory with retention of long-term memory combined with his depression and despair over the loss of his son, is dramatically accurate for a nearly 3,000-year-old description of dementia. Before I ended the interview, I had to use this opportunity to ask Georgios about lessons learned from ancient Greeks and this seemingly timeless disease. Dr. Georgios Tsivgoulis: Thank you for this question. King Laertes was indeed Odysseus's father, and it's a great paradigm describing dementia. However, the ancient history of dementia may be separated according to the Greek philosopher Posidonius in two periods. The first period is called dementia appearing due to old age, which is called in Greek, eros. And the second one is dementia appearing in other ages and mainly due to other reasons, called morosis. Posidonius of Rhodes was a Greek stoic philosopher of the second first century BC who strongly believed and suggested that morosis, which is that dementia appearing in younger ages due to other disorders, should be treated immediately after its onset. So, if I would like to end this podcast, I would just suggest that CAA-ri could be classified as morosis according to Posidonius. And what we could learn is that the early diagnosis is essential since the prompt initiation of corticosteroids should not be unreasonably delayed. Dr. Negar Asdaghi:         And this concludes our podcast for the January 2023 issue of Stroke. Please be sure to check this month's table of contents for the full list of publications, including a series of Focused Updates on post-stroke neurological recovery, from management of post-stroke attention deficit, neglect and apraxia to post-stroke memory decline. And with this, we end the start of our 2023 podcast series. Like all new things, a new beginning can come with new directions, and sometimes a new direction is all that we need. After all, as the legend has it, it was a direction of that falling apple back in the year 1666 that gave Isaac Newton the idea of the universal law of gravitation. Now, Isaac Newton has, without a doubt, given science some of its biggest discoveries in mathematics, physics, and astronomy. But most may not know that Newton had a pretty rough start in life. A January-born premature baby, he was thought not to survive the first few days of life. Newton had a difficult childhood, and at the age of 16, he was pulled out of school by his family and forced to become a farmer, a job he didn't like and he was miserably bad at. So, as we start a new year, let's remember that even the smartest people are not good at everything, and it does take time to find one's passion in life. Now, while things may not always be clear, what is clear is that a great way to find that center of gravity is, as always, staying alert with Stroke Alert. This podcast is produced by Wolters Kluwer and supported by the editorial team of Stroke. Our Stroke Alert podcast and production staff includes Danielle Cross, Eric Goldstein, Nastajjia Krementz, Ishara Ratnayaka, Erinn Cain, Rebecca Seastrong, and Negar Asdaghi. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 21 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2022 issue of Stroke: “Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk” and “Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage.” She also interviews Dr. Shadi Yaghi about his article “Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis.” Dr. Negar Asdaghi:         Let's start with some questions. 1) Do hormone replacement therapies or oral contraceptives increase the risk of stroke? And if yes, does the age of the individual or the duration of therapy modify this risk? 2) Should survivors of intracranial hemorrhage who have atrial fibrillation be treated with antithrombotic therapies for secondary prevention of stroke? 3) And finally, what is the anticoagulant of choice for treatment of cerebral venous sinus thrombosis? We have the answers and much more in today's podcast as we continue to bring you the latest in cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us. Welcome back to another amazing issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The October issue of Stroke covers a number of timely topics. As part of our October Literature Synopsis, we have a nice paper by Dr. Farida Sohrabji and colleague, which summarizes three recently published animal studies to evaluate the association between small vessel ischemic injury and either development of Parkinsonism or the future risk of Parkinson's disease. These studies looked at how ischemia, specifically involving the lenticulostriate arteries, can modulate the nigrostriatal dopaminergic pathway and ultimately lead to Parkinsonism. As part of our Original Contributions, we have the results of a small randomized trial out of Korea, which was led by Dr. Yun-Hee Kim from Sungkyunkwan University School of Medicine in Seoul, where we learned that doing 20 sessions of transcranial direct current stimulation for about 30 minutes for each session at home can improve post-stroke cognition. This was found to be specifically effective in patients with post-stroke moderate cognitive decline. Now, transcranial current stimulation can be given using a handheld device at home, and if truly proven safe and efficacious in larger studies, can dramatically change the landscape of stroke recovery in cognitive rehabilitation. I encourage you to review these articles in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Shadi Yaghi from Brown University. Shadi will walk us through a systematic review and meta-analysis of published studies to compare the safety and efficacy of direct oral anticoagulants to that of vitamin K antagonists in patients with cerebral venous sinus thrombosis. Our devoted Stroke Alert Podcast listeners recall that we did cover this topic in our March podcast when we reviewed the results of ACTION-CVT, a multicenter international study that was led by none other than Shadi himself. I'm delighted to have him as a guest on my podcast today to talk more about the seminal study and all things cerebral venous sinus thrombosis. But first, with these two articles. Millions of women worldwide use exogenous hormones, most commonly in the form of oral contraceptives and hormone replacement therapies. Despite the many different formulations of these drugs that are now available on the market, the two therapies are similar in that both combined oral contraceptives and hormone replacement therapies, or HRTs, contain various dosage of estrogen and progestin. Now, the principal difference between them being that the hormone contents of oral contraceptives are at high enough dosage to prevent ovulation, whereas hormone replacement therapies are considered more physiological as their aim is to return post-menopausal hormone levels to what they were before menopause. Well, by now, you must wonder how is any of this even relevant to vascular neurology? Well, the answer lies in the close relationship between hormonal therapies and stroke. But before we get to that, we have to review a few things. First of all, it's long been known that the endogenous estrogen has strong and protective effects on the arteries. It promotes vasodilation and cell survival of the endothelial layer. It increases the endothelial mitochondrial efficiency and stimulates angiogenesis. In other words, endogenous estrogen is good for vascular health. And in fact, that's why we think that premenopausal women, in general, are at a lower risk of stroke as compared to their age and vascular risk factors–matched male counterparts. And to make things even better for estrogen, there's enough evidence to suggest that exogenous estrogen also does all of these good things for the endothelium. So, why are we even talking about an increased risk of stroke associated with use of hormonal therapies? The problem is, we have to remember that exogenous estrogen also does other things. It can increase the blood concentration of procoagulants, which, in turn, can increase the risk of thromboembolism, especially venous thrombosis. But there's still a lot of unknown on this topic. For instance, the majority of the prior research on the topic involves postmenopausal women using hormonal therapies. Some of that research has actually suggested that HRTs may be protective against vascular events, while others showed the opposite. Well, we know that a majority of oral contraceptive users are actually much younger and use these medications premenopausal. So, there seems to be a lot of gaps in our current knowledge on the simple question of whether or not oral contraceptives and hormonal replacement therapies do, in fact, increase the risk of stroke or not. In the current issue of the journal, a group of researchers led by Drs. Therese Johansson, Torgny Karlsson, and Åsa Johansson from the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden set out to fill some of these gaps with their study titled, "Oral Contraceptives, Hormone Replacement Therapy, and Risk of Stroke," as part of a large UK Biobank population-based cohort. Just a bit about the UK Biobank. This was a large population-based cohort from 2006 to 2010 that included over 500,000 residents of the United Kingdom between the ages of 37 and 73. Participants at the time of enrollment would have extensive information collected from them through questionnaires, interviews, health records, physical measures, as well as some imaging and biological samples. Data on each participant was collected from the time of their birth all the way to the day of assessment, which is interesting, because the day of assessment would then count as the end of the follow-up for each participant. Now, for the current study, they included over 250,000 women of White race in whom information required for the study on whether or not they use hormonal therapies, duration of treatment, age at the time of exposure was available. And just a quick comment about their methodology. They analyzed their cohort once for oral contraceptive use and once for HRT use and compared each group to a reference group of either women who never used their set therapy or the number of years they contributed to the study prior to initiating that set treatment. So, for instance, if a person started using oral contraceptives at the age of 21, all of the years that she contributed to the study before that age would count as non-exposed user years and were included in the control cohort. So now, on to their findings. A total of 3007 stroke diagnosis of any type were identified prior to the initial visit to the assessment center, which, as we mentioned, was the end of the follow-up in the study. Of these, 578 were ischemic strokes, 177 intracerebral hemorrhage, and 478 were subarachnoid hemorrhages. But as expected for any large cohort, over half of total strokes were self-reported as stroke of any type and could not be classified into any of the above subtypes. Now, let's look at the effects of oral contraceptives on the outcome of stroke. Overall of the women included in the study, 81% were classified as oral contraceptive users, while 19% reported never having used oral contraceptives at any point during the study. On the association between oral contraceptive use and the risk of stroke, at first glance, things looked OK. The hazard rates of any stroke for any stroke subtypes were not different between women who had used oral contraceptives as compared to those in the reference group. That's great news. But when they looked deeper, they realized that the odds of development of any stroke was actually quite high during the first year after the initiation of oral contraceptives with hazard rate of 2.49 for any stroke, while there was no difference in hazard rates found during the remaining years of use and after discontinuation of oral contraceptive use. So, meaning that there was no lingering effects of oral contraceptives on increased risk of stroke after the first year or after discontinuing the medication. Now, on to HRTs. In total, 37% of women in the study had initiated HRTs at some point during the study, while 63% had never used this therapy. Here's the bad news. Overall, HRTs did increase the risk of stroke. An approximately 20% increase event rate of any stroke was noted among women who had initiated HRTs as compared to those who had not. When analyzing stroke subtypes, the use of HRTs was associated with increased risk of only the subarachnoid hemorrhage subtypes. We don't know why. Diving deeper, in considering timing of HRT initiation, very similar to what was observed for the oral contraceptives, during the first year after starting the HRTs, the treatment group was twice more likely to suffer from any type of stroke, and the hazard rate was also increased for all three stroke subtypes that were available in the study. But, unlike oral contraceptives, the hazard rate of any stroke remains significantly high even after the first year of use, not just for those who continued HRTs, but sadly, even for those who discontinued the therapy. Though the risk remained high, the hazard ratio declined over time as we went further away from the first year when treatment was initiated. So, bottom line, if women had initiated HRTs at some point in their life, the hazard risk of any stroke increased significantly in the first year. That hazard risk did decline over time, but it always remained significantly higher than non–HRT users. Now, what about timing of treatment in relation to the onset of menopause? Is the risk of stroke any different if women start on HRTs prior to or after their menopause? The answer is no. Initiation of HRTs was associated with an increased hazard rate of any stroke if it was started pre- or postmenopausal, but the risks were higher if the treatment was started prior to menopause. So, in summary, this large population-based cohort has truly given us some very important practical findings. We learned that both oral contraceptives and hormone replacement therapies do, in fact, increase the risk of stroke, an effect that was most notable in this study in the first year after initiation of both of these therapies, and in the case of oral contraceptives, was just actually limited to that one year alone. Why does this happen? I guess the easy answer is that these drugs, as we noted earlier, have an immediate prothrombotic effect, which gradually weakens over time. That's one plausible explanation, but for instance, why HRTs increase the risk of subarachnoid hemorrhage is something we can't explain based on the prothrombotic effects of HRTs. So, we have to come back to the vessels, the impact of hormone therapies and estrogen specifically on the blood vessels, on the endothelial cells, the potential increase in blood pressure, especially early on in the course of treatment with these medications. And also, we have to think about the role these drugs may play in increasing inflammatory markers, providing a more suitable milieu for accelerated atherosclerosis, as to why these associations were noted in this study. And it's fair to say that we need more research on this topic in the future. One challenging scenario that we commonly face in our daily practice is deciding whether or not we should resume antithrombotics in patients with atrial fibrillation who have survived an intracranial hemorrhage. The majority of intracranial hemorrhage survivors with atrial fibrillation actually have a very high CHA2DS2-VASc score, which means that they are actually at a very high risk of future ischemic stroke and systemic embolic events unless they're treated with anticoagulants. On the other hand, the risk of spontaneous intracranial bleeding is substantially higher in a person who has previously suffered from one, let alone if we treat them with anticoagulants. And to make matters worse, we have little evidence from the literature to guide us. So, in the current issue of the journal, in the study titled "Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage," a group of researchers from the UK led by Dr. Deirdre Lane, Professor of Medicine at the University of Liverpool, performed a much needed systematic review and meta-analysis of the available evidence on this subject. I have to say that lately, it seems that we've been covering a few of these reviews in our podcasts, and we are just getting started. In fact, my next paper in today's episode is also a systematic review and meta-analysis. These papers are packed with details, a testament to the work needed to complete them, but I have to say that even summarizing these papers for a podcast has been a bit challenging. So, feel free to put me on pause, go get some coffee, and let's power through this one together. For their methods, they used the usual search engines looking for papers that included adults over the age of 18 with atrial fibrillation who had survived a non-traumatic spontaneous intracranial hemorrhage of any size, any type, and any location, be it lobar, brain stem, deep, cerebellar, subdural, epidural, or subarachnoid hemorrhage. And very importantly, they included even those with evidence of microbleeds on neuroimaging. The intervention of interest was either long-term oral anticoagulation or antiplatelet therapy versus no antithrombotic use for the following three outcomes of interest: number one, recurrent thromboembolic events; number two, recurrent intracranial hemorrhage; and number three, all-cause mortality. Just a quick note that for this analysis, they excluded studies that looked at either short-term anticoagulation or non-oral anticoagulation use for any reason that was given to the patient other than for secondary prevention of stroke. For example, if a patient suffered from a pulmonary embolism and was treated with IV heparin or, for a short period of time after that, with oral anticoagulation, those patients or those studies were excluded from this meta-analysis. So, with this criteria, they pulled over 4,000 citations and abstracts, and finally included 20 papers that were published between 2015 and 2021 for a total of over 50,000 participants for this meta-analysis, very nice sample size. Most of the papers included were observational cohorts, but in addition, we had two small randomized trials, and I want to take a moment and review these trials for our listeners. The first one was a small noninferiority pilot trial out of the UK, the SoSTART trial, that looked at any anticoagulant versus either antiplatelet therapy or no antithrombotics in this population, and the other trial was the Phase 2 trial, the APACHE-AF, that studied apixaban versus no anticoagulation after anticoagulant-associated intracerebral hemorrhage. A reminder that both of these trials were published in Lancet Neurology in 2021. And before we move on to the findings of the meta-analysis, it's worth noting that they had included a mix of patients, some were oral anticoagulant–naive, and some had developed their index intracranial hemorrhage while already on treatment with anticoagulants or antiplatelet therapies. OK, now on to their findings, as mentioned, we're going to review three outcomes of recurrent thromboembolism, recurrent intracranial hemorrhage, and all-cause death for the following three groups: group one, oral anticoagulant therapy versus no therapy; group two, oral anticoagulation therapy versus either antiplatelet treatment or no therapy; group three, comparing new oral anticoagulants versus warfarin. So, for the first outcome of recurrent thromboembolic events in group one, when comparing oral anticoagulant therapy to no therapy, the study showed a significant reduction in thromboembolic events in favor of oral anticoagulation compared to no therapy. That's great news. Next, analysis of the studies that compared oral anticoagulation versus either antiplatelets or no therapy didn't show the same difference in prevention of embolic events in favor of either groups. Actually, no difference was noted between the two groups. Number three, now, in terms of comparing NOACs to warfarin, three studies had the information on this comparison, and they reported a significant reduction in the risk of thromboembolic events with NOAC as compared to warfarin. So, great news for oral anticoagulation overall, and especially for NOACs. Now, on the next outcome. Our second outcome was a recurrent intracranial hemorrhage. Keeping in mind that they included some studies where the outcome was defined as any form of intracranial hemorrhage, meaning they included subdurals, epidurals, etc., and some studies only included the outcome of intracerebral hemorrhage. So, on to the first group, comparing oral anticoagulants to no therapy, the pooled estimate revealed no statistically significant difference between oral anticoagulant–treated patients to those who were not treated with any antithrombotics on the risk of recurrent intracranial hemorrhage. That's great news. Next, on our second group, for the same outcome of recurrent intracranial hemorrhage, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found that oral anticoagulation was associated with a higher risk of recurrent intracranial hemorrhage as compared to antiplatelets or no therapy. And finally, third group comparing new oral anticoagulants to warfarin for the same outcome, the risk of recurrent intracranial hemorrhage was significantly reduced in patients treated with NOACs as compared to warfarin. And now, we're finally on to our last outcome of the study, which is the outcome of all-cause mortality. So, again back to group one, comparing oral anticoagulants to no therapy, this meta-analysis showed a significant reduction in all-cause mortality rate associated with oral anticoagulation. That's, again, great news. Next group, for the same outcome of mortality, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found no significant difference in the mortality rates between the two groups. And finally, comparing NOACs to warfarin, the pooled estimate showed that NOACs were associated with a significantly reduced risk of all-cause mortality. Amazing news for NOACs. So, in summary, here's what we learned from this big study. Oral anticoagulation use after intracranial hemorrhage in patients with atrial fibrillation did significantly reduce the risk of thromboembolic events and all-cause mortality without significantly increasing the risk of recurrent intracranial hemorrhage. In general, new oral anticoagulants, or NOACs, are preferred to warfarin as they do prevent embolic events with a lower risk of recurrent intracranial hemorrhage. But, of course, we still have a lot more questions. For instance, would any of the outcomes mentioned above be different in patients with lobar intracerebral hemorrhage, a condition typically associated with amyloid angiopathy, which carries a high risk of development of intracerebral hemorrhage? Also, we have to keep in mind that the majority of the studies included in the meta-analysis were observational. So, there remains an urgent need for a larger randomized trial on this subject, and we have to stay tuned for more research. Cerebral venous sinus thrombosis, or CVST, is an uncommon form of stroke resulting in headaches, seizure, or focal neurological symptoms due to either intracranial hemorrhage or venous ischemic infarcts. The rarity of the disease has made it difficult to study as part of randomized trials, so current treatment guidelines for CVST are consensus-based with much of the recommendations extrapolated from data on treatment of patients with systemic deep vein thrombosis. In general, based on the current evidence, the field agrees that a patient with CVST should be anticoagulated. The decision that is difficult and sometimes inappropriately delayed in the setting of acute hemorrhage in the brain. And not surprisingly, there's significant equipoise around the choice of anticoagulant, duration of therapy, and the role of heroic therapies, especially in the acute setting. Currently, there are a number of ongoing trials to address some of these issues. The direct oral anticoagulants present an attractive alternative to vitamin K antagonists for treatment of patients with CVST. This is partly because of their convenience of use. But how do direct anticoagulants compare in safety and efficacy to the vitamin K antagonists in the setting of CVST is less known. In our March podcast, we reviewed the results of ACTION-CVT, which was a multicenter international study that compared the safety and efficacy profile of the direct oral anticoagulants to that of warfarin in routine practice. The study included over a thousand imaging-confirmed CVST patients from multiple centers in the US, Italy, Switzerland, and New Zealand. And if you missed it, no worries at all. We're here to review some of the results again, as in this issue of the journal, many of the ACTION-CVT investigators, led by Dr. Shadi Yaghi, present the results of a systematic review and meta-analysis comparing the safety and efficacy of DOACs, or direct oral anticoagulants, to that of vitamin K antagonists. I'm joined today by Dr. Yaghi himself to discuss ACTION-CVT and the current meta-analysis. Dr. Yaghi is a Director of Vascular Neurology at Lifespan and Co-Director of Comprehensive Stroke Center and a Director of Research at the Neurovascular Center at Rhode Island Hospital. Good afternoon, Shadi, and welcome to our podcast. Dr. Shadi Yaghi:               Good afternoon, Dr. Asdaghi. Thank you so much for having me. Dr. Negar Asdaghi:         Thank you. And please call me Negar. Congrats on the paper. Before we talk about the meta-analysis, can you please remind us of the results of ACTION-CVT and why the systematic review, in your opinion, was an important next step to that effort? Dr. Shadi Yaghi:               Thank you so much for having me and for bringing up ACTION-CVT. So ACTION-CVT is a real-world multicenter international study that used real-world observational data to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The reason why we did ACTION-CVT was, as you know, cerebral venous thrombosis is a rare disease, and it's hard to have large studies that would be powered enough to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists. So, most of the studies that were done are small, retrospective. There's one randomized controlled trial, but most of them are underpowered to detect the difference between the two groups. So, we decided to do a large-scale international multicenter study using real-world data to compare the safety and efficacy of both. Dr. Negar Asdaghi:         OK, so we're glad you did. Let's start with the methodology of the current meta-analysis. Can you please give us an overview of the inclusion criteria for selection of the papers and the intervention and outcomes that you were interested in? Dr. Shadi Yaghi:               Of course. So, this is a systematic review and meta-analysis that included studies comparing direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The studies needed to have the two groups included, the direct oral anticoagulants and vitamin K antagonists, and they need to include at least one of the outcomes in our study to compare this outcome between the two groups. In addition, we included articles published in English, and we also included papers that had five patients or more in each group. Dr. Negar Asdaghi:         Perfect. So just recap for our listeners, in order to have been included in the meta-analysis, the paper had to have a reasonable number of patients, and you put that reasonable at the number five, and also they had to have at least one of the outcomes of interest reported in their papers. And those outcomes were either recurrent venous thromboembolism or recanalization rates. Right? Dr. Shadi Yaghi:               Correct. Yes. Dr. Negar Asdaghi:         Perfect. So with that, how many papers did you have to go through to come up with the current number of papers included? Dr. Shadi Yaghi:               That's a great question. We had a little over 10,000 papers, and then we went through a screening process. We used this tool that was developed by Brown University. It's called Abstrackr, and what you do is, we did the search and using several databases like PubMed, Cochrane, and then we included all these studies. We uploaded them in Abstrackr, and Abstrackr was utilized to be able to review all these abstracts and select studies that may or will probably qualify and then go through the studies and details that would qualify. So, we had about 10,000 studies with the initial search, and we had two reviewers go through each abstract, and from these 10,665, we excluded 10,411, and that left us with 254 studies. And then we went through these 254 studies in details. And then finally, we had 19 studies included that met our inclusion/exclusion criteria. And these 19 studies included three randomized control trials and 16 observational studies. Dr. Negar Asdaghi:         Incredible effort. So, three randomized trials in this meta-analysis and 16 observational studies. I think we're very ready to hear the primary outcomes. Dr. Shadi Yaghi:               Yeah, so, the primary outcomes were recurrent venous thrombosis, and that included recurrent venous thromboembolism like peripheral DVTs or PEs, for example, and including recurrent cerebral venous thrombosis. And we know that most of the events are recurrent VTEs, not CVTs, like probably about two-thirds to three-quarters were VTEs, and a third to a quarter were CVT. And then the other efficacy outcome is venous recanalization on follow-up imaging. And we found that direct oral anticoagulants and warfarin were not significantly different in the primary efficacy outcomes. Dr. Negar Asdaghi:         Thank you. I just want to repeat this for our listeners. So, you mentioned some important information here. First one was the fact that about three-quarters of recurrent events were actually systemic thromboembolic events rather than cerebral thromboembolism. So, an important outcome to keep in mind for our practicing physicians. And the fact that DOACs did the same as compared to vitamin K antagonist. So, I think you can already guess my next question, and that is, was there any compromise on the safety profile when using DOACs as compared to vitamin K antagonists in this meta-analysis? Dr. Shadi Yaghi:               Thank you. That's a great question. In ACTION-CVT, we found that there was a lower risk of major hemorrhage with direct oral anticoagulants compared to vitamin K antagonists. In this systematic review and meta-analysis, we didn't find a significant difference, but there were fewer events in patients treated with direct oral anticoagulants versus vitamin K antagonists. This did not reach statistical significance, but if you look at the raw data, it's kind of along the same lines as ACTION-CVT, so the risk of major hemorrhage was about 3.5% with warfarin, and that was about 2% with direct oral anticoagulants. Dr. Negar Asdaghi:         So, again, very important finding, and I want to repeat this for our listeners. So, important finding number one was that there was a superiority in favor of DOACs that you found in terms of a reduced risk of intracerebral hemorrhage in ACTION-CVT. You didn't find this superiority in the meta-analysis, but there was sort of a hint to perhaps lower risk of intracerebral hemorrhage in patients that were treated with DOACs. Did I get that right? Dr. Shadi Yaghi:               Yes, that is correct, and in addition, also major hemorrhage in general, and that included also ICH. Dr. Negar Asdaghi:         Oh, OK, so not just intracranial, but systemic hemorrhages as well. All right. Very good. So, I think my next question would be, why do you think that DOACs have a lower chance of causing hemorrhage? Dr. Shadi Yaghi:               Yeah, that's a really good question. This is not unexpected with DOACs as opposed to vitamin K antagonists. We saw these same trends in patients with atrial fibrillation. We saw improved bleeding profiles with direct oral anticoagulants as compared to vitamin K antagonists. And the risks were along the same lines that we found in patients with cerebral venous thrombosis in ACTION-CVT. Also in the VTE trials as well, there was also reduced bleeding complications with direct oral anticoagulants as compared to vitamin K antagonists. So, it was kind of reassuring to see the same results in patients with cerebral venous thrombosis. Dr. Negar Asdaghi:         Perfect, so kind of expected based on what we know from treatment of systemic conditions with DOACs. The next question I have for you is that in routine practice, treatment of cerebral venous sinus thrombosis almost always starts parenterally with either unfractionated heparin or low molecular weight heparin and then we switch to an oral agent. In the observational studies, did you find any differences in terms of timing of this switch or characteristics of the patients in whom vitamin K antagonists were chosen over direct oral anticoagulants? Dr. Shadi Yaghi:               Thank you very much. Most of the studies did not report these details. I think the one study, off the top of my head, that does report the differences in characteristics between the two groups is RESPECT-CVT. That's the randomized controlled trial comparing dabigatran to vitamin K antagonists. In this study, there was a treatment with parenteral anticoagulation for several days, I think seven to 14 days, prior to transitioning to oral anticoagulation. And this is generally my practice. I typically would treat patients with at least seven days or so parenteral anticoagulation, and once they're clinically stable, then I would transition them to oral anticoagulation, either vitamin K antagonists or direct oral anticoagulant. Dr. Negar Asdaghi:         And I think my next question is along the lines of this question as well. We have several direct oral anticoagulants now available on the market. What was the most common DOACs used for treatment of CVST in these studies, and did you note a preference for the use of any particular agent over others? Dr. Shadi Yaghi:               Thank you so much for the question. Anti-Xa inhibitors were much more common than dabigatran, and the anti-Xa inhibitors most commonly used were apixaban and rivaroxaban. It's in line with what we saw in ACTION-CVT as well, although most of the randomized controlled trials or the largest randomized controlled trial, RESPECT-CVT, used dabigatran, but overall people have been using anti-Xa inhibitors, more particularly apixaban, which was also in line with what we saw in ACTION-CVT. Dr. Negar Asdaghi:         But I think it's fair to say that we don't really have data on superiority of one over others. Is that fair? Dr. Shadi Yaghi:               Yes, that is correct. Dr. Negar Asdaghi:         OK, and so now, where are we at in terms of the future of studies on this topic? We have one ongoing randomized trial now? Dr. Shadi Yaghi:               Yes, we have one randomized controlled trial ongoing, and this is the SECRET trial, and it's looking at rivaroxaban versus vitamin K antagonists in patients with cerebral venous thrombosis. There's another study, it's a prospective observational study that's called the DOAC-CVT study. It's an international study also looking at real-world data prospectively to see if there's a difference in outcomes between the two groups. Dr. Negar Asdaghi:         So, we look forward to the results of those studies. Shadi, a follow-up question I have on this topic is, how long should a duration of therapy be in idiopathic cases of cerebral venous sinus thrombosis? Dr. Shadi Yaghi:               Thank you so much for this question. So, it's unknown at this point for how long should we treat. The key things from the treatment are first achieving venous recanalization, and second is preventing another venous thromboembolic event from happening. So, regarding the venous recanalization, studies have shown that there's not a lot of recanalization beyond four months of treatment. So, a lot of the recanalization really happens early, and continuing anticoagulation beyond the six-months interval, for example, in order to achieve further venous recanalization probably has limited utility. And the second important reason why we treat patients with anticoagulation is also to reduce the risk of a recurrent venous thromboembolic event or cerebral venous thrombosis. And for that, if it's a provoked CVT, then I think usually it's three to six months. If it's unprovoked, up to maybe six to 12 months or even longer, depending on the profile. And if there's a persistent provoking factor, such as cancer, antiphospholipid antibody syndrome, then the treatment is lifelong or until this condition subsides. There's a lot of controversy about the duration of treatment. The European guidelines were very helpful in identifying the duration of treatment. Hopefully, also, we have some guidelines or at least a scientific statement by the AHA that also doles details out and provides some guidance to practitioners. Dr. Negar Asdaghi:         Shadi, what should be our top two takeaways from the current meta-analysis and also ACTION-CVT? Dr. Shadi Yaghi:               So, really, the top two from ACTION-CVT and the meta-analysis are, first is direct oral anticoagulants have a comparable efficacy to vitamin K antagonists in terms of recurrent venous thrombosis and achieving venous recanalization on follow-up imaging. And then the second point is direct oral anticoagulants are probably safer than vitamin K antagonists. We have to keep in mind that this data is based mostly on observational studies. And, as we mentioned earlier, we need more randomized controlled trials to support these findings. Dr. Negar Asdaghi:         Dr. Shadi Yaghi, it was a pleasure interviewing you on the podcast. Thank you very much for joining us, and we look forward to having you back on the podcast and reviewing this topic again in the future. Dr. Shadi Yaghi:               Thank you so much. I appreciate you having me. Dr. Negar Asdaghi:         Thank you. And this concludes our podcast for the October 2022 issue of Stroke Please be sure to check out this month's table of contents for the full list of publications, including an important update from the European Stroke Organisation by Prof. Martin Dichgans. I also want to draw your attention to this month's InterSECT paper, which is our International Stroke Early Career and Training section, to discuss the key topic of burnout and mental health amongst physicians, especially amongst neurologists and stroke neurologists. It's alarming to read in this article that neurology is one of the specialties with the highest reported rates of burnout syndrome, and stroke neurologists are at particularly higher risk than other neurological subspecialties. The article tackles some tough subjects, such as the barriers for physicians to seek help and important strategies to mitigate burnout and how to improve mental health in general. I think it's also timely to know that October is the Mental Health Awareness Month, and the theme for October 2022 is "Back to Basics." The basics of recognizing the burden of stress, anxiety, the burden of isolation and depression, not only on those who we take care of, but also on those who give care to us. So, whether you're a stroke physician, a stroke caregiver, or whether you've been touched by this disease in some way or shape, please know that you are part of the stroke community and a part of our Stroke podcast family. Thank you for listening to us, and, as always, stay alert with Stroke Alert. 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 more, visit AHAjournals.org.  

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism." Dr. Carolyn Lam: Welcome to Circulation On 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 Richmond, Virginia. Dr. Carolyn Lam: In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg? Dr. Greg Hundley: You bet, Carolyn. Well, how about if I go first? Dr. Carolyn Lam: Please. Dr. Greg Hundley: Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4. Dr. Carolyn Lam: Nice. Okay. Important question, what did they find? Dr. Greg Hundley: Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women. Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome. Dr. Carolyn Lam: Oh, you are right. A lot of interesting data here. What's a take home message? Dr. Greg Hundley: Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step. Dr. Carolyn Lam: Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis. Dr. Greg Hundley: Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find? Dr. Carolyn Lam: Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC. Dr. Greg Hundley: Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight? Dr. Carolyn Lam: Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth? Dr. Greg Hundley: Yeah. Remember seven dwarfs, Sleepy. Dr. Carolyn Lam: Sleep. Dr. Greg Hundley: Very good. Great job, Carolyn. Dr. Carolyn Lam: Thank you. Dr. Greg Hundley: Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018. Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression. Dr. Carolyn Lam: Okay, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years. Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group. Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large. Dr. Carolyn Lam: Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility. Dr. Greg Hundley: Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion? Dr. Carolyn Lam: Yes, let's go Greg. Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found. Dr. Senthil Selvaraj: Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites. To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment. The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity. Dr. Carolyn Lam: Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati? Dr. Svati Shah: Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself. To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn. Dr. Carolyn Lam: Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically? Dr. Manuel Mayr: Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress. Dr. Carolyn Lam: Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that? Dr. Senthil Selvaraj: I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space. The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet. Dr. Svati Shah: Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do. Dr. Carolyn Lam: And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps? Dr. Manuel Mayr: Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis. Dr. Senthil Selvaraj: That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process. Dr. Carolyn Lam: Anything to add, Svati? Dr. Svati Shah: No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also. Dr. Carolyn Lam: Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view? Dr. Manuel Mayr: Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure. Dr. Carolyn Lam: Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you. 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 more, please visit ahajournals.org.

On Episode 19 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2022 issue of Stroke: “Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion” and “Recurrent Ischemic Stroke and Bleeding in Patients With AF Who Suffered an Acute Stroke While on Treatment With NOACs.” She also interviews Dr. Alexander Nave about “Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events.” Dr. Negar Asdaghi:         Let's start with a few questions. 1) How much time do we actually save if we were to transfer all patients with suspected target vessel occlusion directly to the angiosuite and practically bypassing our current conventional imaging model? 2) What is the impact of an impaired metabolic state as measured by abnormal glucose and triglyceride tolerance tests on the risk of stroke recurrence in patients with ischemic stroke? 3) And finally, should we or should we not change the anticoagulant therapy of a patient with atrial fibrillation who suffered an ischemic stroke despite appropriate treatment with anticoagulation? We have the answers to these questions and much more in today's podcast because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi:         Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The August 2022 issue of Stroke contains a range of really stimulating articles. We have an interesting study titled "Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young," led by Dr. Amelia Boehme and colleagues from Columbia University, with its accompanying editorial on how influenza-like illness is associated with increased risk of stroke in the young and middle-aged population while vaccinations of any type is protective of this risk. In a different paper, as part of a population-based study out of Scotland, Dr. Rustam Al-Shahi Salman from University of Edinburgh and colleagues report on a positive association between the use of beta-blockers, especially propranolol, and a lower risk of cerebral cavernous malformation, or CCM, associated intracranial hemorrhage. This study's findings are very interesting and quite important, and I encourage you to review the growing literature to suggest how beta-blockers may, in fact, reduce the risk of CCM-related hemorrhages through their anti-angiogenic properties. Dr. Negar Asdaghi:         Later in the podcast, I have the great pleasure of interviewing Dr. Alexander Nave from Charité University Hospital in Berlin to discuss the relationship between having an impaired metabolic state in the setting of acute stroke and the risk of ischemic stroke recurrence, as we'll review the long-awaited results of the Berlin "Cream&Sugar" study, a very catchy title. But first, with these two articles. Dr. Negar Asdaghi:         Time to successful endovascular reperfusion is an important predictor of clinical outcomes in patients with acute ischemic stroke related to a large vessel occlusion. And for years, we've known that the faster we're able to open the affected artery, the better the ischemic stroke outcomes are. Correspondingly, systems of care have adapted to various requirements of this so-called rapid workflow to ensure that all necessary pre-reperfusion steps are completed as fast as possible, preferably most in parallel to one another. And if any steps are unnecessary, they're bypassed altogether. Dr. Negar Asdaghi:         Despite all these modifications to date, time from conventional imaging to angiosuite arrival remains both the longest and the most variable interval in the intra-hospital workflow prior to endovascular therapy. So, it's not surprising that many recent studies have evaluated whether the current model of hospital arrival, then transfer to the scanner for imaging, then transfer to the angiosuite for endovascular therapy, can be replaced by a simpler model where, based on clinical assessment, a patient with high likelihood of having a target vessel occlusion can directly be transferred to the angiosuite, where fast stroke imaging, including CT, CT angiogram, and CT perfusion, are completed on the angiotable using the flat panel imaging technology. Dr. Negar Asdaghi:         If the patient is then found to be eligible to receive reperfusion therapies, including intravenous thrombolytics, they can receive the treatments and then proceed to endovascular thrombectomy without any further delays. So, in this issue of the journal, in the study titled "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion," Dr. Raul Nogueira from Department of Neurology at Emory University and colleagues performed a systematic review and meta-analysis of published articles on this topic. So, they included seven articles for this analysis after pulling over 4000 articles using the common search engines for this meta-analysis. These articles included two single-centered European randomized controlled trials, one conducted in Germany, and the other one conducted in Spain, and five observational studies for a total of 1971 patients. The primary outcome was the odds of achieving favorable neurological recovery as defined by a modified Rankin Scale of zero to two at 90 days. Dr. Negar Asdaghi:         Now, a few things to note: All studies reported door-to-puncture times, but not all reported door-to-reperfusion times or rate of successful reperfusion, and we know that these metrics are important in predicting the odds of safety and efficacy outcomes of endovascular therapy. And also it's important to note that not all details of the safety and efficacy outcome measures were reported in all of those seven studies. So, with that, here are the main findings of the meta-analysis. First off, amongst patients who were directly transferred to the angiosuite across these seven studies, the overall rate of false activation was 28%, meaning that after imaging assessment, 28% of those who were directly taken to the angiotable were not found to have a target occlusion, and as such, there was no need to further proceed to endovascular thrombectomy. And this is a practical finding of this meta-analysis as we deal with resource allocation and concerns of potentially overwhelming the neurointerventional teams. Dr. Negar Asdaghi:         Now, moving on to the next finding of the study, the direct angio approach significantly reduced door-to-puncture times by a median of 30 minutes, and door-to-reperfusion times, when these metrics were available, by a median of 33 minutes as compared to the conventional imaging approach. So, bypassing conventional CT does translate into faster time metrics. These were, of course, expected findings of this meta-analysis, but nonetheless, important to quantify. But these faster time metrics did not improve the endovascular procedural outcomes, meaning that the direct to angio approach did not increase the odds of achieving a TICI 2b or better reperfusion, which is how successful reperfusion is defined, or the odds of achieving full reperfusion, meaning modified TICI 2c or greater reperfusion. Dr. Negar Asdaghi:         So, it's great to get to the angiosuite fast, but that does not impact the procedural outcomes of endovascular therapy. Despite the above, the faster approach resulted in a significantly better functional independence outcome as measured by mRS Scale at 90 days, again emphasizing how important time is when it comes to endovascular outcomes. Now, the authors also performed a number of subgroup analysis in this meta-analysis, which I'd like to highlight some of them. We know that the impact of time on endovascular outcomes is more robust in the early time window. So, not surprisingly, when restricting the primary outcomes to those presenting within six hours from symptom onset, the favorable effect of direct to angio approach persisted in the early time window as well. Dr. Negar Asdaghi:         Another important subgroup analysis was when restricting data to those patients who were transferred from a primary hospital to an endovascularly-capable center, the direct angio method didn't really have a significant impact on improving the primary outcome. Why is that? Let me repeat. So, when they restricted the analysis to those patients who were transferred from one hospital to an endovascularly-capable center, they did not find the same significant positive impact on endovascular outcomes in the direct to angio approach. I think the way we can explain this from a pathophysiological standpoint is that transferred patients are more likely to be slow progressors and, therefore, less likely to be impacted by delays in the workflow process as compared to the fast progressors. Dr. Negar Asdaghi:         Take-home message: We've got to be fast in the fast progressors, and it's safe to assume that those who are within the first six hours after presentation are more likely to be fast progressors, and these workflow modifications are, therefore, much more robust and much more impactful in patients who present early on after their symptoms onset. And finally, in terms of safety outcomes, there were no significant differences in the rate of symptomatic intracerebral hemorrhage rate or the 90-day mortality rates either for the whole study population or when the analysis was restricted to those treated in the early time window. Dr. Negar Asdaghi:         So, in summary, what we learned from this large meta-analysis is that as compared to the current conventional imaging model, the direct transfer to angio model is not only plausible and unlikely to overwhelm the interventional teams, as only less than 30% of patients in a direct method were not eligible for endovascular thrombectomy, but also this method is safe and results in significant improvements in workflow time metrics and functional outcomes. So, as the saying goes, select faster, select less, and treat more will likely be the future of endovascular therapy, particularly in the early time window. Dr. Negar Asdaghi:         We know that oral anticoagulants reduce the risk of ischemic events in patients with atrial fibrillation. Nonvitamin K antagonist oral anticoagulants, or NOACs, also known as direct oral anticoagulants, or DOACs, are currently the standard of care for treatment of patients with non-valvular atrial fibrillation. Now, we have to keep in mind that although NOACs reduce the risk of ischemic stroke and systemic embolism in atrial fibrillation, they don't completely abolish the risk. So, they're not curative treatments for AFib, and patients can still experience embolic events despite appropriate treatment with these agents. In a meta-analysis of randomized trials, the residual risk of ischemic events in patients treated with NOACs was estimated at 1.4% per year, but this number is a lot lower than what is reported by real-life observational studies. Dr. Negar Asdaghi:         In the large multicenter RENO study, which was published in this journal in 2019, we learned that in the setting of atrial fibrillation treated with a NOAC, a number of factors, including atrial enlargement, dyslipidemia, scoring high on the CHA2DS2-VASc score, and the use of low dose of NOACs, especially off-label low dose use of these medications, are significantly associated with increased risk of recurrent ischemic events despite treatment. But there's still a number of important questions that we routinely encounter in practice, most important of which is how to manage these patients with these so-called breakthrough ischemic events moving forward? Do we switch them to a different NOAC or go back to a vitamin K antagonist? Should we add an antiplatelet treatment to the regimen? And importantly, how do we counsel these patients and their families on their future risk of recurrent ischemic or hemorrhagic events? Dr. Negar Asdaghi:         So, in the current issue of the journal, the RENO investigators, led by Dr. Maurizio Paciaroni and Valeria Caso, set out to answer some of these important questions as part of the RENO-EXTEND study, which basically followed the patients in the RENO cohort for at least 12 months, evaluating them for either recurrent ischemic or hemorrhagic events, whether occurring intra or extracranially. So, a bit about this cohort. The RENO study was a multicenter observational cohort across 43 centers in Europe and the United States, including consecutive patients with atrial fibrillation who presented to the hospital with an acute ischemic stroke despite being on a NOAC therapy. Patients were enrolled in the study only if they were compliant with their NOAC treatment and they had not missed their treatment for any reasons for greater than 24 hours prior to their index event. Dr. Negar Asdaghi:         The patients were followed in the cohort and the choice of whether or not to start and timing, very importantly, for resumption of anticoagulation therapies were left to the discretion of the treating physicians. For the current paper, they analyzed 1240 patients. After the index event, 39.5%, so close to 40%, had their NOACs changed to another NOAC, mostly to a different class of NOAC. 42.5% continued with the same NOAC at the same dose. 6.7% continued with the same NOAC, but the dose was increased, and a small percentage were shifted to warfarin, that was only 4.7% of the patients. And 6.6% were shifted to low molecular weight heparin or were never prescribed oral anticoagulations after that index event for a variety of reasons, such as earlier ischemic recurrence, early hemorrhagic transformation, or early death or severe index stroke. And the overall median follow up in the study was 15 months. Dr. Negar Asdaghi:         So, with that, here are the main study findings. The annual rate of the primary outcome of recurrent ischemic or hemorrhagic events, again, a reminder that these could have been intra or extracranial events, was 13.4%. The majority of these events were ischemic stroke, followed by major extracranial bleeding, then intracranial bleeding and systemic embolism. We have to note that this overall primary outcome rate is a lot higher than what was observed as part of the randomized trials of NOACs, as we noted earlier, which is an important finding of these real-life studies. Now, with regards to the factors predicting the primary outcome, having a higher CHA2DS2-VASc score and persistent hypertension were both predictive of recurrent ischemic events, whether ischemic stroke or systemic embolism. Next, the predictive factors for hemorrhagic events, either intracranial or major extracranial bleeding, included age, for each year increase in age, the odds increased by 1.1; history of major bleeding in the past; and, very importantly, a scenario that not uncommonly happens in routine practice, which is the addition of antiplatelet to a NOAC after the so-called NOAC failure. Dr. Negar Asdaghi:         And finally, it turns out that changing that failed NOAC to a different agent didn't really seem to make a difference at all. As we mentioned earlier, close to 40% of patients were changed from one NOAC to another agent after the index ischemic event, and when they looked at the primary outcome, there was no difference in the rate of combined ischemic and hemorrhagic events, or the ischemic events alone, or bleeding outcomes alone, amongst patients who changed their NOAC to a different agent as compared to those who did not. The authors performed a number of subanalyses to see whether a particular strategy, for example, a switch from a particular class of NOACs to another class, or change in dosage, or NOAC to warfarin change, may be more or less beneficial in reducing the primary outcome, and there was really no difference between any of these strategies with the exception of one group. Dr. Negar Asdaghi:         It turns out that the cumulative risk of ischemic and hemorrhagic events were a lot higher in those 6.6% of patients in whom NOAC treatment was changed to low molecular weight heparin injection. But I think one should consider this observation as hypothesis generating. First off, it was just a very small percentage of patients in this study that actually did go through this switch. And also we should note that in practice, we reserve a switch to low molecular weight heparin injection in only special cases. Some examples would be patients in whom there's a consideration of a hypercoagulable state, whether cancer related or not. But regardless, I think what we learned from this finding is that the patients in whom low molecular weight heparin injection is considered after a NOAC or an anticoagulant failure are likely very high risk patients for recurrent thromboembolic and hemorrhagic events. Dr. Negar Asdaghi:         So, in summary, we learned a number of important lessons from RENO-EXTEND study. Number one, patients with atrial fibrillation presenting with a breakthrough ischemic stroke, despite treatment with NOAC, represent a high-risk group of patients who continue to be at a substantial risk for recurrent events, mostly ischemic, but also hemorrhagic. And this substantial risk was actually over 10% in the current study. Number two, we also learned that various strategies of changing the dose or class of anticoagulants don't seem to have much, if any, benefit in reducing the recurrent event outcomes. And finally, the addition of antiplatelet to oral anticoagulant therapies in this situation is not a good idea. This strategy gets us more in trouble and can increase the risk of bleeding and confers practically no benefits. Finally, these are the types of patients in whom we may have to consider other treatment options, such as left atrial appendage closure, and I'm sure we'll hear more on this in the future. Dr. Negar Asdaghi:         Having an abnormal lipid profile has long been recognized as a risk factor for development of vascular disorders, particularly leading to atherosclerosis, but this association varies for the different components of the lipid panel and is most robust for elevated low density lipoprotein cholesterol levels, or LDL, causing various vascular disorders. Amongst patients with ischemic stroke and TIA, randomized trials have also shown that lowering LDL can reduce the risk of major cardiovascular events, including the risk of ischemic stroke, but the connection between elevated triglyceride levels and the risk of recurrent ischemic stroke is less clear. Moving from lipids to sugar, the presence of uncontrolled diabetes increases the risk of stroke by two to five folds, depending on the patient population studied and coexistence of other risk factors. In contrast, impaired glucose tolerance, which is an intermediate metabolic state between normal glucose tolerance and diabetes, has also been found to be associated with an increased risk of stroke in patients with coronary artery disease, but this association is less clear amongst patients with ischemic stroke. Dr. Negar Asdaghi:         In clinical practice, fasting blood glucose and lipid profiles are routinely measured post-stroke, but we put a greater emphasis on the elevated LDL and hemoglobin A1C levels, and, in general, pay less attention, if any, to other metabolic derangements, including the impaired glucose tolerance state or even abnormal triglyceride levels. So, the question is, what is the impact of these metabolic derangements on the risk of stroke recurrence amongst patients presenting with ischemic stroke? In the current issue of the journal, in the study titled "A Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin 'Cream&Sugar' Study," we learn about these important associations. Joining me now is the first author of this paper, Dr. Alexander Nave. Dr. Nave is a neurologist and clinician scientist at Charité University Hospital in Berlin. He leads a junior research group as part of the Center of Stroke Research in Berlin and has a special interest in stroke rehabilitation and cardioembolic risk factors of stroke. Good morning, Alex, from Miami. Good afternoon to you in Berlin. Thank you for joining us. Welcome to our podcast. Dr. Alexander Nave:       Hi, thank you very much. I'm very happy to be with you. Dr. Negar Asdaghi:         All right. Let's go over the background of what we knew on the association between elevated triglyceride levels and the risk of recurrent stroke. Dr. Alexander Nave:       Sure. So, as you pointed out earlier, diabetes and hypercholesterolemia are well established risk factors for first and recurrent ischemic stroke. However, for triglyceride levels, this association is less well understood and somewhat inconclusive. So, prior large epidemiological studies of the healthy population from the U.S. and from Denmark have shown an independent association of triglyceride levels in the risk of vascular events, including ischemic stroke. This association was actually stronger for non-fasting triglycerides levels compared to fasting triglycerides levels. In the ischemic stroke population, however, there were only a few investigations with conflicting results. So, the SPARCL trial, for example, which was a large secondary prevention stroke trial with more than 3000 stroke patients, showed that triglyceride levels were associated with major cardiovascular events, but not with recurrent ischemic stroke. So, therefore, we designed the Berlin “Cream&Sugar” study to investigate the association of postprandial triglyceride levels following an oral triglyceride tolerance test with recurrent vascular risk. Dr. Negar Asdaghi:         So, let me just summarize. From SPARCL, actually, we knew that an increased level of triglycerides were associated with increased risk of development of cardiovascular events, so things such as coronary artery events and so on, but not an increased risk of stroke. And that's where you come in with the new study, the Berlin “Cream&Sugar” study. Now, before we talk about the study, can you tell us a little bit about the tests that were done, the oral triglyceride and glucose tolerance tests? Dr. Alexander Nave:       Absolutely. So, both tests eventually help us to evaluate the glucose and lipid metabolism of a patient. So, the OGTT, the oral glucose tolerance test, as most of the listeners probably know, is a test that helps us to assess the ability of the patient to metabolize glucose after receiving a drink with a standard dose of 75 grams of glucose. The blood glucose levels after one hour and two hours then help us to diagnose diabetes or pre-diabetic state of the patient. So, we're not only evaluating the fasting state, but we can also quantify the body's response to a glucose challenge. And as an equivalent, the OTTT, the oral triglyceride tolerance test, will test the ability of a patient to metabolize triglycerides after oral ingestion of a lipid challenge, which is usually a certain amount of fat. However, this test is less well studied and without any standardized diagnostic criteria so far. And in contrast to the OGTT, the OTTT has not been tested in the stroke population so far. Dr. Negar Asdaghi:         So, we're not just looking at those metrics of fasting sugar or fasting lipids and triglycerides specifically, we're looking at the patient's ability to metabolize glucose or triglyceride levels. So, now, with that understanding, can you tell us a little bit about the methodology of the study? Dr. Alexander Nave:       Yes, of course. So the Berlin “Cream&Sugar” study was a prospective observational study recruiting acute stroke patients between 2009 and 2017 at the Charité University Hospital in Berlin. And we included first-ever ischemic stroke patients within three days to seven days after onset of stroke, and all patients received a sequential OTTT OGTT. So, all recruited patients received fasting blood sampling in the morning before taking the OTTT with 250 cc of cream, which corresponds to 30% of fat intake. So, all patients without known diabetes mellitus additionally had the OGTT with 75 grams of glucose starting three hours after the OTTT. Dr. Alexander Nave:       And all patients received consecutive blood tests at three hours, four hours, and five hours after start of the OTTT to determine the course of glucose and triglyceride levels in the blood. And after one year, we performed follow up of all patients. The primary outcome was recurrent fatal or non-fatal ischemic stroke, and secondary outcome was a composite endpoint of recurrent vascular events, including ischemic stroke, TIA, myocardial infarction, and coronary revascularization, as well as cardiovascular death. And we compared patients with high versus low fasting and nonfasting triglyceride and glucose levels, respectively, using Cox regression analysis. Dr. Negar Asdaghi:         Okay. 250 cc of cream and 75 grams of sugar right after a stroke. Was it challenging to recruit patients? Dr. Alexander Nave:       Yes, that was a task. And we did experience some difficulties during the course of the study. It was not easy to ask a patient to drink a glass of cream during the first week after suffering from a stroke, obviously. In fact, a substantial number of patients eventually did not participate or did not complete the OTTT. However, in our study, we showed that performing a sequential OGTT OTTT within seven days after stroke was feasible. Approximately 10% of patients reported only minor adverse events such as nausea, diarrhea, and bloating. But with regards to the study population, overall, we enrolled 755 patients, 523 have completed the challenge and entered follow up. So, considering the fact that we had some difficulties in recruitment, was not surprising that we predominantly ended up with minor ischemic stroke patients, considering that we did not include patients with dysphagia or patients that were not able to give informed consent in the early phase after stroke. The median NIHSS was one with an interquartile range of zero to three. And, as I mentioned previously, this was because patients with impaired swallowing could not be included into the study. Dr. Negar Asdaghi:         Okay. So, 750 patients within a week after their stroke, majority of them, as you mentioned, had mild ischemic events, were enrolled, and then they underwent sequential OTTT and OGTT tests. And then they were followed for a year for the primary outcomes. Now I think we're ready to hear the primary results. Dr. Alexander Nave:       Sure. So, overall, 54 patients, 10% of the total population, reached a study endpoint within one year follow up. 31 patients experienced recurrent ischemic stroke within one year. So, when we compared the highest quartiles of triglyceride levels to the lowest quartiles, neither fasting nor postprandial triglyceride levels were associated with recurrent stroke. Similarly, fasting triglyceride levels were not associated with major cardiovascular events one year after stroke. Surprisingly though, higher postprandial triglycerides, measured at five hours after OTTT, were significantly associated with a lower risk for recurrent vascular events. The hazard ratio was 0.42, and the confidence interval 0.18 to 0.95. So, regarding glucose levels, on the other hand, we found no associations between glucose levels and recurrent vascular risk at all. Dr. Negar Asdaghi:         Interesting. So, before I ask you what your takeaway is from all of this, the first question is the 10% rate of primary outcome. Were you at all surprised by this? This seems quite high for the recurrent rate of vascular events after the first year after ischemic stroke and TIA. Dr. Alexander Nave:       Well, actually, when the “Cream&Sugar” study was designed, we expected the recurrent event rate to be even higher, approximately 10% of recurrent stroke events within one year and not 10% recurrent vascular events as a composite outcome. But as we know from previous registries, such as the TIA registry, the recurrent risk of vascular events after TIA and minor stroke is much lower now. So, I think with the reported 7% of recurrent stroke events, we're actually quite in line with the reports of the TIA registry, considering the fact also that we had no TIA patients enrolled in our study and had quite a high proportion of patients with large artery atherosclerosis as well as atrial fibrillation. Dr. Negar Asdaghi:         So, thank you. This is a grim reminder that ischemic stroke patients remain at high risk of having recurrent vascular events. Alex, what should be our top two takeaway messages from your study? Dr. Alexander Nave:       So, first, I think a sequential OTTT OGTT probably does not contribute a lot to future vascular risk stratification in ischemic stroke patients. So, I think all patients and carers can be relieved. There's no need to implement an OTTT into routine clinical care. However, based on our results, I think further studies are necessary and needed to better understand the importance of glucose and lipid metabolism in patients after acute ischemic stroke. And eventually we might figure out some nice information how we can improve risk prediction. Dr. Negar Asdaghi:         So, it's good to know that we don't have to ask patients to drink a lot of cream after stroke. Can you tell us a little bit about the future of the Berlin “Cream&Sugar” study group? What are the next steps for the authors and the study group? Dr. Alexander Nave:       Absolutely. Well, since there's no urgent need to start another large study soon, I think it would be reasonable to get our data and merge it with datas from other groups who also investigated the role of an OTTT in cardiovascular risk cohorts, also to increase power and detect some other signals. And we want to have a more detailed look at the variability of triglycerides and glucose levels following sequential OTTT OGTT. So, not only go into the absolute levels that you can measure at certain time points, but also how much these parameters fluctuate over time. Dr. Negar Asdaghi:         To Alexander Nave, it's been a pleasure interviewing you on the podcast today. We look forward to covering more of your work in the future. Dr. Alexander Nave:       Thank you very much. It was a pleasure to talk to you. Dr. Negar Asdaghi:         And this concludes our podcast for the August 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three topical reviews, from “Strategies for Maintaining Brain Health: The Role of Stroke Risk Factors Unique to Elderly Women” to “Ethical Considerations in Surgical Decompression for Stroke.” These articles summarize a large body of evidence, which I encourage you to review. And before we end our August podcast, I'd like to take a moment to recognize the incredible dedication and hard work of our medical students and fellows, especially the young doctors who are just starting their training this year. Dr. Negar Asdaghi:         And if you happen to be one of those young doctors who is listening to our podcast in one of those sleepless on-call nights, I want to recount the story of Dr. Carl David Anderson, who won the Nobel Prize in physics for his discovery of the first particle of antimatter known as positron on August 2, 1932. A positron is actually the identical twin of the well-known negative electron, and its discovery in the 1930s truly changed our understanding of the origin of the universe, and it's practically impacted all aspects of science, not to mention it's impacted medicine and medical imaging. But the moral of the story lies in the fact that on August 2, when Anderson announced his discovery, he was a post-doctoral fellow himself, hadn't even graduated yet. So, if you are such a trainee, I hope you know that your hard work, combined with that incredible scientific inquisition, has the potential to change our understanding of the universe. And what better way to do this? You guessed it, than staying alert with Stroke Alert. Dr. Negar Asdaghi:         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 more, visit AHAjournals.org.

The First Principles of Atrial Fibrillation that can get you through the OSCE: Dr Will Courtney teaches us all how to succeed in this OSCE scenario. === Other Links === Check out our Notion document for First Principles, Free Anki flashcards, and Podcast: https://bit.ly/3RekXpe Check out our Instagram: https://www.instagram.com/firstprinciplesofmedicine/ Recorded 24 May 2022 Co-hosts: JT Yeung, Adian Izwan, Jason D'Silva, Daniel Bontempo feat. Dr Will Courtney. If you have any ideas or feedback, comment on this Notion document, or shoot us an email at firstprinciplesofmedicine@gmail.com === Timestamps === (01:03) Recognizing AF (04:47) Causes of AF (08:02) CHA2DS2-VASc (09:58) Anti-coagulation (12:21) AF definitions (15:03) Rate of rhythm control (16:04) Exceptions to anticoagulation (16:37) Paroxysmal AF (19:50) Summary (22:05) OSCE Do's and Dont's (25:08) Follow-up

This podcast is the second in a series of three featuring insights from expert cardiology pharmacists on nonvalvular atrial fibrillation (NVAF). In this episode, cardiology pharmacist Stephanie Dwyer Kaluzna, PharmD, BCCP, reviews key literature and guideline recommendations for stroke prevention in patients with NVAF. Dr Dwyer Kaluzna discusses the most recent evidence for prescribing, dosing, and monitoring direct oral anticoagulants (DOACs); using the risk-screening tools HAS-BLED and CHA2DS2-VASc to design patient-specific pharmacotherapy plans; and the use of DOACs in special patient populations, including older patients, patients with end-stage renal disease, and patients with low or high body weights.Presenter:Stephanie Dwyer Kaluzna, PharmD, BCCP  Clinical Assistant ProfessorDepartment of Pharmacy PracticeUniversity of Illinois Chicago College of PharmacyCardiovascular Clinical PharmacistUniversity of Illinois Hospital and Health Science SystemChicago, IllinoisContent is based on an online CE program supported by an educational grant from the Bristol Myers Squibb Pfizer Alliance.This podcast series was first delivered as live webinars, which are now available as on-demand, CE-certified microlearning modules with downloadable slidesets. The program also features a ClinicalThought commentary and a downloadable infographic reference guide. To access the full program, go tohttps://bit.ly/3OMazV8

Episode 73: Anticoagulation in Afib. When should you start anticoagulation in atrial fibrillation? What medications are appropriate? Virginia Bustamante, Charizza Besmanos and Dr Arreaza discuss this topic.  By Charizza Besmanos, MS4; Virginia Bustamante, MS4; and Hector Arreaza, MDCharizza: Hello, welcome to today's episode of Rio Bravo qWeek Podcast. My name is Charizza Besmanos, a 4th year medical student from American University of the Caribbean and I am joined here today by Virginia Bustamante.  Virginia: I'm Virginia Bustamante, an incoming 4th year medical student from Ross University.  Arreaza: And I'll be here just to make sure that you guys behave during this episode. Charizza: Before we get started on our discussion, I have a quick patient case to share with you.  This is a 66-year-old woman who is brought to the ED with sudden onset of severe difficulty speaking and weakness while having breakfast. She has hypertension, hyperlipidemia, severe left atrial enlargement seen on previous ECHO, and is noncompliant with her medications. She is a lifetime nonsmoker and does not drink alcohol. On admission, her blood pressure is 152/90 and pulse is 124/min and irregularly irregular. She is awake and alert but has difficulty finding words while trying to speak. She has severe right lower facial droop and marked weakness and sensory loss in the right arm and mild weakness in right leg. Fingerstick glucose is at 105. ECG shows atrial fibrillation. Acute stroke management is started right away. CT shows occlusion of the left MCA. What management could have prevented this complication?  Virginia: This patient clearly has multiple risk factors for thromboembolism events but given her irregularly irregular pulse consistent with atrial fibrillation, she would've warranted long-term anticoagulation to prevent stroke, which she most likely had.  Charizza: Exactly. Today's topic is atrial fibrillation, specifically the use of anticoagulation. __________________This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it's sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. __________________ Virginia: Anticoagulation is indicated to decrease the risk of thromboembolic events such as ischemic stroke in patients with atrial fibrillation (A-fib). Not all patients receive anticoagulation. Like most things in medicine, you must decide to start anticoagulation when the benefits of decreasing the risk of stroke outweighs the risk of bleeding. So, for assessing the risk of stroke in A-fib, the American College of Cardiology along with American Heart Association and the Heart Rhythm Society published a guideline in the Journal of the American College of Cardiology in 2014 and was recently updated in 2019[1] detailing in which patients anticoagulation is recommended.  Charizza: Yes, according to the guideline, “high risk patients” are all patients with valvular A-fib, and those with nonvalvular A-fib with a CHADVASC score of >/= 2 in men or >/= 3 in women, and those with nonvalvular Afib and hypertrophic cardiomyopathy. Those with “medium risk” are patients with nonvalvular Afib with CHAD2VASc score of 1 in men or 2 in women. In these patients, anticoagulation is considered but the risk and benefits are discussed with the patient. Those with “low risk” are patients with CHAD2VASc score of 0 in men or 1 in women and anticoagulation is not routinely recommended in these patients. Can you tell us briefly what CHA2DVASc score is?  Virginia: CHA2DS2-VASc score is the stroke risk assessment tool of choice by the AHA/ACC/HRS guideline. It is great because it is a mnemonic. Each letter is assignment 1 point except for 2 criteria. C stands for congestive heart failure, H for HTN defined as >140/90, A2 is for or Age>75 which is for 2 points, D for diabetes, S2 is for stroke or TIA and it's for 2 points, V for vascular disease such as MI, A for age 65-74, S for female sex.  Charizza: That certainly makes it easy to remember. Not only that, but you can also find CHA2DS2-VASc score of MDCalc to make it even easier. Virginia: Now that we've established which patients should receive anticoagulation, how do we choose which anticoagulant?  Charizza: For this discussion today, I would like to focus on nonpregnant patients. There really are 2 main anticoagulants, DOACs (or the direct oral anticoagulants) and warfarin. DOACs are the direct thrombin INH (dabigatran) and the direct factor Xa INH (rivaroxaban, apixaban, and edoxaban). DOAC is recommended as first-line in the long-term management of nonvalvular afib as trials have shown DOACs are more successful at reducing risk of thromboembolic events and have a lower risk of bleeding than warfarin and warfarin requires INR monitoring with dose adjustments. Although, in patients with valvular Afib, warfarin is preferred. Arreaza: All of them are by mouth.  Virginia: Dosing of DOACs depends on the kidney function, so it is important to obtain the creatinine clearance. For dabigatran, the direct thrombin INH, the recommended dose for patients with CrCl >30 mL/min is 150mg PO twice daily based on the results from the RE-LY trial (2), which evaluated the efficacy and safety of dabigatran with warfarin in patients with Afib. For patients with CrCl of 15-30 mL/min, the recommended dose is 75mg PO BID. Those with CrCl 1.5, patient who is > 80years old or body weight

This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis." 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 co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up. Dr. Carolyn Lam: First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance. Dr. Carolyn Lam: What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen. Dr. Greg Hundley: Really interesting, Carolyn. Clinically, what are the implications today as we see these patients? Dr. Carolyn Lam: Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg? Dr. Greg Hundley: Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury. Dr. Carolyn Lam: Oh, wow. Interesting, Greg. what did they find? Dr. Greg Hundley: Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits. Dr. Carolyn Lam: Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic. Dr. Greg Hundley: Wow, Carolyn, really interesting. Can you summarize it for us? Dr. Carolyn Lam: Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy. Dr. Carolyn Lam: Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood. Dr. Carolyn Lam: Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find? Dr. Greg Hundley: Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production. Dr. Carolyn Lam: Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece. Dr. Greg Hundley: Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles? Dr. Carolyn Lam: Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation? Dr. Carolyn Lam: Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found? Dr. Alexander Benz: Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies. Dr. Alexander Benz: Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable. Dr. Alexander Benz: Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy. Dr. Carolyn Lam: Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation? Dr. Lars Wallentin: I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients. Dr. Lars Wallentin: This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments. Dr. Carolyn Lam: Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex? Dr. Alexander Benz: Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from. Dr. Carolyn Lam: Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable? Dr. Lars Wallentin: Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples. Dr. Carolyn Lam: Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish? Dr. Alexander Benz: Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this. Dr. Lars Wallentin: Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course. Dr. Carolyn Lam: Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion. Dr. Carolyn Lam: Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found? Dr. Timothy McKinsey: Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension. Dr. Carolyn Lam: You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found? Dr. Timothy McKinsey: Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction. Dr. Timothy McKinsey: We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction. Dr. Carolyn Lam: Very nice. If you could just give us a one-line on how will you find this hidden fibrosis? Dr. Timothy McKinsey: We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at extracellular matrix protein expression in the heart, there was really a profound increase in ECM protein expression in this mouse model, even though the staining for fibrosis was negative. That told us that there was this underlying hidden fibrosis. Dr. Carolyn Lam: Oh, that is really interesting. And so it is that form of fibrosis that was actually reversed, perhaps, by the HDAC inhibition, and that's what you showed. Would that be accurate to say? Dr. Timothy McKinsey: Yeah. So the HDAC inhibitor really had this profound ability to block that ECM remodeling, the hidden fibrosis, to the point where initially we thought it was an artifact. We thought maybe there was a mix-up of samples. It wasn't a mix up. It's just that the compound, this inhibitor of HDAC enzymatic activity, really has this amazing ability to block the formation of hidden fibrosis. Dr. Carolyn Lam: Oh, wow. Wow, Tom, I really, really loved your editorial where you put all of this in context and talked a little bit about the translational and clinical potential. Could you maybe share your thoughts here? I love the title by the way, Erasing Hidden Fibrosis. Dr. Thomas Gillette: Thanks. Thanks for that. Yeah, first of all, Tim, it was a really great piece of work, and it's actually really exciting because when we think of this diastolic dysfunction, and really it's the development of HFpEF, I think, that a lot of people are... It's the single most critical unmet need in cardiovascular medicine, is the treatment for HFpEF. That diastolic dysfunction, it's really that stiffness that Tim was measuring with his atomic force microscopy and those changes in ECM that really seemed to be critical, at least in that model. Dr. Thomas Gillette: And we know from other models as well that these underlying changes in fibrosis and stiffness, perhaps in the ECM, play a really important role, not only in the diastolic dysfunction, but also if you think about in strain as well, because I know in our models of HFpEF and this mouse model of HFpEF, we have the two-hit model published that Gabrielle, a Allie developed with Dr. Hale in Nature. It's that strain that we could measure that really seems to correlate well with the heart failure phenotype. And so it begs the question, has he caught a very early change in the ECM that's really critical to the development of this pathology? And is there a way that we could detect it early on in patients? Is there a way we could measure that in patients and really get a sense of who's progressing and how they're progressing? Dr. Thomas Gillette: Then there's a second point, and I mentioned a little bit in the editorial, I didn't go into it too deeply, and that is, it's really intriguing what this might mean for the development of the disease, because the matrix not only is involved in stiffness, but it's also a reservoir for growth factors, it helps recruit inflammatory cells, and inflammation plays a huge role in HFpEF. And so it begs the question, how many of those changes may proceed a lot of that pathology as well? Dr. Carolyn Lam: Wow, Tom, I really couldn't agree more. I made a big deal earlier about agreeing with Tim, calling this a diastolic dysfunction model rather than HFpEF, but I completely agree with you that the implications are for the development of HFpEF, and it needed the begs, the question of how many patients actually have this hidden fibrosis? And we know that in patients with HFpEF, there is a stage of advanced fibrosis where we feel patients don't respond to treatment as well. So have we caught an early phase that may be clinically applicable? I really loved the way you worded that. But finally, with Sergio, could you put it all together and what the editors thought of this paper? Why you invited Tom to write this editorial? And perhaps what next steps are? Dr. Sergio Lavandero: Okay, Tim, this is really a fascinating work. I have a long road, because in Italy, you develop the most important new concept. The new concept, the hidden fibrosis. The second important, originally, most of the HDAC inhibitors were developed for other diseases, originally for cancer. So now we have more data that, probably, this compound can apply to other diseases like cardiovascular disease. It was difficult to convince at the beginning some reviewers about the concept of hidden fibrosis, because it's not traditional. But finally, we asked to another expert to, "Okay, why don't you explain, please, this new technique?" For the future, Tim, what do you think? How can we evaluate hidden fibrosis in patients? Dr. Timothy McKinsey: Ideally, and you would have a non-invasive approach to assessing hidden fibrosis in patients. Obviously I know myocardial biopsies could be analyzed using the mass spec approach and atomic force microscopy, but not everyone is going to want to get a myocardial biopsy. So ultimately, we would like to correlate data that we obtain with biopsies, with circulating factors to see if there is a non-invasive surrogate circulating factor that correlates with the existence of hidden fibrosis. I think that would be very powerful clinically. Dr. Sergio Lavandero: What do you think the specificity of this research, because maybe it's too broad? What do you think? Dr. Timothy McKinsey: Yeah, that's a great point. There's a negative impression of general HDAC inhibition, because people just can't believe that you could inhibit a large number of HDAC enzymes throughout the body and not kill someone. But you can. And in our models you can use pretty low doses of these HDAC inhibitors and see efficacy. But obviously, the holy grail in this field would be to identify specific HDAC isoforms that regulate specific disease processes. So we have an active area of investigation where we're trying to tease apart the roles of different HDACs in the heart, with the ultimate goal of finding the HDAC or a subset of HDACs that regulate in fibrosis. Then you could selectively inhibit those and perhaps have a safer drug than a general HDAC inhibitor. Dr. Carolyn Lam: Thank you, once again. This is an amazing discussion and really, really an example of just the kind of papers we love publishing at Circulation. So novel and with such translational potential. Thank you, Tim, again, and Tom and Sergio. Thank you, audience, for joining us today. From Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

This week feature a Double Feature of Discussions. In our first discussion, author Larry Allen and Associate Editor Justin Grodin discuss the article "An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial." Then in our second discussion, author Benjamin Scirica and Associate Editor Sandeep Das discuss the Research Letter "Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control." 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 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. Dr. Carolyn Lam: Dr. Greg, I really love these double features that we have in 2021. Let me tell you about the first one. We are going to be talking about the EPIC heart failure trial. That's the electronically delivered patient activation tool for intensification on medications in HFrEF. Very important results. Dr. Greg Hundley: Yes, Carolyn. And the second feature is going to evaluate an algorithm based cardiovascular risk management program to improve lipid and hypertension control. But before we get to the double feature, how about we grab a cup of coffee and start with some of the other articles in the issue? Dr. Carolyn Lam: My coffee is right here and I want to talk about, guess what? SGLT2 inhibitors again for this first paper. Dapagliflozin, as we know, reduces the risk of end stage renal disease in patients with chronic kidney disease. We saw that in the DAPA-CKD trial. However, the primary and secondary preventive effects of SGLT2 inhibitors on cardiovascular outcomes have not been studied in patients with chronic kidney disease, with and without diabetes. Dr. Greg Hundley: Well Carolyn, remind us a little bit, what were the end points in the DAPA-CKD trial? Dr. Carolyn Lam: Okay, well yes. DAPA-CKD as a reminder, randomized more than 4,000 participants with chronic kidney disease to dapagliflozin, 10 milligrams daily or placebo. The primary endpoint was a composite of sustained decline in GFR of more or equal to 50% or end stage kidney disease or kidney or cardiovascular death. The secondary end points were a kidney composite outcome, the composite of hospitalization for heart failure or cardiovascular death and all cause death. Now the current paper is a pre-specified subgroup analysis where authors led by Dr. John McMurray from University of Glasgow, divided patients into primary and secondary prevention subgroups according to the history of cardiovascular disease. And results showed that dapagliflozin reduced the risk of the primary composite outcome to a similar extent in the primary and secondary prevention groups. This was also true for the composite of heart failure hospitalization or cardiovascular death and all cause mortality. The combined cardio renal benefits of SGLT2 inhibitors in patients with chronic kidney disease with and without diabetes therefore are substantial, whether there is history of cardiovascular disease or not. Dr. Greg Hundley: Not very nice, Carolyn. Well, my paper comes from Dr. Pradeep Natarajan and his colleagues at the Massachusetts General Hospital. And Carolyn, this study evaluated whether premature menopause is associated with CHIP. For our listeners, CHIP stands for clonal hematopoiesis of indeterminate potential and it is the age related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy. And previously it's been shown associated with accelerated atherosclerosis. Dr. Carolyn Lam: Yikes. Greg, is pretty much our menopause associated with CHIP? Dr. Greg Hundley: Well Carolyn, the investigators, among 19,606 women, they identified 418 or 2.1% with natural premature menopause and 887 or four and a half percent with surgical premature menopause. Premature menopause, especially the natural premature menopause was independently associated with CHIP among post-menopausal women. Natural premature menopause, therefore may serve as a risk signal for predilection to develop CHIP and CHIP associated cardiovascular disease. Dr. Carolyn Lam: Interesting. Okay. Well, my next paper really provides the first evidence for endogenous induction of type-1 protein kinase A disulfide formation in the heart and this occurring after ischemia and re-profusion in both humans and mice. Dr. Greg Hundley: Ah Carolyn, so tell us more about this interesting paper. Dr. Carolyn Lam: Well, this is from Dr. Simon from University of Oxford and colleagues who used high spatial and temporal resolution imaging modalities in conjunction with an interesting redox dead type-1 protein kinase A knock-in mouse model and demonstrated that disulfide modification targets this type-1 protein kinase A to the lysosome where it acts as a gatekeeper for two poor channel mediated calcium release and prevents inappropriate triggering of calcium release from the sarcoplasmic reticulum. In the post ischemic heart, they found that inhibition of lysosomal calcium release by these oxidized molecules was crucial for limiting infarct size and preserving cardiac function during re-profusion. All this thus offering a novel target for the design of cardio-protective therapeutics. This is discussed in an editorial by Doctors Westenbrink, Nijholt, and deBoer from University Medical Center Groningen. Dr. Greg Hundley: Thanks, Carolyn. Very nice. Well, my last paper comes from Dr. Nicholas Marston and colleagues from the TIMI study group at Brigham and Women's Hospital of the Harvard Medical School. Carolyn, genome wide association studies have identified single nucleotide polymorphisms or SNIPs that are associated with an increased risk of stroke. The authors sought to determine whether a genetic risk score could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors across five trials involving the spectrum of cardiometabolic disease. Dr. Carolyn Lam: Interesting. And these genetic risk scores are very hot. What did they find? Dr. Greg Hundley: Thanks, Carolyn. Among 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up of two and a half years. Across a broad spectrum of subjects with cardiometabolic disease, a 32 SNIP genetic risk score was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation, but lower CHA2DS2-VASc two scores, the genetic risk score identified patients with risk comparable to those with higher CHA2DS2-VASc two scores. Dr. Carolyn Lam: Wow, that really is impressive. Well, guess what? We've got some other articles in today's issue. There's a beautiful White Paper about the definitions and clinical trial design principles for coronary artery chronic total occlusion therapies and this from the CTOARC consensus recommendations by Dr. Rinfret and colleagues from McGill University. There's a Research Letter entitled, The Randomized Control Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients with Type II Diabetes. And this is from Dr. Hong and colleagues from Yonsei University College of Medicine in Korea. Dr. Greg Hundley: Thanks, Carolyn. Well I have an exchange of letters from Doctors Albiero and Xie regarding the previously published paper, Patent Foramen Ovale Could be a Source of Paradoxical Embolism and Lead to Adverse Outcomes in Hospitalized Patients with COVID-19 Pneumonia and DVTs.” There's also a Perspective piece to the 2020 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease from Dr. Bavry. And finally Carolyn, Dr. Tung has an ECG Challenge entitled, “Narrowing the Differential Diagnosis for a Wide Complex Tachycardia.” Well, how about we get on to both of our double features. Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Well listeners, we are here for our first feature discussion and we have with us today, Dr. Larry Allen from University of Colorado and our own associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical School in Dallas, Texas. Welcome gentlemen. Larry, could you walk us through the background that really formulated your hypothesis? And then what was the hypothesis that you wanted to test with your study? Dr. Larry Allen: Well, thanks again for having me. I'm a heart failure doctor. The research group that I work with has spent a lot of time on patient empowerment and think about medication prescribing for HFrEF as shared decision making. Thinking about this as a discussion between the patient and me, rather than me deciding what to do. As you know, patients are now coming into the office because they've seen direct to consumer advertising around medications, but typically those are very biased. They're advertisements that are for only patented drugs. And what I'm really trying to think about is what is my patient's overall regimen in terms of heart failure? Dr. Larry Allen: And so we developed a tool which was a three minute video to tell patients that they should come into their visit and be excited to have discussions about their medicines and then a one page checklist that basically said, "Here's what an optimal regimen of medicines looks like for a patient with heart failure and reduced ejection fraction and nobody's really on a perfect regimen, but these are all the possibilities that you could have." Our hypothesis was that if we delivered that to patients before the clinic visit, that it would lead to better prescribing of these drugs. Essentially we imparted on a randomized trial within our healthcare system to do that and that's what we're discussing today, the results of the EPIC heart failure trial. Dr. Greg Hundley: Very nice, Larry. Tell us a little bit, what patients did you enroll in your trial? And then what outcomes did you work to assess? Dr. Larry Allen: We're part of the UC Health System, which has 12 hospitals, but a number of cardiology clinics across the front range of Colorado. Our entire system is on a single instance of the EPIC electronic health record so we're now able to essentially automatically identify all the patients in our system who have HFrEF. We generated lists of patients who had HFrEF who were going to see a cardiology provider in clinic and then we identified them ahead of time, enrolled them in the study prospectively. And the enrollment was for them to agree to be randomized in the study and then for us to be able to collect data on them. Dr. Larry Allen: The patients were kind of a wide range of HFrEF. They were an average of 65 years old, about 70% of the patients were male and reflected the race and ethnicity of Colorado with 11% Blacks and about 7% Hispanics. And everybody in the study had an ejection fraction of 40% or less on their last echocardiogram or other recent cardiac study. And then they were randomized to either get this three minute video sent to them as an email or as a text link that kicked them over to the one page checklist. And then we had them come in. A 145 patients came to clinic having got the information and a 145 patients just came to clinic like usual. Dr. Greg Hundley: Very nice. What did you find, Larry? What were your results? Dr. Larry Allen: Yeah, so we found not surprisingly that the majority of patients who were in usual care had no change to their medical regimen. What we found in the patients who received the EPIC heart failure three minute video and checklist, we saw about a 19% absolute increase in intensification of guideline directed medical therapy. And then we found that most of that was actually an increase in beta blocker dose prescribing. To some extent, the cheapest therapy that could be increased on a drug that people are already on. Dr. Greg Hundley: Very good. Well Justin, we'll turn to you. Help us put the results from Larry's work in the context of A, management of patients with heart failure and reduced ejection fraction and then also B, tell us a little bit about what attracted you to this article and maybe even where you see some of this going next. Dr. Justin Grodin: Thanks, Greg. And Larry, obviously I want to echo Greg's comments by thanking you for your submission. This was a paper that we thought obviously very highly of. Greg, for your first point, we've got novel therapies, but really one of the major issues now is not can we find a newer, better drug? I think we've all come to this realization, it's scalability and implementing these therapies into our regular practice, like beta blockers, RAS inhibitors and mineralocorticoid receptor antagonists. And as Larry said, the problem now is not the quality of our therapies, it's really scaling it and getting it to everyone. It's also increasing these therapies to optimum dosages in patients that can tolerate it over time. Dr. Justin Grodin: And then, to answer your second question, I think some of the things that struck us by this was that this is a wonderfully simple intervention that truly does empower patients. The majority of our interventions to optimize medical therapy has been targeting the physicians, the APP, the nurses, et cetera. This is beautiful in that it empowers the patient and we are putting the ball in their court. And I think to kind of dovetail with your third question, this is a health system clinical trial and I think that tells us a few things. I think one, it provides the framework on how one could perhaps implement that in their health systems. And we'll have to see if this is something that could translate to other health systems across the country or multiple centers. But I think really the intrigue with this work is that it all comes back to empowering the patients. Dr. Greg Hundley: Very nice. Dr. Larry Allen: Greg, I wanted to just add one thing that in the heart failure community, there's this argument going back and forth about whether the lack of optimization of guideline directed medical therapies is due to intolerance or whether it's due to therapeutic inertia. And one of the things I like about this study is on face value, we're empowering patients, but the fact that by asking patients to get involved in prescribing decisions, I think one of the take home messages is that this is partially about therapeutic inertia and that as clinicians, we have a lot of things we're dealing with. And if patients come in to the clinic visit and they're motivated to make these changes actually, we can intensify the therapy. Dr. Greg Hundley: Very good. Larry and Justin, both one at a time here quickly, in the last minute that we have, what do you see as the next study, Larry, that needs to be performed in this space? Dr. Larry Allen: I see two things quickly. One is, as Justin mentioned, validating that this kind of intervention, while simple can be pragmatically deployed in other health systems and in other contexts. The second thing is how do we integrate this kind of small intervention with the larger overall care of patients? One of the concepts that I've talked a lot about over the years with others, including Len Stevenson, is this concept of an annual heart failure review, where rather than seeing people on multiple short visits where we tackle small issues, we actually create a little bit of time to stand back and take a global view of heart failure therapy and how that heart failure therapy fits into the goals of care for the patient, the other medical problems they have and where they're headed. Dr. Greg Hundley: Very good. Justin, anything? Dr. Justin Grodin: Greg, I have to agree with Larry. I think he hit the nail on the head with his first comment. At least for me from an editorial standpoint is really we like to see how generalizable this is and really this implemented in other health systems. I think that's the logical next step. I can tell you, at least from our discussions at our medical center about this manuscript since it's been published at Circulation is, is there something like this we could implement in our own health system? Or in the health systems that we're affiliated with? Dr. Larry Allen: And I would just add that this research and the intervention was funded by the American Heart Association under the strategically focused research network for heart failure and so we've made the interventions public they're online at the research website we have, patientdecisionaid.org. Dr. Greg Hundley: Well fantastic. Well listeners, we want to thank Dr. Larry Allen from University of Colorado and our associate editor, Dr. Justin Grodin from UT Southwestern, for bringing us this article, demonstrating a process that facilitates patient physician interactions to improve the administration of guideline based therapy to patients with heart failure and reduced ejection fraction. And so we're going to wind up this feature discussion and we will head to our next feature. Dr. Greg Hundley: And we have with us Dr. Benjamin Scirica from Brigham and Women's Hospital and our own associate editor, Dr. Sandeep Das from UT Southwestern. Benjamin, could you tell us a little bit about the background information that you used to formulate your hypothesis that you wanted to test for this study? Dr. Benjamin Scirica: Thanks so much first for the invitation. It's a great honor to obviously be in Circulation and to be part of this podcast. We started with the recognition that in our practice, which is similar, I think to a lot of the United States, we are not doing as good a job as we could in terms of care for a lot of the chronic cardiovascular conditions we see. And hypertension and high cholesterol are one of those clear areas where we know there are very good guidelines with clear indication for therapy in specific situations and that these drugs that are available are predominantly generic. But when we looked at our registries, we found that we were not doing as well as we thought. We felt that there are a lot of reasons for that. Dr. Benjamin Scirica: A lot of it was based on the fact that for something good to happen, the right thing to happen, you have to have a patient and a doctor in the same room, the doctor has to recognize that there's a problem. They have to know that there is something they can do about it. They have to be able to convince the patient or educate the patient that they should start this new therapy. They have to know how to start the therapy and then have the ability to follow up and make sure that there is longitudinal care for these chronic diseases. Dr. Benjamin Scirica: And that's a lot to ask for any of us when we have 15 minutes to see the patient, we may only see the patient a couple times a year at most. And so we felt that our hypothesis is, could we design a program, would be delivered remotely, that would not require a doctor in the middle of all of these decisions and that we could scale by using lower cost resources, non-licensed healthcare coordinators or navigators and pharmacists who could follow very clear treatment algorithms to be able to identify patients and prescribe the right medicines to patients at the right time, based on their cardiovascular risk. Dr. Greg Hundley: What was your study design? And what was your study population? Dr. Benjamin Scirica: This is an active, ongoing quality improvement program where our hypothesis is that by doing this, we could improve patients' lipids and cholesterol prescriptions compared to prior. And we did some analysis and we saw that a lot of these patients had not been on optimal therapy for many years, even though they've been in our system. With the limitations of not having randomization, we identified these patients and through different clinics in the different hospitals, and would either have patients referred to us by providers or more commonly go and find them within the registries and identify the patients and contact them and have them enter our program where they would usually take somewhere between eight to 12 weeks to be actively managed, to get to their goals and then they'd enter a maintenance program. The report that we do now is that the story of the first 5,000 patients who we enrolled in our program of whom about 35% were still in management at the time we presented these ongoing results. Dr. Greg Hundley: Roughly how old were these participants? And what was the breakdown in terms of gender or sex distribution? Dr. Benjamin Scirica: We found that about 12% were over 75 years old, a little over half were female. We had 71% who are non-Hispanic Caucasian and 8% who were non-English speaking. In terms of their cardiovascular risks, about a third of the patients had established cardiovascular disease, about a quarter of the patients had diabetes and about a third had an LDL of more than 190 milligrams per deciliter, but no history of ASCVD or diabetes. And then for hypertension, we really would take anybody whom the physician felt required further blood pressure management, because their blood pressure was over 130 over 85. Dr. Greg Hundley: And what did you find? Dr. Benjamin Scirica: We found that of the 5,000 patients that we enrolled, about 4,000 were in the lipid program, a little over 1,400 we're in the hypertension program, so some patients were in both programs and in the lipid patients, in those patients who achieved maintenance, we increased lipid therapy, any lipid lowering therapy, from about 78% up to 97%. And that was predominantly through statins but we doubled the use of ezetimibe from 9% to 17%. We saw a small increase in PCSK9 inhibitor use from 1% to 3%. And if we looked at LDL reductions, it was a 52 milligram per deciliter reduction in LDL from an average LDL of a 125 down to 73 in those folks who achieved maintenance. For blood pressure, again, in those patients whom we successfully treated who are about 600 patients, we saw a 14 millimeter systolic blood pressure reduction and a seven millimeter mercury diastolic blood pressure reduction. Dr. Greg Hundley: Wow. Well Sandeep, what drew your attention to this? And then also, how do you put the context of these results with others that really are working in this wing of data science in cardiovascular medicine? Dr. Sandeep Das: Great question. We have a large body of literature that suggests that the use of these fantastic evidence based therapies like statins, like blood pressure medications is poor and we really struggle to improve those numbers. I wanted to applaud Ben and his group for really taking on, in a robust way, an important topic and subject. The other thing that really attracted me to this study, there was a hypertension expert here named Ron Victor back when I first started as a fellow. Fantastic researcher and he did a project called Colloquia called the Barbershop Project about leveraging pharmacists and barbers to improve the blood pressure control of African American men in the community. Dr. Sandeep Das: The idea is that you get out there, you got to go to where the patients are rather than expecting them to come to you. And you got to figure out ways to engage them, activate them, get them to participate in their own care. A fantastic study, but the one thing that always, we discuss that study, the thing that always jumps out is, well how do you scale it? How do you use it in a real practice? To me was also a very exciting aspect to this. The goal is to take steps to generalize from clinical trials to real world practice, because we got to get this to patients. Dr. Greg Hundley: Very nice. Well Ben, coming back to you, what do you see as next steps for your research here? And then even in the field? Dr. Benjamin Scirica: The first is, are there other disease areas we can do this in? I think the second part is how to test different techniques to try to improve the ability to scale it to broader populations and keep the cost down. And I think it is a combination of trying to find the right tools, whether they're digital or not and the right techniques to be able to activate patients, educate them, such that they are asking the question, "How come I'm not on these medicines? How come I'm not on this?" And I think we could do a lot in terms of AB testing in there. The part that I think is challenging in these healthcare studies and quality improvement studies, is that randomization would be great. How can we do it streamline? Do we need to get consent? Can it just be that approved drug A can be tested against approved drug B because there is clear equipoise. And I think by doing that, we could lower the bar for really pragmatic randomization in practice and be able to have much more rapid cycles of improvement and optimization on therapy. Dr. Greg Hundley: Very good. Sandeep, do you have anything to add? Dr. Sandeep Das: I'll echo Dr. Scirica's called arms here that we need to have a way to do this, do trials in this space pragmatically. I agree with that strongly. I did have a few thoughts on next directions. I work in a population of the urban poor of Dallas County with a lot of my clinical time and these patients have poor health literacy so I think that one question, not question but suggestion or comment to Ben and his group would be to think hard about how you would expand this to lower resource setting or to people that would be a little harder to reach. And even as sort of an aspirational goal, how do you expand it into the community? The other question that I would have is how much of this can we get by with adherence interventions? It's one thing to prescribe, but it's another thing to figure out how to get people to adhere to meds. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Ben Scirica for Brigham and Women's and Dr. Sandeep Das from UT Southwestern, bringing us this really interesting research that has been providing early results of a remotely delivered pharmacist led lipid and hypertension management strategy that dramatically increased medication compliance and improved hypertension control and lipid management. Dr. Greg Hundley: 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, 2021.  

Paul J. Wang: Welcome to the monthly podcast, On the Beat for Circulation: Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, Editor-in-chief, with some of the key highlights from this month's issue. In our first paper, Zak Loring and associates examined 3,139 patients undergoing atrial fibrillation (AF) ablation, between 2016 and 2018 in the Get With The Guidelines-Atrial Fibrillation Registry from 24 US centers. Patients undergoing AF ablation were predominantly male (63.9%) and Caucasian (93.2%) with a median age of 65. Hypertension was the most common comorbidity (67.6%), and persistent atrial fibrillation patients had more comorbidities than paroxysmal AF patients. Drug refractory, paroxysmal AF was most common ablation indication (class I, 53.6%) followed by drug refractory, persistent AF (class I, 41.8%). Radio-frequency, RF ablation, with contact force sensing was the most common ablation modality (70.5%) and 23.7% of patients underwent cryoballoon ablation. Pulmonary vein isolation was performed in 94.6% of de novo ablations. The most common adjunctive lesion included left atrial roof or posterior/inferior lines and cavotricuspid isthmus ablation. Complications were uncommon (5.1%) and were life-threatening in 0.7% of cases. In our next paper, Brian Howard and associates hypothesize that pulse field ablation (PFA) would reduce pulmonary vein stenosis risk and collateral injury compared to irrigated radiofrequency ablation (IRF). IRF and PFA deliveries were randomized in eight dogs with two superior pulmonary veins (PVs), ablated with using one technology and two inferior PVs ablated with the other technology. IRF energy (25-30 watts) or PFA with delivered (16 pulse trains) at each PV in a proximal and in a distal site. Contrast computed tomography (CT scans) were collected at 0, 2, 4 and 8, and 12 week, including termination time points to monitor PV cross-sectional area at each PV ablation site. Maximum average change in normalized cross-sectional area at 4 weeks was 46.1%±45.1% post IRF compared to -5.5±20.5% for PFA (P≤ to 0.001). Necropsy showed expansive PFA lesions without stenosis in the proximal PV sites compared to more confined and often incomplete lesions after IRF. At the distal PV sites only IRF ablations were grossly identified based on focal fibrosis. Mild pulmonary chronic parenchymal hemorrhage was noted in three left superior pulmonary vein lobes after IRF. Damage to vagus nerves, as well as evidence of esophagus dilation, occurred at sites associated with IRF. In contrast, no lung, vagal nerve, or esophageal injury was observed at PFA sites. In our next paper, Mohamed Diab and associates aimed to assess the safety of ablation for atrial fibrillation (AF) with trans-esophageal (TEE) screening on intracardiac echocardiography (ICE) imaging of the appendage in direct oral anticoagulant (DOAC) compliant patients. They studied 900 patients with a medium CHA2DS2-VASc score of two. Interquartile range one to three. All consecutive patients presenting with AF or atrial flutter on DOAC were included. All were on DOACs (333 Rivaroxaban, 285 Dabigatran, 281 Apixaban and one Edoxaban). Thromboembolic complications occurred in four patients (0.3%), two ischemic strokes, one transient ischemic attack without residual deficit and one splenic infarct, all with no further complications. Bleeding complications incurred in 5 patients (0.4%), including 2 pericardial effusions (1 intraoperative, 1 after 30 days, both drained), and 3 groin hematomas (1 due to needing heparin for venous thrombosis, none requiring intervention). No patients required emergent surgeries. In our next paper, Alexios Hadjis and associates aim to explore the role of complete diastolic pathway activation mapping on ventricular tachycardia (VT) recurrence. They studied 85 consecutive patients who underwent VT ablation using and guided by high-density mapping. During activation mapping, the presence of electrical activity in all segments of diastole defined the evidence of having had recorded the whole diastolic interval. Patients were categorized as having recorded the full diastolic pathway, partial diastolic pathway or no diastolic pathway map performed. Recurrences of VT were defined as appropriate IC therapies or on the basis of EC documented arrhythmia. Complete recording of the diastolic pathway was achieved in 36 of 85 (42.4%). Partial recording of the diastolic pathway of clinical VT was achieved in 24 of 85 (28.2%). No recording of the diastolic pathway of clinical VT was feasible in 25 of 85 patients (29.4%). At a mean of 12.8 months, freedom from VT recurrences was 67% in the overall cohort. At a mean of 12.8 months, freedom from VT recurrence was 88% in patients who had full diastolic activity recorded, 50% of partial diastolic activity recorded and 55% in those who underwent substrate modification (P=0.02). The authors concluded that mapping of the entire diastolic pathway was associated with a higher freedom from VT occurrence compared to partial diastolic pathway recording and substrate modification. The use of multielectrode mapping catheters in recording diastolic activity may help predict those VTs employing intramural circuits and further optimize ablation strategies. In our next paper, Hui-Nam Pak and associates investigated whether electrical posterior box isolation (POBI) may improve rhythm outcome of catheter ablation in patients in whom persistent atrial fibrillation changes to paroxysmal atrial fibrillation after antiarrythmic drug medication and cardioversion. They prospectively randomized 114 patients, 75% male, 59.8 years old to circumferential pulmonary vein ablation (CPVI) alone (n=57) and an additional POBI group (n=57). Primary endpoint was AF recurrence after a single procedure, and secondary endpoints were recurrence pattern, cardioversion rate and response to antiarrhythmic drugs (AAD). After a mean follow-up of 23.8 months, the clinical recurrence rate did not significantly differ between the CPVI alone and additional POBI group (31.6% versus 28.1%; P=0.682). The recurrence rate as atrial tachycardias, 5.3% versus 12.3% (P=0.14) and cardioversion rates, 5.3% versus 10.5% (P=0.25) were not significantly different between the CPVI and POBI group. At the final follow-up, sinus rhythm was maintained without antiarryhthmic drug in 52.6% of CPVI group and 59.6% of the POBI group (P=0.45). No significant difference was found in major complications between the two groups, 5.3% versus 1.8% (P=0.618). But the total ablation time was significantly longer in the POBI group (4187 seconds versus 5337 seconds; P

Ouça dica rápida sobre o assunto com a Dra. Ana Luiza Moreno

Bu yazıda, Avrupa Kardiyoloji Derneği (ESC) ve Avrupa Kardiyo-Torasik Cerrahi Derneği (EACTS) işbirliğiyle geliştirilen atriyal fibrilasyonun tanı ve yönetimi 2020 kılavuzunda​1​ yer alan güncel noktaları paylaşmak ve kılavuzda acil pratiğimizi etkileyen maddeleri vurgulamak istedim. Bu yazı kılavuzun tamamını içermemektedir, acil servis yaklaşımı ön planda tutulmuştur.  Kılavuzun tamamına buradan ulaşabilirsiniz. 2016 kılavuzunda yer alan bilgiler içinse Ş. Kerem Çorbacıoğlu’nun ilgili yazısına buradan ulaşabilirsiniz. Atriyal Fibrilasyon Tanımı ve Klinik Özellikleri Atriyal fibrilasyon, koordine olmayan atriyal elektriksel aktivasyon ve inefektif atriyal kontraksiyon sonucu meydana gelen bir supraventriküler taşiaritmidir. EKG bulguları şu şekildedir: Düzensiz R-R aralıkları  (atriyoventiküler iletimin bozulmadığı durumlarda)Belirgin tekrarlayan P dalgalarının olmamasıDüzensiz atriyal aktivasyon Klinik olarak AF; EKG ile gösterilmiş, semptomatik veya asemptomatik AF durumudur.  Tanı koymak için gereken izleme süresi en az 30 saniye veya 12 derivasyonlu EKG’nin tamamıdır. Atriyal yüksek hızlı epizod/subklinik AF tablosu ise AF semptomu olmayan, klinik AF'nin daha önce tespit edilmediği kişilerde kardiyak implante edilebilir ya da giyilebilir cihazlarla tespit edilmiş, atriyal fibrilasyon, atriyal flutter ya da atriyal taşikardi ataklarıdır. Semptomatik AF hastalarda senkop, baş dönmesi, göğüste sıkışma/ağrı, palpitasyon, nefes darlığı, egzersiz kapasitesinde azalma gibi şikayetlere neden olabilir. Senkop, semptomatik hipotansiyon, akut kalp yetmezliği/pulmoner ödem, devam eden miyokardiyal iskemi ve kardiyojenik şok durumu varsa hemodinamik anstabilite söz konusudur.  AF’ye bağlı komorbiditeler nedeniyle ölüm riski 1.5 ila 3.5 kat artar. Başlıca komorbiditeler arasında inme (iskemik inmelerin %20-30’u AF nedenlidir), sol ventrikül disfonksiyonu ve kalp yetmezliği ve bunlara bağlı gelişen klinik tablolar yer almaktadır. AF Sınıflaması İlk tanı: Semptom varlığı/ağırlığı ve süreye bakılmaksızın AF’nin ilk defa saptanmasıParoksismal AF: Kendiliğinden ya da başlangıçtan sonraki 7 günde sona eren AF atağıSürekli (persistent) AF: 7 günden fazla süren, devamlı ve sürekli AF atağı (ilaç veya elektriksel kardiyoversiyonla 7 gün sonra sonlanan epizotlar dahil)Uzun süreli ve sürekli AF: Ritim kontrol stratejisi belirlenen 12 ay ve üzerinde AFKalıcı (permanent) AF: Ritim kontrolü için müdahale yapılmayan 12 ay ve üzerinde AF Antikoagülasyon/İnmeyi Önleme Genel olarak AF, inme riskini beş kat artırır. Sık rastlanan inme risk faktörleri, kliniğe dayalı CHA2DS2-VASc skorunda özetlenmiştir. Bu skor riskli hastalarda tromboembolik olayları öngörmede ve buna yönelik tedaviyi belirlemede kullanılır. CHA2DS2-VAScSkorKonjestif kalp yetmezliği1Hipertansiyon1Yaş ≥ 752Diyabetes mellitus1İnme/GİA/Tromboemboli2Damar hastalığı(geçirilmiş MI, PAH ya da aortik plak)1Yaş 65-741Kadın cinsiyet1 Antitrombotik tedaviye başlarken, potansiyel kanama riskinin de değerlendirilmesi gerekir. Bu riskin öngörülmesi adına çeşitli skorlar mevcuttur ancak yüksek risk gruplarını (HAS-BLED skoru > 3) tanımada genel olarak HAS-BLED skoru daha başarılıdır. HAS-BLED skoruPuanHipertansiyon1Böbrek veya karaciğer hastalığı (her biri için 1 puan)1 veya 2İnme1Kanama öyküsü veya yatkınlık1Labil INR1Yaş > 651İlaç veya alkol kullanımı (her biri için 1 puan)1 veya 2 Akut Hız Kontrolü Hız kontrolü, AF yönetiminin ayrılmaz bir parçasıdır ancak AF’de optimal kalp hızı hedefi kesinleşmiş değildir. Farmakolojik hız kontrolü beta blokerler, digoksin, diltiazem ve verapamil veya bu ilaçların kombinasyonu ile sağlanabilir. Hız kontrol ilaçlarının seçimi semptomlara, komorbiditelere ve olası yan etkilere bağlı değişir. Akut hız kontrolünde enfeksiyon veya anemi gibi altta yatan nedenler her zaman değerlendirmelidir. İlacın seçimi ve hedef kalp hızı hasta özelliklerine, semptomlara, LVEF değerine ve hemodinamiye bağlı yapılır.

Bu yazıda, Avrupa Kardiyoloji Derneği (ESC) ve Avrupa Kardiyo-Torasik Cerrahi Derneği (EACTS) işbirliğiyle geliştirilen atriyal fibrilasyonun tanı ve yönetimi 2020 kılavuzunda​1​ yer alan güncel noktaları paylaşmak ve kılavuzda acil pratiğimizi etkileyen maddeleri vurgulamak istedim. Bu yazı kılavuzun tamamını içermemektedir, acil servis yaklaşımı ön planda tutulmuştur.  Kılavuzun tamamına buradan ulaşabilirsiniz. 2016 kılavuzunda yer alan bilgiler içinse Ş. Kerem Çorbacıoğlu’nun ilgili yazısına buradan ulaşabilirsiniz. Atriyal Fibrilasyon Tanımı ve Klinik Özellikleri Atriyal fibrilasyon, koordine olmayan atriyal elektriksel aktivasyon ve inefektif atriyal kontraksiyon sonucu meydana gelen bir supraventriküler taşiaritmidir. EKG bulguları şu şekildedir: Düzensiz R-R aralıkları  (atriyoventiküler iletimin bozulmadığı durumlarda)Belirgin tekrarlayan P dalgalarının olmamasıDüzensiz atriyal aktivasyon Klinik olarak AF; EKG ile gösterilmiş, semptomatik veya asemptomatik AF durumudur.  Tanı koymak için gereken izleme süresi en az 30 saniye veya 12 derivasyonlu EKG’nin tamamıdır. Atriyal yüksek hızlı epizod/subklinik AF tablosu ise AF semptomu olmayan, klinik AF'nin daha önce tespit edilmediği kişilerde kardiyak implante edilebilir ya da giyilebilir cihazlarla tespit edilmiş, atriyal fibrilasyon, atriyal flutter ya da atriyal taşikardi ataklarıdır. Semptomatik AF hastalarda senkop, baş dönmesi, göğüste sıkışma/ağrı, palpitasyon, nefes darlığı, egzersiz kapasitesinde azalma gibi şikayetlere neden olabilir. Senkop, semptomatik hipotansiyon, akut kalp yetmezliği/pulmoner ödem, devam eden miyokardiyal iskemi ve kardiyojenik şok durumu varsa hemodinamik anstabilite söz konusudur.  AF’ye bağlı komorbiditeler nedeniyle ölüm riski 1.5 ila 3.5 kat artar. Başlıca komorbiditeler arasında inme (iskemik inmelerin %20-30’u AF nedenlidir), sol ventrikül disfonksiyonu ve kalp yetmezliği ve bunlara bağlı gelişen klinik tablolar yer almaktadır. AF Sınıflaması İlk tanı: Semptom varlığı/ağırlığı ve süreye bakılmaksızın AF’nin ilk defa saptanmasıParoksismal AF: Kendiliğinden ya da başlangıçtan sonraki 7 günde sona eren AF atağıSürekli (persistent) AF: 7 günden fazla süren, devamlı ve sürekli AF atağı (ilaç veya elektriksel kardiyoversiyonla 7 gün sonra sonlanan epizotlar dahil)Uzun süreli ve sürekli AF: Ritim kontrol stratejisi belirlenen 12 ay ve üzerinde AFKalıcı (permanent) AF: Ritim kontrolü için müdahale yapılmayan 12 ay ve üzerinde AF Antikoagülasyon/İnmeyi Önleme Genel olarak AF, inme riskini beş kat artırır. Sık rastlanan inme risk faktörleri, kliniğe dayalı CHA2DS2-VASc skorunda özetlenmiştir. Bu skor riskli hastalarda tromboembolik olayları öngörmede ve buna yönelik tedaviyi belirlemede kullanılır. CHA2DS2-VAScSkorKonjestif kalp yetmezliği1Hipertansiyon1Yaş ≥ 752Diyabetes mellitus1İnme/GİA/Tromboemboli2Damar hastalığı(geçirilmiş MI, PAH ya da aortik plak)1Yaş 65-741Kadın cinsiyet1 Antitrombotik tedaviye başlarken, potansiyel kanama riskinin de değerlendirilmesi gerekir. Bu riskin öngörülmesi adına çeşitli skorlar mevcuttur ancak yüksek risk gruplarını (HAS-BLED skoru > 3) tanımada genel olarak HAS-BLED skoru daha başarılıdır. HAS-BLED skoruPuanHipertansiyon1Böbrek veya karaciğer hastalığı (her biri için 1 puan)1 veya 2İnme1Kanama öyküsü veya yatkınlık1Labil INR1Yaş > 651İlaç veya alkol kullanımı (her biri için 1 puan)1 veya 2 Akut Hız Kontrolü Hız kontrolü, AF yönetiminin ayrılmaz bir parçasıdır ancak AF’de optimal kalp hızı hedefi kesinleşmiş değildir. Farmakolojik hız kontrolü beta blokerler, digoksin, diltiazem ve verapamil veya bu ilaçların kombinasyonu ile sağlanabilir. Hız kontrol ilaçlarının seçimi semptomlara, komorbiditelere ve olası yan etkilere bağlı değişir. Akut hız kontrolünde enfeksiyon veya anemi gibi altta yatan nedenler her zaman değerlendirmelidir. İlacın seçimi ve hedef kalp hızı hasta özelliklerine, semptomlara, LVEF değerine ve hemodinamiye bağlı yapılır.

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, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we are going to have a great discussion coming right up regarding intensive versus standard ambulatory blood pressure control and its effects on cerebrovascular outcomes in older people. It's the INFINITY trial, but that's all I'm going to tell you for now because I want to hear all about your picks for this week's journal first. Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear about that discussion regarding hypertension. My first paper though is about titin and it comes from Dr Charles Murry from the University of Washington. The giant sarcomere protein titin is important in both heart health and disease as mutations in the gene encoding for titin are the leading cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within titin motivated the authors of this article to seek a more complete understanding of this gene and the isoform it encodes in cardiomyocyte sarcomere formation and function. Dr Carolyn Lam: Cool. What did these investigators find? Dr Greg Hundley: Using genetically engineered human induced pluripotent stem cell derived cardiomyocytes, the authors experimentally confirmed that the gene encoding for the giant sarcomere protein titin includes an internal promoter and start site. This internal start site encodes for the isoform Cronos, which the authors demonstrate support some sarcomere formation in these human induced pluripotent stem cell derived cardiomyocytes. Dr Carolyn Lam: Oh, nicely summarized. What are the clinical implications Greg? Dr Greg Hundley: Well, Carolyn identification that Cronos titin, a previously unstudied form of titin is necessary for normal human cardiomyocyte function could be contributing to some of these titinopathies that are relevant for some patients with dilated cardiomyopathy. Dr Carolyn Lam: Cool. Mine has to do with heart failure as well and presents new results regarding heart failure and heart failure related outcomes from the EXSCEL trial. Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it find? Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest glucagon-like peptide-1 receptor agonist or GLP-1 receptor agonist trial reported to date where once weekly, exenatide had a neutral effect on hospitalization for heart failure with no differential treatment effect on major adverse cardiovascular events or MACE, by baseline heart failure status. However, the question remains, what about exenatide's effects on secondary endpoints based on the heart failure status? This is from Dr Rob Mentz and colleagues from Duke Clinical Research Institute who aim to explore the effects of exenatide on secondary outcomes in patients with and without baseline heart failure and test the effects of exenatide on recurrent heart failure hospitalization events. Now they found that out of more than 14,750 EXSCEL participants, 16% had heart failure at baseline and when stratified by the presence or absence of baseline heart failure, there was no observed reduction in all cause death with exenatide in patients with baseline heart failure. While the risk of mortality was reduced with exenatide in the no heart failure group. And that was a significant interaction P value of 0.031. Similar results were observed for the combined outcome of all cause death or heart failure hospitalizations. Now regarding recurrent heart failure hospitalizations, 450 patients experienced at least one hospitalization for heart failure, but there were 713 hospitalization heart failure events in total. The effect estimate that included the recurrent events was separately, statistically significant while the primary analysis based on just first events was not. In conclusion in EXSCEL, the use of exenatide in patients with or without heart failure was well tolerated, but the benefits of exenatide on reduction in all cause death and first heart failure hospitalization were attenuated in patients with baseline heart failure. Now this is accompanied by a great editorial by Bruce Neil and Claire Arnett who caution against using post talk subgroup analysis, but the interaction of exenatide tout with baseline heart failure, it's interesting, although should be treated with caution until confirmed by findings from another trial. Dr Greg Hundley: Very nice Carolyn, especially a nice issue regarding heart failure and I'm going to steer a little bit away from that and talk about atrial fibrillation duration and CHA2DS2-VASc scores. Putting those two together and this article comes from Rod Passman from Northwestern University. Studies of patients with cardiovascular implantable electronic devices show a relationship between atrial fibrillation duration and stroke risk though the interaction with a CHA2DS2-VASc score is poorly defined. The objective of their study was to evaluate rates of stroke and systemic embolism in those patients with cardiovascular implantable electronic devices as a function of both the CHA2DS2-VASc2 score and A-fib duration. Dr Carolyn Lam: Interesting. What did the authors do? Dr Greg Hundley: They had 21,768 non-anticoagulated cardiovascular implanted electronic device patients from the Optum electronic health record, de-identified database from 2007 to 2017 and they link those to the Medtronic CareLink TM database of CIEDs capable of continuous AF monitoring. Now the age averaged about 69 years and 63% were men and they found that increasing a fib duration, and of course increasing CHA2DS2-VASc2 score were both significantly associated with annualized risk of stroke and systemic embolism. These rates were low however, in those individuals with CHA2DS2-VASc2 scores of zero to one, regardless of the device detected a fib duration. Dr Carolyn Lam: Ah. Were there any particular threshold values that seemed important? Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk crossed an actionable threshold defined as greater than 1% per year in those with CHA2DS2-VASc2 score patients of two or more with greater than 23 and a half hours of a fib or those patients with CHA2DS2-VASc2 scores of three or four with greater than six minutes of a fib duration or finally in those individuals with CHA2DS2-VASc2 scores greater than five even if they had no atrial fibrillation. Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions here. Thanks Greg. I'm going to tell you what else is in this issue. There's also a research letter by Dr Rosenmeier entitled, “Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin 6 Receptor Dependent Mechanism.” And this is a cardiac analysis of a double blind randomized controlled trial in abdominal obese humans. We have an on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to Explore the Role of Genetic Heterogeneity in Conferring Phenotypic Variability.” And this discusses among other things, the role of induced pluripotent stem cells and functional studies of bioengineered HFpEF patient derived cardiac micro tissues that could potentially enable several important questions to be answered for the first time. There's an ECG challenge as well by Dr Naru Kanya, and it's really interesting. It's a hiccup artifact. If you haven't heard about that, you should take a look. And finally cardiology news by Dr Kuhn and it's entitled, “Nourishing Native American Communities by Increasing Access to Traditional Food.” A very interesting paper right there. Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten provides a perspective piece regarding emerging affinity reagents for high throughput proteomics, sort of an emerging field, everyone doing proteomic studies, we have to pay a special attention to the reagents that are being used. And then Andrew DeFilippis from University of Louisville as well as Johns Hopkins reviews important concepts related to the definition of MI. Dr Carolyn Lam: Is this pertaining to that fourth universal definition of MI? Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this white paper, the authors review the epidemiology, risk factor associations and diagnostic tools that may assist in differentiating between non-ischemic myocardial injury, type 1 MI and type 2 MI. And then finally from Suowen Xu from the University of Rochester, there's a letter discussing the CCN family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are mechano-sensitive proteins that are differentially regulated by sheer stress, the frictional force exerted by blood flow in our vessels. Well Carolyn, that's a great issue. How about we move on to our feature article? Dr Carolyn Lam: Let's go Greg. For our feature discussion today we are talking about intensive versus standard ambulatory blood pressure control and that effect on cerebral vascular outcomes in older people or the INFINITY trial. Very, very important stuff and I'm so pleased to be with the corresponding author, Dr William White from Calhoun Cardiology Center in University of Connecticut School of Medicine. Dr White, thank you so much for being here. Could you maybe set up already the background of what you were thinking when you started this trial? Especially given the results that we know from SPRINT and SPRINT mind. Could you perhaps comment on how this INFINITY trial is different? Dr William White: We started work in this area about 15 years ago and we initially were interested in interactions among vascular risk factors including ambulatory blood pressure, lipids and other sort of thrombotic factors and so forth with the development of small vessel disease in the brain that led to these fairly classic images on MRI called white matter hyperintensity lesions. And we learned from a prospective cohort study that we started about 15 years ago, that there was a very strong relationship between ambulatory blood pressure and the development and progression of these white matter hyperintensity lesions on MRI, but not very nice relationship with the clinical blood pressures measured in the standard office practice. We decided to pursue a clinical trial, a randomized clinical trial in which we would evaluate different levels of ambulatory blood pressure versus the development of the small vessel disease as imaged by MRI, but very importantly we also wanted to link it to functional outcomes because this was in older people, typically in their late seventies, eighties and even nineties in which cognitive impairment begins to develop. There's problem with mobility, bladder function and things of that nature. And since our funder was always the National Institute of Aging of the NIH, there's a great deal of interest in more than just the vascular risk factors and even the cerebral vascular disease that we would detect on the MRI. That was the background of why the study got developed the way it did. Dr Carolyn Lam: That's so interesting. You've already pointed out ways that this was very different from SPRINT OR SPRINT MIND in looking at ambulatory instead of clinic blood pressure and I suppose in the population you selected, out of curiosity, you mentioned that your prior work showed a relationship between white matter hyperintensity on MRI and perhaps future dementia. In which direction? And is there any basis to suspect low, too low blood pressure may also be bad in these older people who already have microvascular brain disease? Dr William White: Absolutely. Very important point. When we look at our prospective cohort which was about a 100 older people, we followed for four years without any intervention. This was just a mixture of normal tensive and hypertensive individuals. Some on meds, some not on meds. But we did show that when you got too low or if you stay too low during those four years with a systolic blood pressure of under 115 on a 24-hour blood pressure monitor, it seemed like there was an almost like U shaped relationship with progression of white matter disease. Below 115 there was more accrual of white matter disease. Above 150 there was a systolic blood pressure, there was also a greater accrual, but in between about 125 and 145 we weren't really sure if there was going to be a difference. And that there was the target is that everybody's talking about for clinical measurement, so we decided to pursue that in this study to determine if we could figure out whether or not there was a sweet spot for the desk blood pressure without getting into trouble with hypotensive symptoms. Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely. Now I get it that you chose the targets that you did, which just for everyone, just a reminder, it was a 24 hour mean systolic blood pressure by ambulatory blood pressure control and the two targets were 130 millimeters mercury and less versus 145 millimeters mercury and less. With that, could you please tell us the results? Dr William White: Right. We called the 130 or less systolic group, the intensive treatment group and the 145, the standard group. We focused on the primary endpoint was changes in mobility parameters in conjunction with changes in white matter hyperintensity lesion growth. And after a period of about three to four months of randomization, post randomization, we achieved a 24-hour systolic blood pressure about 128 millimeters of mercury in the intensive treatment group and 144 in the standard group. And we maintained a pretty good separation in blood pressure, ambulatory blood pressure throughout the three years of treatment. Now the changes in gait speed, which was one of our primary parameters for mobility actually turned out not to be different between the treatment groups. That is intensive versus standard. However, the changes in the accrual of light matter hyperintensity volume was smaller in the intensive treatment group of a 0.29% versus a 0.48% in the standard treatment group. That was significant at a P value of 0.03. We actually also had a pre-specified sensitivity analysis, sort of a per protocol analysis that allowed us to look at people who stayed in their sort of assigned treatment groups based on blood pressure throughout the three years of the trial. And in that circumstance, there was actually a stronger separation because these are people who stayed clearly at 130 or less than about 145 throughout the three years and now the differences were approximately 0.23% in the intensive group and 0.58% in the standard group. And now the P value is smaller, .0028. I think we proved in the study that maintaining a systolic blood pressure on the ambulatory recorder over 24 hours of 130 or less benefited patients by reducing the accrual of white matter hyperintensity lesions by about 40% relatively speaking compared to a standard ambulatory blood pressure value of a 145. One of course caveat is that after that happened within three years, but we did not see the expected benefit on mobility or on most of the cognitive parameters either. And while we were a little bit surprised about that, when we went back and analyzed our situation with where people started from as far as this particular cohort of patients, they might've been a little on the healthy side compared to some other studies. A very educated group, very compliant with everything that they did. And probably three years was just not long enough to show the result of this white matter hyperintensity benefit on some of the functional outcomes. Dr Carolyn Lam: That's really interesting and I'm glad you sort of tackled head on that sort of apparent dissociation between the clinical end points and the MRI end point. Could I also ask, wouldn't those findings also be consistent with SPRINT and SPRINT MIND? Dr William White: In many ways our results were consistent with SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course, just let me mention the differences between the two studies. Of course, SPRINT was very large but there are sub-studies were not as large as the parent study. The MRI study had about 300 plus patients randomized into it, but the measurement of blood pressure was done in the standard clinical fashion and used that digital device that was able to take measurements without somebody present in the exam room. Though they were a bit lower than what I would have seen on an ambulatory monitor during the day time. And their goals were 120 systolic versus 140, whereas ours were an ambulatory systolic of 135 and 145. But the results were actually comparable because they showed a benefit with regards to lesser accrual of white matter hyperintensity volume in the intensive group versus this banner treatment group. But they also showed no differences after 3.4 years in the incidence of dementia. And they also showed in a separate study, no differences in gait speed in the population who are in intensive versus standard treatment. One would say that results were really actually comparable despite the age differences and the blood pressure measurement differences. And I think both studies really point to the fact that lower systolic blood pressures in older people should be our target because it's safer actually then than maintaining people in the 140s. Dr Carolyn Lam: Maybe the follow-up period was not long enough. Could it be possible too that maybe blood pressure control should start earlier in life. Could that be it? And then also, could you give us an idea of the kinds of changes, the magnitude of the change on MRI that you see for those of us that don't think about this all the time, is this a big change considered for your cohort or is it a little change? Dr William White: I think it's true that these people started out around 81 years old in this trial and so by the time they got to that age and had systolic hypertension for probably as many as 20 years, that some of the damage that was done was obviously permanent and we don't really know how long it took for that to accrue. What we did know is that with three years of intensive treatment, we benefited patients by reducing the continued growth or confluency of these small vessel lesions in the brain. Now the range in the amount of damage varies from about half a percent of the overall brain volume to about 5%, so a 10-fold magnitude difference in our cohort. And as a result of that, certainly somebody who's got about two to 3% of their brain occupied by better hyperintensity lesions or damage is going to have a great deal more functional disability than somebody who's .5%. I think we have to look at the outliers as well as the mean and median changes that we saw. The mean changes are not huge. The difference between 0.2 and 0.6% for example, in our protocol analysis, 0.4% to me it's clinically relevant because I know that that means that there are some people who went up by a percent or two over the years versus the standard versus the intensive treatment group. That's a big difference in an individual over that period of time. Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my brain. Dr William White: Yeah. Plus it's also where it's located because the lesions are typically around the ventricles of the brain and it's exactly where neurons are going sort of posteriorly to anteriorly to transmit information. For example, from the visual center to the sort of spatial motor cortex. And when those are interrupted, even if it's in one or 2% of the tissue, it can cause substantial difficulties for people. And it's for both the flow of cognitive information as well as this flow of a mobility and balance. I think that it is very relevant, but the gray matter is affected much less by this compared to the white matter. But there are still studies that show that gray matter sort of follows in line with that so that of course also enhances thought processes and cognitive function as well. Dr Carolyn Lam: Wow. I love the way you explained that. Very important question would of course be the safety and tolerability of this more intensive approach. Any comments there? Dr William White: Our sponsor, the National Institute of Aging did recruit a data safety monitoring board that was independent from the study for all the years. Impressively over the course of this trial, even though there wasn't a large sample, it was a 199 people, we saw a significant benefit in the intensive group for cardiovascular events, so there were less admissions for heart failure. There were less myocardial infarctions, there was less strokes. All these kinds of things that we worry about in our patients as they get older with vascular disease was reduced by about 75% in the intensive treatment arm versus the standard arm. As far as the events that we were concerned about, such as falls and syncope and presyncope and things of that nature, they were virtually identical in the intensive treatment group and `the standard treatment group. When you take that into consideration, along with the fact that you're reducing the accrual of small vessel disease in the brain, it's clear that this population, even though they're older, would benefit from a lower systolic blood pressure. Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That was a beautiful summary. That is the take home message right there. Listeners, I'm sure you agree with me. Thank you so much for joining us this week, and don't forget to tune in again next week. This program is copyright American Heart Association 2019.  

Dominate perioperative medication management with tips from Kashlak’s newly minted Chief of Perioperative Medicine, @aoglasser, Avital O’Glasser MD, FACP, FHM (OHSU). We cover perioperative anticoagulation, why “bridging is dead”, aspirin, dual antiplatelet therapy, DMARDS, diabetic medications, buprenorphine, and much more! Be sure to check out Dr. O’Glasser’s previous episode #135 Perioperative Medicine: Assess and Optimize Risk to get a full overview of perioperative medicine. ACP members can claim CME-MOC credit at https://www.acponline.org/curbsiders (CME goes live at 0900 ET on the episode’s release date).  Full show notes https://thecurbsiders.com/episode-list. Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Credits Written and Produced by: Avital O’Glasser MD, FACP, FHM and Matthew Watto MD, FACP  CME Questions: Matthew Watto MD, FACP Infographic: Matthew Watto MD, FACP Cover Art: Kate Grant MBChB DipGUMed Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP  Editor: Matthew Watto MD, FACP Guest: Avital O’Glasser MD, FACP, FHM Time Stamps 00:00 Intro, disclaimer, guest bio 03:20 Guest one-liner 04:46 Picks of the Week*: A Moment of Lift (book) by Melinda Gates; Crawl (film); Rich Roll (podcast) episodes w/Valter Longo and David Sinclair 09:35 Avi’s mantras for perioperative management and other core tenants 14:40 NPO and The Consult Guys 17:23 Medical cannabis (marijuana) in perioperative medicine 19:24 Case #1 Ms. Bridge - perioperative anticoagulation: to bridge or not to bridge 25:00 Low bleeding risk surgeries and anticoagulation 27:25 Moderate to high bleeding risk surgeries and anticoagulation; What about the CHA2DS2 Vasc of 7? 28:42 Bridging for venous thromboembolism (VTE) 31:30 How to give instructions for holding warfarin 32:30 Bridging a DOAC 36:16 Recap on bridging VKAs and use of DOACs 37:48 Neuraxial anesthesia and anticoagulation 39:49 Biologic DMARDS; Nonbiologic DMARDS 43:48 Supplements and herbals 48:40 Case #1 wrap up 50:16 Case #2 -Mr. DAPT; Perioperative Aspirin; DAPT -dual antiplatelet therapy 57:20 Summary of perioperative antiplatelet therapy 63:18 Statins 64:45 Beta blockers 67:21 ACEI and ARB; Diuretics 69:17 Oral hypoglycemics and newer diabetes agents (SGLT2 inhibitors, GLP1 agonists); What about metformin? 72:04 Insulin 74:40 Case #2 wrap up 75:35 Case #3 Ms. GB Stone who takes lithium and buprenorphine 77:30 NSAIDS, Buprenorphine 81:45 ART, transplant meds, Lithium, MAOIs, Levothyroxine; Watch out for lithium 86:34 Case #3 wrap up 87:25 Take Home Points 88:45 Outro 90:15 Avi and Mr. Rogers  *The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on my Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra. Goals Listeners will develop a practical approach to perioperative medication management and review special considerations for the various drug classes. Learning objectives After listening to this episode listeners will... Frame perioperative medication management decisions as another type of patient-centered, surgery-specific perioperative “risk/benefit” decision Discuss guideline recommendations for the perioperative management of multiple classes of medications Examine more nuanced or challenging medications to manage in the perioperative setting Explore professional, patient-centered and multidisciplinary communication techniques when disagreements arise regarding best medication management recommendations Disclosures Dr O’Glasser reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.  Citation O’Glasser A, Williams PN, Watto MF. “#174 Perioperative Medication Management”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list. September 23, 2019.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's 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 Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today? Dr Greg Hundley:             My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes.                                                 As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation. Dr Carolyn Lam:                Interesting, so what did they find, how did they do this? Dr Greg Hundley:             Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription. Dr Carolyn Lam:                And so? What did they find? Dr Greg Hundley:             Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes.                                                 So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings.                                                 So, Carolyn, how about your next study? Dr Carolyn Lam:                Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial. Dr Greg Hundley:             Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us? Dr Carolyn Lam:                Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment.                                                 Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine.                                                 So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group.                                                 Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension. Dr Greg Hundley:             Wow, so we're getting back toward renal denervation? How about that?                                                 Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner.                                                 Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure. Dr Carolyn Lam:                Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes? Dr Greg Hundley:             The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice.                                                 The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis.                                                 So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy. Dr Carolyn Lam:                Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells.                                                 So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz? Dr Greg Hundley:             You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us? Dr Carolyn Lam:                Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice.                                                 Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice.                                                 So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands.                                                 So, Greg, interesting stuff, huh? Dr Greg Hundley:             You bet! Let's go on and here a little bit more about diabetes. Dr Carolyn Lam:                And dapagliflozin coming right up.                                                 Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern.                                                 All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please? Dr Stephen Wiviott:        So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention.                                                 Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke.                                                 And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation. Dr Carolyn Lam:                Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis? Dr Eri Kato:                         So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF.                                                 So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints.                                                 There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction.                                                 Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF.                                                 So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events.                                                 And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction.                                                 So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction. Dr Carolyn Lam:                Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined? Dr Eri Kato:                         We collected data at the baseline and the heart failure was collected based on the medical record. Dr Carolyn Lam:                So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds? Dr Darren McGuire:        First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction.                                                 And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications.                                                 So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results? Dr Carolyn Lam:                Subodh, I'm going to let you go first. Dr Subodh Verma:           First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE.                                                 I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other.                                                 So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure.                                                 So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents.                                                 But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically. Dr Carolyn Lam:                Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials.                                                 But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find? Dr Stephen Wiviott:        I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke.                                                 In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population.                                                 So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure.                                                 And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI.                                                 And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction.                                                 Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction. Dr Carolyn Lam:                Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next? Dr Darren McGuire:        I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients.                                                 And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes. Dr Carolyn Lam:                Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you?                                                 You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019  

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.                                                 In our first manuscript, Marie Bayer Elming and associates, examined whether the right ventricular ejection fraction can identify patients with non-ischemic systolic heart failure, more likely to benefit from ICD implantation. The Danish study, to assess the efficacy of ICDs in patients with non-ischemic systolic heart failure, on mortality, the Danish study, randomized patients with non-ischemic systolic heart failure to ICD our control. In 239 patients with interpretable cardiovascular magnetic resonance images, the right ventricular volume and ejection fraction was measured. Right ventricular ejection fraction was an independent predictor of all-cause mortality, with a hazard ration 1.34 per 10% absolute decrease in our right ventricular ejection fraction. P=0.02. There is statistically significant interaction between right ventricular ejection fraction and the effect of ICD implantation. P=0.001. ICD implantation significantly reduced all-cause mortality in patients with right ventricular systolic dysfunction. Hazard ratio 0.41, but not in patients without right ventricular systolic dysfunction.                                                 Thus, in this post-hoc analysis of the Danish trial, ICD therapy was associated with survival benefit in patients with bi-ventricular heart failure.                                                 In our next paper, Dawn Pedrotty and Volodymyr Kuzmenko and associates, have proposed a concept of using a stretchable, flexible, bio patch, with conductive properties, to attempt to restore conduction across regions in which activation is disrupted. They use carbon nanotube patches, composed of nanofibrillated cellulose, in single wall carbon nanotube ink, 3-D printed in conductive patterns onto bacterial nanocellulose.                                                 Electro anatomic mapping was performed on normal epicardium and repeated over surgically disruptive epicardium, and finally with the patch applied passively. The patch resulted in restored conduction based on mapping.                                                 In our next paper, Ayman Hussein and colleagues developed a fully automated platform to collect patient reported outcomes in a prospective cohort of atrial fibrillation ablation. Two thousand one hundred and seventy-five patients were eligible to receive 10,903 patient reported outcome assessment invitations. More follow up assessments were obtained with automated patient reported outcomes in routine follow-up, compared with routine follow up alone, P > 0.001, which allowed for longer duration of follow up, 378 vs 217 days. By automated patient reported outcomes, a large number of disease specific variables were collected and showed improvement in quality of life. Baseline median AF symptom severity score of 12 and ranged between 2 and 3 on subsequent assessments, P > 0.0001. This improvement was also true for each of the atrial fibrillation symptom severity score components. In patient reported outcomes, there was a significant reduction in atrial fibrillation burden, such as frequency and duration episodes and associated healthcare utilization including emergency visits and hospitalizations after the ablation procedures.                                                 In our next paper, Nicolas Johner, Dipen Shah, and associates, examined the role of post pacing intervals shorter than tachycardia cycling during entrainment mapping. The author studied 24 non-cavotricuspid isthmus dependent macro oriented atrial flutters in 19 consecutive patients. High density electro anatomic activation maps were acquired with a 64-electrode basket catheter of 102 entrainment mapping sites. Post pacing interval difference less than 30 was observed at 72 sites on complete maps of 24 atypical atrial flutters compared to sites with the difference in post pacing intervals 0 to 30, with 45 sites difference in the post pacing interval less than 0 at 27 were more commonly located within isthmuses less than 15mm wide and more frequently located in within 5mm of the leading wave front. It also exhibited slower local conduction, lower voltages in more frequently fractioned electrograms. The authors concluded that in atrial flutter, sites with differences with the post pacing interval are markers of limited width critical isthmuses with slower conduction velocity, while sites with difference in post pacing interval 0 to 30ms are often not in close proximity to the reentrance circuit. Virtual electrode simultaneous down and up stream, antidromic capture of a confined isthmus of slow conduction can explain a difference in the post pacing interval less than 0.                                                 In the next paper, José Manuel Alfonso-Almazán, and associates studied the safety and efficacy parameters associated with catheter-based radiofrequency delivery at the root of the aorta and pulmonary artery. The author studied 34 pigs undergoing in vivo catheter based ablation using continuous contact force and lesion index monitoring during 60 second radiofrequency delivery with an open, irrigated tip catheter. Twenty-eight animals were allocated to groups receiving 40 watts, 50 watts, or 60 watts and acute, chronic arterial damage was quantified by multi photon microscopy in ex vivo samples. Adjacent microlesion were quantified in parallel samples. The remaining 8 pigs, these were used to validate safety and efficacy parameters. Acute collagen elastic alterations were significantly associated with radiofrequency power, although chronic assessment revealed vascular wall recovery in patients without [steam pop 00:06:56]. The main parameters associated with steam pops were median peak temperature greater than 42C, and impedance falls greater than 23 ohms. Unlike other parameters, lesion index values of 9.1 units were associated with the presence of adjacent myocardial lesions in both univariate and multivariate analyses. In the validation group, lesion index values using 40 watts over a range of contact forces correlated with the size of radiofrequency lesions. Lesion index values obtained during 40 watts radiofrequency application reliably monitor safe and effective lesion creation at the root of the great arteries.                                                 In our next paper, Eiichiro Oka and associates examine the prevalence and significance of the early repolarization electrocardiographic pattern and its mechanistic insight based on cardiac magnetic resonance findings in patients with acute myocarditis. The author studied 30 patients with the diagnosis of acute myocarditis. Nine had an early repolarization electrocardiographical pattern, which was defined as a terminal QRS notching or slurring with an amplitude of greater than zero-point millivolts in at least two inferior and/or lateral leads. The early repolarization group, while the remaining 21 cases had broad ST elevation or pathological QAs.                                                 The non-early repolarization group. The cardiac prepotency level was significantly higher in the non-early repolarization group than the early repolarization group. The ECD changes returned to baseline, along with a normalization of the cardiac biomarkers. Nine of the 21 non-early repolarization group patients, but none of the 9 early repolarization groups developed fulminant course of lethal ventricular arrhythmias. T2-weighted cardiac magnetic resonance imaging showed high intensity signals over the entire transmittal left vertical in the non-early repolarization group, where as they were localized to the left ventricle epicardium in early repolarization group. The early repolarization pattern in acute myocarditis was transient and reversible, and was not associated with a worse prognosis. Inflammation or swelling localized to the left ventricular epicardium, due to myocarditis, may provide a mechanistic insight into the early repolarization pattern.                                                 In our next paper, Beatrix Scholz and Jan Sebastian Schulte and associates analyzed whether the histone deacetylase class I and II inhibitor valproic acid is able to attenuate atrial remodeling in CREM-IbΔCx (TG) transgenic mice. A mouse model of extensive atrial remodeling with age dependent progression from spontaneous atrial ectopy to paroxysmal and finally long lasting atrial fibrillation. Valproic acid was administered for 7 or 25 weeks to transgenic and control mice. Valproic acid attenuated many components of atrial remodeling that were present in the transgenic mice.                                                 Valproic acid significantly reduced atrial dilation, cardiomyocyte enlargement, atrial fibrosis, and the disorganization of myocytes ultrastructure. It significantly reduced the occurrence of atrial thrombi, reversed action potential alterations, and finally delayed the onset of atrial fibrillation by 4 to 8 weeks. Increased histone H4 acetylation in atria from valproic acid treated transgenic mice verified effective in in vivo histone deacetylase inhibition. Cardiomyocyte specific genetic inactivation of histone deacetylase HDAC 2 in transgenic mice attenuated the ultrastructural disorganization of myocytes compared to valproic acid. The author suggests that valproic acid, clinically available, well tolerated, and prescribed to many patients for years, has a therapeutic potential to delay the development of atrial remodeling in the onset of atrial fibrillation in patients at risk.                                                 In our next paper, Bence Hegyi and associates measure the major inward currents in their calcium channel and beta-adrenergic dependence under physiologic action potential clamp in rabbit ventricular myocytes in chronic pressure volume overload induced heart failure versus age matched controls. They found that CAM kinase II dependent up regulation of late sodium current in heart failure significantly contributes to the action potential prolongation in increased short-term variability of action potential repolarization, which may lead to increased arrhythmia propensity and is further exacerbated by adrenergic stress.                                                 In a research letter, Arnaud Bisson and associates examined mitral regurgitation in 838, or 10%, of 8675 patients with atrial fibrillation. A total 135, or 16%, had severe mitral regurgitation. During mean follow-up with 2.5 years, 688 ischemic stroke or thromboembolic events were recorded. mitral regurgitation was associated with a non-significant higher risk of these embolic events. After adjustment for anticoagulant and antiplatelet use, CHA2DS2-VASc and HAS-BLED scores, patients with mitral regurgitation tended to have a higher all cause or cardiovascular mortality but had similar risks of ischemic stroke or thromboembolic events, when compared to patients with no mitral regurgitation. Severe mitral regurgitation was also associated with similar risk for ischemic stroke and thromboembolic events when compared with other atrial fibrillation patients. However, our findings indicate that in patients with atrial fibrillation, neither mitral regurgitation nor severe mitral regurgitation, appears to independently be associated with a different risk of ischemic stroke or thromboembolic events. The perceived protective effect of mitral regurgitation against the risk of thromboembolic events is not relevant in atrial fibrillation when using a contemporary risk score scheme, the CHA2DS2-VASc score.                                                 In our final research paper, Jack Z. Li and associates noted that in 2017, an aggregate of four manufacturers of devices yielded 89.6% with the DF-4 ICD implants. While DF-4 and DF-1 leads generally have comparable performance, several concerns over reduced versatility of the DF-4 have been raised. First, to downgrade an ICD with a DF-4 lead to a pacemaker, a generator change, a new right ventricular pace sense lead must be implanted. The DF-4 pin is incompatible with the IS-1 port and there is no straightforward way to bridge this gap. In contrast, the DF-1 IS-1 lead requires only capping of the DF-1 pin. Second, if an ICD with DF-4 lead has either a distal coil or a right ventricular pacing malfunction, a new lead must be implanted. Third, if a ICD with DF-4 lead has a high defibrillation threshold, management requires either a new DF-1 IS-1 lead with an adapter for a subcutaneous array, or an adapter that inserts into the DF-4 port and receives both the DF-4 lead and the DF-1 pin of the subcutaneous lead. Physicians should have the foresight to select DF-1 leads at the time of initial implant in selected circumstances, such as high possibility for elevated defibrillation threshold requiring a subcutaneous lead or array.                                                 That's it for this month! We hope that you'll find the journal to be the go-to place for everyone interested in the field. See ya next time.                                                 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. We're your co-hosts. I'm Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center in Richmond, Virginia, VCU Health Sciences. Dr Carolyn Lam:                How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg. Dr Greg Hundley:             Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.                                                 So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months. Dr Carolyn Lam:                Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to. Dr Greg Hundley:             So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.                                                 Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise. Dr Carolyn Lam:                Well, don't keep us in suspense now. What did the study show? Dr Greg Hundley:             So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.                                                 So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.                                                 So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together. Dr Carolyn Lam:                Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.                                                 Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.                                                 Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk. Dr Greg Hundley:             So, Carolyn, how do we use this clinically? I mean, do we measure this in folks? Dr Carolyn Lam:                Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.                                                 So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.                                                 So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median. Dr Greg Hundley:             So should we start checking this in all our patients now, these lipoprotein little A levels? Dr Carolyn Lam:                Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.                                                 Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space. Dr Greg Hundley:             Yeah, so it sounds like another wonderment of PCSK9 inhibitors. Dr Carolyn Lam:                Yeah. Dr Greg Hundley:             Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.                                                 So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored. Dr Carolyn Lam:                Huh, interesting. So, what did they find? Dr Greg Hundley:             Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.                                                 Interesting, Carolyn. Another role for iron in acute MI and more research to come. Dr Carolyn Lam:                Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?                                                 For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come? Dr William Lewis:             The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.                                                 So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint. Dr Carolyn Lam:                Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results? Dr Jonathan Piccini:         I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.                                                 And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well. Dr Carolyn Lam:                Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here? Dr Jonathan Piccini:         It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.                                                 And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well. Dr Carolyn Lam:                Bill, did you expect such remarkable results? Dr William Lewis:             No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions. Dr Carolyn Lam:                That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this? Dr Jonathan Piccini:         That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world. Dr William Lewis:             I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others. Dr Carolyn Lam:                John, before we end, what are the take-home messages for clinicians listening out there? Dr Jonathan Piccini:         I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program. Dr Carolyn Lam:                Thank you so much for sharing that with us.                                                 Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Dr Paul Wang:                   Welcome to the monthly podcast, On the Beat for Circulation: Arrhythmia, and Electrophysiology. I'm Dr Paul Wang, editor in chief, with some of the key highlights for this month's issue.                                                 In our first paper, Pasquale Vergara and Associates develop a predictive risk score to assess the outcome of ventricular tachycardia ablation creating what they call the IVT score. The authors examined 16 demographics, clinical, and procedural related variables in 1,251 patients. They used a technique called survival tree analysis, which uses a recursive partitioning algorithm to find relationships among variables.                                                 They then compared the survival time and time to VT recurrence in groups derived from survival tree analysis using a log rank test. A random forest analysis was then run to extract a variable importance index and internally validate the survival tree models. They found that the left ventricular ejection fraction, ICD, or CRT device, previous ablation were the best predictors of ventricular tachycardia recurrence. While left ventricular ejection fraction, previous ablation, electrical storm was identified as best predictors of mortality.                                                 They identified a high-risk group in which 65% of patients survived and 52.1% were free from VT occurrence. A medium risk group in which 84% survived and 72% were free of VT, and a low risk group in which 97% of patients survived and 88% were free of VT recurrence.                                                 In our next paper, Alwin Zweerink and Associates examined the relationship between cure restoration and left ventricular dimension as predictors of outcomes after cardiac re-synchronization therapy. The present study evaluates the effect of normalization of the cure restoration to left ventricular dimension on the prediction of survival after CRT implantation. They study 250 heart failure patients with left ventricular ejection fraction less than or equal to 35% in cure restoration greater than or equal to 120 milliseconds, and they normalize the cure restoration based on the left ventricular dimension. The left ventricular and diastolic volumes obtained using cardiac magnetic resonance imaging.                                                 Before CRT implantation were used for cure restoration normalization. During a follow up period of 3.9 years, 79 patients or 32% reached the primary end point, which combined death, left ventricular assist device, or heart transplantation. Using univariable cox regression they found that although the unadjusted cure restoration was unrelated to CRT outcome, P=0.116, the normalized cure restoration was a strong predictor of survival. Hazard ratio 0.81 per 0.1 milliseconds per milliliter, P=0.008.                                                 Women demonstrated higher normalized cure restorations than men, 0.2 milliseconds per milliliter, versus 0.55 millisecond per milliliter, P=0.003, and showed better survival after CRT. Hazard ratio 0.52 with P=0.018.                                                 In our next study, Markus Linhart and Associates examined the impact of catheter ablation gaps on outcomes after first pulmonary vein isolation. Using delayed gadolinium enhancement cardiac magnetic resonance imaging three months after radio frequency ablation, they found that in 94 patients, 62% with paroxysmal atrial fibrillation, that there was a mean number of 5.4 gaps per patients. Atrial fibrillation recurrence within the first year of ablation was observed in 21 patients with paroxysmal AF, 36%, and 19 patients with persistent atrial fibrillation, 53%.                                                 In the unit variate analysis, CHA2DS2 -VASc score, afib type and relative gap length were predictors of recurrence. In multi-variant analysis, only relative gap length was significantly associated with recurrence. Hazard ratio 1.16 per each 10% of the gap.                                                 In our next paper, Antonius van Stipdonk, Iris ter Horst, Marielle Kloosterman, Alexander Maass, Kevin Vernooy and Associates examined the value of cueres area compared to that of cure restoration and morphology as predictors of clinical echocardiographical outcomes following cardiac resynchronization therapy. The authors found that in 1,492 cardiac resynchronization therapy patients during a mean follow up of 3.4 years, 32% of patients reached the combined prior endpoint of all-cause mortality, cardiac transplantation, and left ventricular assist device implantation.                                                 The authors found that cure restoration identified patients that did not experience the primary endpoint better than QRS morphology in cure restoration area under the curve 0.61 versus 0.55 and 0.51, P value less than 0.001. They also found that QRS area identifies patients with echocardiograph remodeling in response to CRT better than the QRS morphology and duration, area under the curve 0.69 versus 0.58 and 0.58, P < 0.001. In addition, QRS area was the only independent electrocardiographic determine associated with the primary endpoint. Hazard ratio 0.50 QRS area retained its significant associative outcomes in both patients with and without left bundle branch block in cure restoration greater than 150 milliseconds.                                                 Our next paper is a research letter in which Brian Hansen, Ning Li and Associates report the first in-vivo use in a canine model of near infrared optical mapping. In-vivo optical action potential showed a sharp upstroke that corresponded with atrial activation at a neighboring electrode. Imaging during in-vivo atrial fibrillation episodes showed re-entrant activation around the sinoatrial region minimizing the effect of motion artifact in validation in structurally remodeled hearts would be the next steps for this promising technology.                                                 Also, in a research letter, James Hummel and Associates studied whether infrared thermography over a six-centimeter segment can be effectively used to guide atrial fibrillation ablation. Thermography continuously sampled 7,680 points over a full 360 degree and refreshed every second. Ablation was guided by 3D mapping and performed using a 3.5-millimeter irrigated tip. Power was reduced to 25-watts on the left atrial posterior wall and could be further reduced to 20-watts in areas where there was excessive esophageal temperature rise. Esophageal temperature cutoff for radio frequency power delivery was initially 46 degrees and progressively raised to 50 degrees throughout the study at the discretion of the operators.                                                 All patients underwent upper endoscopy on post-ablation day one to three by a gastroenterologist blinded to temperature data. Thirty-four patients were studied, 94% of patients had luminal esophageal temperatures above 40 degrees during ablation of the posterior wall. Thermal events with Tmex greater than 40 degrees occurred commonly averaging 6.5 seconds during a procedure. On average, 231 seconds of ablation were performed with Tmex greater than 40 degrees centigrade. However, the excursions above threshold cutoff Tmex greater than 50 degrees centigrade lasted only 1.5 seconds per patient. In total, 38% of patients, 13 out of 34 had at least one energy delivery discontinued for exceeding threshold. This occurred eight out of 17 times or 47% when the cutoff was 46 degrees centigrade and five out of 15, or 33% at 50 degrees centigrade.                                                 On endoscopy one patient, 3% had thermal injury related to malpositioning of the infrared thermal probe below the region of ablation. Another patient had three lesions spanning 16 centimeters likely related to mechanical trauma with probe placement. The authors concluded that esophageal injury does not seem to occur with esophageal temperatures less than 50 degrees centigrade using thermography.                                                 In a review paper in this issue, Bruce Lerman and Associates discussed adenosine as a potent but underutilized tool that is useful in clarifying in clinical diagnoses of arrhythmias. Adenosine mediates its electrophysiological effect through binding to the cell surface adenosine receptor A1R, a G-protein receptor. In the sinoatrial node, activation of IKADO by adenosine results in negative chronotrophy, a manifestation of its modern effects on membrane hyperpolarization and a decrease in the rate of phase four depolarization. Adenosine also mediates its cellular effects in atrial and AV nodal cells predominantly through activation of IKADO. In atrial myocytes, this results in a shortening of action potential duration in decrease in refractoriness. By shortening the atrial refractory period without changing atrial conduction velocity, the wavelength of activation is shortened. A mechanism through which adenosine can facilitate induction of atrial fibrillation. Adenosine also exerts an antiadrenergic effect in atrial tissue, reducing cyclic AMP stimulated levels of L-type calcium current.                                                 Adenosine has a negative dromotropic effect on the AV node. The most potent effects of adenosine are expressed in N-cells. In these cells, as well as AN-cells, adenosine decreases excitability by reducing the plateau amplitude in abbreviating action potential duration. In addition, it reduces the rate of rise of the upstroke of N-cells. NH-cells are insensitive to adenosine. Adenosine terminates permanent form of junctional recipriatachycardia in the retrograde accessory pathway limb. The mechanism in which adenosine causes block in the retrograde decremental accessory pathway is thought to be by hyper-polarizing the pathways membrane potential. Adenosine has been helpful in illuminating differences in etiology of decremental conduction in three predominant antigrid decremental accessory pathways. Atrial ventricular pathways, atrial physicular pathways, and nodoventricular pathways.                                                 Adenosine can elicit dormant conduction defined as a restoration of excitability by adenosine in tissue rendered inexcitable by partial cellular damage secondary to ablation. There are three discrete clinical scenarios in which adenosine reveals dormant conduction - after pulmonary vein isolation, after achieving bi-directional cavo-tricuspid isthmus block, and following successful ablation of antegrade and retrograde accessory potential. Adenosine, through activation of IKADO hyperpolarizing these cells so that the sodium channels are reactivated, restoring excitability. Adenosine, though its inhibition of cyclic ANP mediated increases in the slow inward calcium current and its downstream inhibitory effects on SR-calcium release, INCX and ITI, terminates focal arrhythmias caused by triggered activity. The response to adenosine may indicate triggered activity where termination occurs versus insensitivity of localized re-entry to adenosine.                                                 That's it for this month, we hope that you will find The Journal to be the go-to place for everyone interested in the field. See you next time.

The American College of Chest Physicians (ACCP) recently updated their guideline recommendations for the use of antithrombotics for the prevention of stroke in patients with atrial fibrillation (aka the Chest Guidelines).  Find out what's new, who shouldn't receive treatment based on the CHA2DS2-VASc score, and why the guideline panel recommends calculating a patient's SAME-TTR score. Guest Author:  Dylan Lindsay, PharmD Music by Good Talk

This week's View explores the addition of P-wave indices to improve the predictive ability of the CHA2DS2-VASc score for atrial fibrillation-related stroke risk, the effects of liraglutide on cardiovascular and safety outcomes in subgroups of patients with type 2 diabetes and chronic kidney disease, and whether percutaneous septal radiofrequency ablation can be effective treatment for patients with hypertrophic cardiomyopathy with obstruction.

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.                                 In our first study, Filip Plesinger and associates examined whether a computerized analysis of the body surface 12-lead ECG can be used to measure the ventricular electrical activation delay as a predictor of heart failure or death following resynchronization therapy in a MADIT-CRT trial.                                 The authors found that left bundle branch block patients with baseline ventricular electrical activation delay less than 31.2 milliseconds had a 35% risk of MADIT-CRT endpoints, while patients with ventricular electrical activation delay greater than or equal to 31.2 milliseconds had a 14% risk, P value of less than 0.001.                                 The hazard ratio for predicting primary endpoints in patients with low ventricular electrical activation delay was 2.34 with a P value of less than 0.01. However, ventricular electrical activation delay was not predicted in patients with right bundle branch block or IVCD.                                 In our next study, Karl-Heinz Kuck and associates examined the predictors of long-term clinical outcomes after catheter ablation of atrial fibrillation in 750 patients in the FIRE AND ICE Trial. Using propensity score stratification methods to count for differences in baseline characteristics between sexes, the authors found that female sex with a hazard ratio of 1.37, P equals 0.01, and prior direct current cardioversion with a hazard ratio of 1.40, P equals 0.013 were independently associated with atrial fibrillation recurrence.                                 Female sex with hazard ratio of 1.36, P value of 0.035 and hypertension with a hazard ratio of 1.48, P value of 0.013 independently predicted cardiovascular rehospitalization. A longer history of atrial fibrillation with a hazard ratio of 1.03, P value of 0.039 increased the rate of repeat ablation.                                 After propensity score adjustment, women continued to have higher rates of primary efficacy failure with adjusted hazard ratio of 1.51, P less than 0.05 and cardiovascular rehospitalization with a hazard ratio of 1.40, P less than 0.05.                                 In the next study, Laura Bear and associates examined the reliability of inverse electrocardiographic mapping of cardiac electrical activity from recorded body surface potentials. In five anesthetized closed-chest pigs, torso and ventricular epicardial potentials were recorded simultaneously during sinus rhythm, epicardial, and endocardial ventricular pacing. Two approaches, coupled finite/boundary element methods and a meshless approach based on the method of fundamental solutions, were compared.                                 The authors found that inverse mapping underestimated epicardial potentials more than twofold, P less than 0.0001. Mean correlation coefficients for reconstructed epicardial potential distributions ranged from 0.60 to 0.64 across all methods. Epicardial electrograms were recovered with reasonable fidelity at approximately 50% of the sites, but variation was substantial.                                 General activation spread was reproduced with a mean correlation coefficient of 0.72 to 0.78 for activation time maps with spatio-temporal smoothing. Epicardial foci were identified with a mean location error approximately 16 millimeters. Inverse mapping with method of fundamental solutions was better than coupled finite/boundary element methods.                                 The authors concluded that spatio-temporal variability of recovered electrograms may limit the resolution, with implications for accuracy of arrhythmia localization.                                 In the next study, Pejman Raeisi-Giglou and colleagues examined the incidence of pulmonary vein stenosis in 10,368 patients undergoing atrial fibrillation ablation from 2000 to 2015. Computed tomography scans were performed three to six months after the procedures. Severe pulmonary vein stenosis was observed in 52 patients, or 0.5%. The left superior pulmonary vein represented 51% of all severely stenosed veins.                                 Percutaneous interventions were performed in 43 patients, and complications occurred in five, including three pulmonary vein ruptures, one stroke and one phrenic injury. Over a median follow-up of 25 months, 41, or 79%, of patients remained arrhythmia-free.                                  In our next paper, Koichi Nagashima and associates compared hot balloon ablation and cryoballoon ablation in a 165 consecutive patients who underwent initial atrial fibrillation catheter ablation. Of the 165 patients, 74 propensity score-matched patients equally divided between hot balloon ablation and cryoballoon ablation were studied.                                 Patients' characteristics included age, sex, body mass index, atrial fibrillation subtype, CHA2DS2-VASc score, and left atrial dimension were similar between the two groups. 52% of the hot balloon ablation patients required touch-up with radiofrequency ablation for residual/dormant pulmonary vein conduction versus 24% of the cryoballoon ablation patients with a P value of 0.02.                                 The anterior aspect of the left superior pulmonary vein was the site in 41% of the touch-ups after hot balloon versus the inferior aspect of the inferior pulmonary veins in 22% of the touch-ups after cryoballoon ablation. Hot balloon lesions were smaller with an area of 23.8 centimeters squared compared to cryoballoon ablation lesions having an area of 33.5 centimeters squared with a P value of 0.0007. Within 12 months, both methods had an AF recurrence of 16%.                                 In our next paper, Mildred Opondo and associates randomized 61 patients, mean age 52 years, to either 10 months of high intensity exercise or yoga. The authors found that left atrial volume, Vo2 max, and left ventricular end-diastolic volume increased in the exercise group with no change in the control with a P value of less than 0.0001.                                 The authors did not find significant changes in atrial electrical activity and hypothesized that a longer duration training may be required to induce electrical changes.                                 In our next paper, because there's evidence that the distal part of the ligament of Marshall might be a sympathetic conduit between the left stellate ganglion and the ventricles, Shan Liu and associates randomly divided 29 dogs into a sham ablation group, a ligament of Marshall ablation group, and a left stellate ganglion ablation group. Ablation was performed before occlusion of the left anterior coronary artery.                                 Ligament of Marshall ablation attenuated blood pressure elevation induced by left stellate ganglion stimulation. Both ligament of Marshall ablation and left stellate ganglion ablation similarly prolonged ventricular refractory period and reduced the incidence of ventricular arrhythmias compared with sham ablation.                                 In our next study, Smith and Tester and associates examined the heterologous functional validation studies of putative long-QT syndrome subtype 2, LQT2, associated variants. Genetic testing of 292 sudden infant death syndrome cases identified nine KCNH2 variants, while some of the channels associated the variants can lead to accelerated deactivation and activation gating. Other current levels were similar to wild-type.                                 The authors examined the electronic health records of patients who were genotype positive for these particular sudden infant death syndrome–linked KCNH2 variants and found all of them had a median heart rate–corrected QT intervals less than 480 milliseconds and none had been diagnosed with long-QT syndrome or suffered cardiac arrest.                                 Simulating the impact of dysfunctional gating variants using computational models of the human ventricular action potential predicted that they have little impact on action potential duration. The authors concluded that these rare Kv11.1 missense variants are not long-QT2 causative variants and, therefore, do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.                                 In our next study, Tina Baykaner and associates performed a systematic literature review and meta-analysis to determine outcomes from ablation of atrial fibrillation drivers in addition to pulmonary vein isolation or as a stand-alone procedure. The authors found 17 studies with a cohort size of 3,294 patients.                                 Atrial fibrillation driver ablation, when added to a pulmonary vein ablation or a stand-alone procedure compared the controls, produced an odds ratio of 3.1 with a P value of 0.02 for freedom from atrial fibrillation and an odds ratio of 1.8 with a P value of less 0.01 for freedom of all arrhythmias in four controlled studies.                                 Adding atrial fibrillation driver ablation to pulmonary vein ablation resulted in a freedom from atrial fibrillation of 72.5%, P value of less than 0.01 and a freedom from all arrhythmias of 57.8% with a P value less than 0.01. Atrial fibrillation termination was 40.5% and predicted favorable outcome from ablation with a P value of less than 0.05. Large multicenter randomized trials are needed to precisely define the benefits of adding driver ablation to a pulmonary vein isolation.                                 In our next study, Hidekazu Kondo and associates found that the adverse atrial remodeling, including atrial inflammation, lipidosis and fibrosis, were induced in both wild-type and Interleukin-10 knockout mice by high fat diet, but the effects were exaggerated in the Interleukin-10 knockout mice. Vulnerability to atrial fibrillation was also significantly enhanced by the high fat diet.                                 The total amount of epicardial and pericardial adipose tissue volume was increased with high fat diet. Proinflammatory and profibrotic cytokines of epicardial and pericardial adipose tissue were also upregulated. In contrast, the protein level of adiponectin was downregulated by the high fat diet. Systemic Interleukin-10 administration markedly ameliorated the high fat diet induced obesity-caused left atrial remodeling and vulnerability to atrial fibrillation.                                 The authors concluded that Interleukin-10 treatment may limit the progression of atrial fibrillation occurring in the setting of a high fat diet.                                 In our next paper, Garcia and Campbell and associates demonstrated the ability to deliver amiodarone epicardially over a sustained period of time. The authors demonstrated in a pig model of atrial fibrillation that an amiodarone containing polyethylene glycol-based hydrogel placed directly on the atrial myocardium in a minimally invasive catheter procedure significantly reduced the duration of sustained atrial fibrillation at 21 and 28 days. The authors found that inducibility of atrial fibrillation was also reduced.                                 In our final paper, Htet Khine and associates examined the effect of spaceflight on the changes in atrial structure, supraventricular beats, and atrial electrophysiology, and to determine whether spaceflight could increase the risk of atrial fibrillation.                                 The authors found that, in 13 that in astronauts, the left atrial volume transiently increased after six months in space without changing atrial function. Right atrial size remained unchanged, while one astronaut had a very large increase in supraventricular ectopic beats, none developed atrial fibrillation. The P-wave amplitude duration did not change over time, but RMS 20 decreased on all fight days except landing day.                                 That's it for this month. Thanks for listening to On the Beat. We hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next month.  

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

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. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. This week's issue is the Go Red for Women issue, my favorite discussions of the year happened during this podcast.                                                 Today, I am so delighted to have with me, our Editor-in-Chief himself, Dr. Joe Hill, from UT Southwestern, as well as, of course, the editor that made this issue possible, Dr. Sharon Reimold, also from UT Southwestern. Joe, would you like to tell us a little bit about this year's Go Red issue? From the birds eye view. Dr. Joseph Hill:                  Well Carolyn, I share your enthusiasm. This is our second annual Go Red for Women issue and it is fantastic. It has generated great interest in the community. We had a number of papers coming in, unsolicited. Our frame of reference-type content. Original research articles. State of the art.                                                 We clearly touched a nerve with this issue. As we will discuss further, we shine a bright light here on some of the very best science, focusing on sex-based differences in the biology of heart disease, the presentation of heart disease, how women function, and are treated in the academic environment. The ways in which they are impacted by psychological stress. It's an absolute bonanza of science, in this issue. Dr. Carolyn Lam:               You took the words out of my mouth. It is a bonanza issue. I mean, we had seven original articles. Lots of new stuff, but lots of good, important papers on plain old ischemic heart disease. What I really liked was that, three of these original papers focused on myocardial infractions, in the young, and their risk factors, prevention, and so on. Sharon, shall we go through those? I mean, there was the one on genetics, lifestyle, and LDL in young women. Dr. Sharon Reimold:        That would be great. That manuscript looked at, sort of, a distribution of lipids, in women, that would have otherwise expect to be healthy. They sorted them out by individuals that had extremely low LDL levels and those that had high LDL levels. They pointed out that the individuals with high LDL levels. Ended up having hypercholesterolemia heritable, but they also found genetic variance of related to those with low LDL levels. I think this manuscript points out the importance of screening younger women for lipid disorders and incorporating those data into their clinical management. Dr. Carolyn Lam:               Absolutely. Then, there was that paper that, again, talked about young women experiencing myocardial infarction, and the sex differences in their presentation, and perception. That was super cool. From the Virgo trial. Dr. Sharon Reimold:        There are several other papers, that are published, demonstrating that women tend to have multiple symptoms when they present with symptoms of ischemia. That's true for both myocardial infarction, as well as for other unstable syndromes. They certainly have more symptoms than men.                                                 But what was very interesting about this particular paper, is that when women presented with multiple symptoms, providers were less likely to think that the symptoms were due to a cardiac etiology. So even when women are trying to tell their providers what is going on, sometimes, they're not taken seriously, because they have multiple symptoms. So I'm hoping that this resonates with our providers, clinical providers, and we think about this. Whether we're cardiologist, or emergency room providers, or even EMTs. Dr. Carolyn Lam:               Exactly. Then, the third original paper in these young women, kind of scary, mental stress induced myocardial ischemia. Dr. Sharon Reimold:        Right. So there's been a lot of interest in the myocardial infarction without obstructive coronary disease, in the last year or two. Because a lot of those individuals, even thought, they don't have typical atherosclerotic pathologies, they don't have good outcomes. So this article looks at the role that mental stress plays in inducing ischemia, by EKG, in these individuals.                                                 I think we still need to understand more about how this contributes to the biology, and outcomes, in these individuals. Also, get a better understanding if this is also true in older women, who have ischemic heart disease. Dr. Carolyn Lam:               Exactly. You know, but speaking of the older women, it's not like the issue left out the older women this time either. I did think that the study on the metabolic predictors of incident ischemic events, in postmenopausal women, was really interesting, as well. Basically, the authors identified a cluster of novel metabolites, that were related to oxidative stress, that added to. you know?                                                 They weren't correlated with the traditional biomarkers. Really suggesting that there may be a whole area of metabolites, and other biomarkers, that we may be needing to check, and to understand better, for risk prediction. At least, in older women. But, of course, in men as well. Then, finally, there was the data on sex differences from the STICH trial, on surgical revascularization. What did you think of that one? Dr. Sharon Reimold:        Well, I thought that this was a very important addition to the cardiology literature. Because we are accustomed to thinking of women as having poor outcomes, after they have cabbage revascularization surgery. Certainly, the STICH trial enrolled patients who were more sick than the average patient, with their underline LV dysfunction. They found that sex did not influence the outcomes in this trial.                                                 So the importance of that, for the medical community, is obviously we should not consider sex as a barrier to sending women to surgery, even if they're at high risk, because they can have equally good outcomes. Dr. Carolyn Lam:               Exactly. Important message. Important paper. Then, moving from ischemic heart disease. We also had a paper focusing on stroke, which I thought was a really intriguing one, talking about atrial fibrillation, and questioning if being a woman is a risk modifier, or a risk factor. Do you want to elaborate on that one? Dr. Sharon Reimold:        So instead of the using the CHA2DS2–VASc algorithm they use the CHADS2-VA program and then looked to see how well that predicted risk, and how much the S and C, the gender actually influenced outcome. I think this is an important issue. I'll say it's for women, perhaps. because as a woman, you know, without doing anything, you start out with a risk factor of one. Then, once you get to a certain age you have a risk factor of two. That's even for somebody who has no other disease processes. Dr. Carolyn Lam:               Yeah. Dr. Sharon Reimold:        So I think it's a little different way to look at how the risk is modified. They propose that if your CHADS2-VA score is two, or greater, certainly, your risk goes up if you're also female. They propose, then, that you would treat those patients more intensively. It's just a little twist on the CHA2DS2–VASc and maybe will provide us different ways to refine our knowledge about outcomes in atrial fibrillation. Dr. Carolyn Lam:               Yeah. I love that paper, too, because it's quite different from the papers that we had in the first Go Red issue. Isn't it? But in the first Go Red issue, we had lots of papers on pregnancy. The current issue certainly has those papers as well. Dr. Sharon Reimold:        Yes. There are increasing number of pregnancy related complications. Both maternal, and offspring, complications that predict increased cardiac risk, down the line. This issue has a series of women who had, had preeclampsia during pregnancy, and found that 17% of their women had a coronary artery calcium score of greater than 95th percentile. While that doesn't entirely get you from the biology, in between those two, it at least gives you an idea of where to start going back, and taking a look at what's going on. Dr. Carolyn Lam:               What about the one in rheumatic mitral valve disease? Pregnancy outcomes in women with those? Dr. Sharon Reimold:        So rheumatic heart disease and pregnancy outcomes, you know, we don't see much written about it anymore. because most of the active disease is in certain areas, in the world. But obviously, these women can have symptoms related to their mitral stenosis and/or their regurgitation during their pregnancy, with heart failure being the most common presenting cardiovascular complication. While some of that is much more quantitative, than perhaps, it was in the past, which is useful.                                                 I think that the take-home message from this particular trial is that you need to talk to these patients, and screen them, prior to pregnancy, if possible, to help achieve the best possible outcome. I think that the risk of heart failure was a little bit less than 2% during the trial, which is obviously much higher than the average woman's cardiovascular risk during pregnancy. Dr. Carolyn Lam:               this is still definitely an important issue, in many other parts of the world. I really appreciate that you invited this editorial, that gave that global perspective. The editorial, by Athena Poppas and Katharine French, really beautiful work there. You know, I have to say that one of my favorite papers, in this issue, was that in depth paper, regarding gender versus sex, as a social determinant of cardiovascular risk. I found that so intriguing, the first time I read it, and just love it. Dr. Sharon Reimold:        Social determinants of health is a hot topic, in a lot of different areas of medicine these days. But they point out some really interesting things, that I don't think I had thought about. One is the fact that, when you are a child, you know maybe 10 or 12, that boys are encouraged more to be physically active. Athletics and other sorts of activities. Whereas many girls, don't have the opportunity or are not as interested. Perhaps we set up an abnormal social situation very early in most people's lives. Dr. Carolyn Lam:               Yeah, that represents cardiovascular risk. I know. That stuck out to me too. Dr. Sharon Reimold:        Obviously, how and where people live, as children, can influence outcome. That can be influential for both boys and girls. But I think bringing the idea back to cardiovascular diseases, and risk, are really long term, lifelong processes, that we can make changes in, from a preventative standpoint, even in young people. Dr. Carolyn Lam:               Something we don't usually think about and I just love the way it was presented, so clearly, and I just love it. Now, to an area that really cuts close to the heart. Pun intended. That is the bias in research grants, bias in manuscript authorship. Joe you mentioned that, right from the introduction, I would love your comments on those papers. Dr. Joseph Hill:                  The reality, that we all are aware of, is, in many countries, including the United States, 50% of medical students now are female. But as we move through the ranks, into the different subspecialties, and up the career ladder of academic cardiology, we see a thinning of female representation. Arguably, it's been improving, over the last number of years.                                                 But the reality is, that there remains a bias against representation of women, in terms of extra mural grant funding, authorship on high-profile papers. This article digs into that, and analyzes those numbers, takes a snapshot of what it looks like at the present time. In some ways, I believe it's a call to arms on how we must do a better job of recognizing this and rectifying it, going forward. Dr. Carolyn Lam:               Sharon, did you have comments to add? Dr. Sharon Reimold:        Yeah. I mean, I think, I wholeheartedly agree with Joe about those sorts of things. I mean, we see the same types of issues in clinical cardiology as well as in the research components of what we do. we need to figure out how to do this better, so that we all can be productive, going forward. Dr. Carolyn Lam:               You know it's just such a beautiful issue. So rich, in so many ways. Was there anything else you might want to highlight to our listeners? Dr. Joseph Hill:                  I might add that Sharon and I kicked off the issue with a brief introduction. Pointing out that the reality is, that one and four women will die of heart disease. Most women don't know that. Most healthcare providers don't know that. Many Cardiologist don't know that.                                                 When you compare that to the realities of breast cancer, it's 1 in 40. It's 10 times different. Now, that community has done a fantastic job. The Susan G. Komen program, in the United States. The pink ribbons, that we see all around the world. That community has done a fabulous job of getting the message out about that grievous disorder.                                                 We have to do better. We have to do better educating ourselves, educating the lay public, about the realities of heart disease in women. 1 in 4, around the world. We also have to do a better job of digging into the science. That's where this issue does an especially good job.                                                 That the reality is that heart disease is different in men and women. It presents differently. It presents at a different age. The way in which women respond to therapies, can differ from men. So there's work to be done, in terms of awareness. There's work to be done, in terms of the underline biology. This is an especially exciting time in this arena. Dr. Carolyn Lam:               I couldn't agree more. I'd add to it, even sex differences and the perceptions about own symptoms, and that of women versus men with chest pain. Then, the whole gender, social element to it. Oh, just so much to discuss, so much to learn from.                                                 Well, listeners you heard it right here. I want you to please send this episode, share it with as many other women as you can think of. Do help us to spread this message, it's such an important one.                                                 Thank you so much, Joe and Sharon, for joining me today. Thank you, listeners, as well. Tune in again next week.  

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

Dr. 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.                                                 In just a moment, we will take a deep dive into the issue of age and its association with outcomes of primary prevention ICDs in patients with non-ischemic systolic heart failure.                                                 Yes, a long-awaited discussion from the Danish trial. That, in just a moment. First, here's your summary of this week's Journal.                                                 The first original paper provides evidence of a true association between disturbed genetic imprinting and Preeclampsia. This paper is from co-first authors, Dr. Zadora, and Dr. Singh, and co-corresponding authors, Dr. Izsvak, from the Max Delbrück Center for Molecular Medicine; Dr. Hurst, from the University of Bath; and Dr. Dechend, from the Experimental and Clinical Research Center of Berlin.                                                 These authors performed an unbiased analysis of genome-wide molecular data on raw characterized patient material, from normal controls, and patients with  Preeclampsia, and identified DLX-5 as an imprinted target gene, with novel placental function in Preeclampsia. Due to loss of imprinting, DLX5 was upregulated in 69% of placentas from Preeclampsia patients. Levels of DLX5 correlated with the classical Preeclampsia markers.                                                 DLX5 was expressed in human, but not in urine trophoblast, underlying the known human specificity of Preeclampsia. Finally, DLX5-induced overexpression if trophoblasts faithfully modeled Preeclampsia in a cell culture system. In summary, this paper shows that disturbed imprinting is common, and may play a causal role in Preeclampsia.                                                 The next study affirms that stenosis severity is better discriminated using coronary invasive physiologic indices, than using coronary angiographic assessment. First author, Dr. Lee, corresponding author Dr. Koo, colleagues of Seoul National University Hospital, studied 115 patients with left anterior descending artery stenosis, who underwent both ammonia positron emission tomography, or PET, an invasive physiologic measurement.                                                 Myocardial blood flow measured using PET, and invasively measured coronary pressures, were used to calculate microvascular resistance, and stenosis resistance. They found that both fractional flow reserve, or FFR, and instantaneous weight free ratio, or IFR, decreased as angiographic stenosis severity, resistance, and pressure gradient increased, and hyperemic myocardial blood flow decreased.                                                 When the presence of myocardial ischemia was defined by both low hyperemic myocardial blood flow, and low coronary flow reserve, the diagnostic accuracy of FFR and IFR did not differ, regardless of cutoff values for hyperemic myocardial blood flow, and CFR. However, at any given stratum of a given stenosis, physiologic classification of stenosis severity using FFR or IFR showed better discrimination of a unique relationship between absolute myocardial blood flow, and pressure gradient, than anatomic classification using angiographic percentage.                                                 In summary, by demonstrating coronary physiologic responses to coronary stenosis, these authors showed that stenosis severity is better discriminated, using invasive physiologic indices, than using angiographic assessment.                                                 The next paper identifies a previously unknown angiogenic growth factor that can be enhanced therapeutically to repair the heart after myocardial infarction. This novel growth factor is endoplasmic reticulum membrane complex, Subunit 10, or EMC10, which the authors previously identified by bioinformatic secretome analysis in bone marrow cells.                                                 In the current paper, from co-first authors Dr. [Rabel 00:04:35], and [Krof Clengobill 00:04:37], and corresponding author Dr. Wollert, from Hanover Medical Center, and colleagues, the authors investigated the angiogenic potential of EMC10, and its mouse homologue, in cultured endo fetal cells and infarcted heart explants. They found that EMC10 and its mouse homologue signal a virus, small GTAPases; p21-activated kinase; and p38 mitogen-activated protein kinase, to promote endothelial cell migration.                                                 In mice with acute myocardial infarction, bone marrow derived monocytes and macrophages produced EMC10 endogenously, to enhance infarct vascularization, tissue repair, and heart function. Furthermore, subcutaneous treatment with recombinant EMC10 for one week, after myocardial infarction, augmented infarct vascularization and repair, and led to a sustained improvement in heart function and survival.                                                 The next study is the first prospective randomized trial of screening for atrial fibrillation, with a smartphone-based, single-lead, electrocardiographic system in 1,001 patients, aged 65 years and above, with a CHA2DS2-VASc score of two and above, and without a history of atrial fibrillation.                                                 In this paper, from first and corresponding author Dr. Halcox, from Swansea University Medical School, in the United Kingdom, and colleagues, patients were randomized, either to biweekly electrocardiographic recordings with the iPhone device, or to routine over a 12-month period.                                                 The smartphone-based electrocardiographic approach was at least three times more likely to identify incident atrial fibrillation, than routine care, and at a cost of just over $10,000 per case identified, and was judged to be a highly acceptable approach in this group of patients. These results support consideration of evaluation in an appropriately-powered, event-driven randomized trial, to confirm the clinical and cost effectiveness of such an approach to stroke prevention in atrial fibrillation.                                                 Well, that wraps it up for your summaries. Now for our feature discussion. The Danish trial really created a huge splash last year, when it was reported that a primary prevention ICD in patients with non-ischemic systolic heart failure, may not actually reduce all cause mortality. Something that we had, perhaps, taken for granted, and in fact, entered our guidelines.                                                 Now, however, there was a pre-specified subgroup analysis at the time, that suggested a possible age-dependent association, between ICD and mortality, in the Danish trial. This week, we are so pleased to be discussing an in-depth analysis of the association between age and outcomes in the Danish trial.                                                 I'm so pleased to have the first author of today's featured paper, Dr. Marie Bayer Elming, of Copenhagen, Denmark, as well as Dr. Sana Al-Khatib, who's not only an associate editor of circulation, but also the author of an accompanying, and she is from Duke, Durham, North Carolina. Welcome, ladies! Dr. Bayer Elming:              Thank you. Happy to be here. Dr. Sana Al-Khatib:          Thank you so much. Dr. Carolyn Lam:               Sana, could you start by framing why this paper is so important, and why we've been looking forward in anticipation to these results? Dr. Sana Al-Khatib:          Absolutely. As you know, data on the outcomes of primary prevention ICDs in patients with non-ischemic cardiomyopathy started emerging in the early 2000s, or so. Then in 2005, the sudden cardiac deaths and heart failure trial was published, that included a large number of patients with non-ischemic cardiomyopathy, and absolutely showed survival benefits from primary prevention ICDs in those patients. Of course, there were also patients with ischemic cardiomyopathy.                                                 But really, that trial formed the basis of the guidelines, recommendations, that have informed our practice for the last 12 years, that basically tell us that we should consider implanting a primary prevention ICD in patients with non-ischemic cardiomyopathy, who have an EF of 35% or less, who have Class II or III heart failure symptoms. As long as they are on optimal care at the end, they have a reasonable life expectancy.                                                 So that's what's we've been doing for years, and then, the Danish trial was published this past year, that really called into question the prior findings, and the current practice. Because Danish, as you stated, showed no survival benefit with primary prevention ICDs, but there are many aspects about the trial that people need to pay attention to, to put the results in perspective.                                                 The fact that 58% of patients in the trial, in those arms, received cardiac resynchronization therapy ... the fact that the trial required that patients have an elevated NTproBMB level, to be considered for enrollment ... that may have biased the results toward a higher risk of non-sudden cardiac deaths, so on, so forth.                                                 I think what was really interesting, and caught people's attention, when the paper was published, was this subgroup analysis that showed that younger patients may benefit more than older patients. I think, many of us, Carolyn, were really awaiting the results of a more dedicated analysis, looking at age in Danish, and Dr. Elming and her colleagues did a great job looking at this very closely in their paper, and showed great results, and probably will let Dr. Elming share those results with us. Dr. Carolyn Lam:               Yes, absolutely, Sana. Actually, I just wanted to echo how surprised everyone was, and the immediate thing was, "Oh, my goodness. What do we do with the guidelines?" Maybe we should get back to that later, and Marie, please share with us, what did you do, and what did you find this time? Dr. Bayer Elming:              The reason why we did this study was that, in this main Danish trial, age was the only one of the 13 pre-specified subgroups that had a significant treatment by a subgroup interaction. This suggested that a younger patient might have a survival benefit from ICD ... the implication, even though the overall study was neutral. So we wanted to further investigate this relationship between age and effective ICD implantation.                                                 What we did was to look at the relation between age and effective ICD, and we found that there was this linear relation, for each year of younger age, that was associated with a reduction, a 3% reduction in the hazard ratio, for the benefit of ICD.                                                 Also, we did this selection impact curve, which is a bit technical, but what it does is to describe the expected survival for the population, on as a whole, for the different age cutoffs for ICD treatments.                                                 So, if we take into account, both the patients receiving an ICD, and those who did not, we could see why we would get the highest survival for the population as a whole. What we found was that, when no one in the population received an ICD, around 70% would survive.                                                 If everyone in the population received an ICD, only 72% would survive, but if we chose 70 years as the age cutoff ... so, patients younger than 70 years received an ICD, and patients older than 70 years did not receive an ICD, we got the highest survival for the population, and 75% would survive. Dr. Carolyn Lam:               Thank you, Marie. What important results. So, maybe, still consider ICDs for primary prevention ... in our non-ischemic systolic heart failure, patients were less than 70 years old. Is it as simple as that, Sana? You wrote a beautiful editorial. Tell us, what are the clinical implications? Dr. Sana Al-Khatib:          This is an important question. Danish was an important trial, but in my mind, it truly doesn't refute the role of primary prevention ICDs in patients with non-ischemic cardiomyopathy. As I mentioned earlier, the majority of patients enrolled in Danish received a CRT device. And so, you end up questioning, what does that actually mean, for those patients who are not eligible for cardiac resynchronization therapy?                                                 So, I actually believed that, and as you know, Carolyn, and maybe Marie knows, as well, there have been several meta analyses that have been published, combining data on patients with non-ischemic cardiomyopathy only, and excluding patients with cardiac resynchronization therapy from Danish, that have actually now shown, consistently, a significant improvement in survival, with a primary prevention ICD ... including one that was done by our group.                                                 So, no, I don't think that, based on the results, we should say, "No, we shouldn't be offering primary prevention ICDs to patients with non-ischemic cardiomyopathy," and this beautiful analysis that was done by Marie and her group actually shows that, at least for those patients who are 70 years of age and younger, I think we should absolutely continue to consider them for the therapy, and offer them the therapy, if they're appropriate candidates.                                                 Then, of course, if the patients are older than 70,, and they meet criteria for cardiac resynchronization therapy, I think it will be important for us to be talking to the patients about ... is the RTD with a defibrillator, versus a CRTP only, with a pacemaker, and talking about the pros and cons, and everything else? But in those patients who are older than 70, who don't meet criteria for CRT, I think more research is needed, to really understand the role of primary prevention ICDs in those patients. We definitely need more data there. Dr. Bayer Elming:              I definitely agree that, of course, for the patients older than 70 years were not candidates for CRT treatment. These patients, we do not know very much about 'em, and this study that we did, do not answer that question. Based on the Danish study, and this further analysis of the age inspection, the guidelines in Denmark also state that patients younger than, we say, 68 years, because that was the age cutoff used in the '08 Danish trial, you should definitely think of giving patients with non-ischemic cardiomyopathy an ICD.                                                 But for the older patients, it depends on a variety of co-factors, such as co-morbidity, or frailty, and it should be an individual assessment of the patient. So, I agree with you, Sana. Dr. Carolyn Lam:               That's wonderful. Hey, just one more question. Sana, I'd like you to put on your AE hat, now, and sort of think with me. In circulation, we don't ... well, we're careful about publishing subgroup analyses, so to speak, right, of results. You articulated, in your editorial, reasons why this, perhaps subgroup analysis, may be different from others. Could you elaborate on that a bit? Dr. Bayer Elming:              Yeah, and absolutely, that's a great question. As you pointed out, I mean, you really ... the conventional wisdom in clinical research is to be careful, interpreting subgroup analyses. I think there are some strengths in this particular analysis, as Marie stated: "Here's what we specified." The other thing is, I believe that Marie and her group then came, and did their very robust statistical methods, and really, probably most importantly, if you look at their findings, they actually really align well, and support their main conclusion.                                                 For example, looking at the fact that older patients had the higher presence of co-morbidities, that they had a higher level of [Co-BMP 00:17:00], they had had a longer duration of heart failure ... I mean, all those things most likely had an impact on their mode of death, really making it more likely for those patients to succumb to non-sudden cardiac death. I think the whole story makes a lot of sense. Dr. Bayer Elming:              If I can elaborate a bit on this, I think one of the important findings from the study is that we show that mode of death varied according to age. So, the rates of sudden cardiac death were almost similar, between the younger and the older part of the population. But the rates of non-sudden death were almost twice as high in the older part of the population. This is a really good explanation why the ICD implantations have less impact in the older patients. Dr. Carolyn Lam:               Yeah, because ICDs would definitely not be expected to reduce non-sudden cardiac deaths. Really, really, well put. Oh, thank you so much, Marie. We're so proud to be publishing your beautiful paper, as well as your editorial, Sana, and thank you for this great conversation.                                                 Well, listeners, I'm sure you enjoyed that as much as I did. Thank you for joining us this week, and don't forget to tune in next week.

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore. Have you ever wondered what the clinical implications of very brief episodes of device-detected atrial tachyarrhythmias are? Well, we will be discussing this with novel data from the RATE registry in just a moment. First, here's your summary of this week's journal.     The first study provides the first evaluation of the Sweden nationwide abdominal aortic aneurysm screening program. Of almost 303,000 men invited for screening, 84% attended. The prevalence of screening detected abdominal aortic aneurysm was 1.5%. After a mean of 4.5 years, 29% of patients with aneurysms had been operated upon with a 30-day mortality rate of 0.9%. The introduction of screening was associated with a significant reduction in aneurysm-specific mortality. The number needed to screen to prevent 1 premature death was 667, while the number needed to operate on to prevent 1 premature death was 1.5.     Furthermore, the authors showed that their screening program was highly cost-effective in the contemporary setting in Sweden. These findings confirm results from earlier randomized controlled trials in a large population-based setting, and may be important for future healthcare decision-making. This and the diverse requirements for efficient population screening for abdominal aortic aneurysm, from program management to maintaining skills in open repair are discussed in an excellent accompanying editorial by Dr. Cole from Imperial College London.     The next study looks at thoracic epidural anesthesia and suggests that caution may be needed in patients with or at risk for right ventricular dysfunction. You see, thoracic epidural anesthesia involves blockade of cardiac sympathetic fibers, which may affect right ventricular function and interfere with the coupling between the right ventricle and right ventricular afterload. Dr. Wink and colleagues from the Leiden University Medical Center therefore used combined pressure volume conductance catheters to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular pulmonary artery coupling in 10 patients scheduled for lung resection.     Thoracic epidural anesthesia resulted in a significant reduction in right ventricular contractility, stroke work, dP/dt max and ejection fraction. This was accompanied by a reduction in effective arterial elastance such that ventricular pulmonary coupling remain unchanged. Clamping of the pulmonary artery increased right ventricular contractility but decreased ventricular pulmonary coupling. These effects of increased afterload were the same before and after thoracic epidural anesthesia. In conclusion, therefore, thoracic epidural anesthesia impaired right ventricular contractility but did not inhibit the native positive ionotropic response of the right ventricle to increase afterload. These findings are clinically relevant for daily practice in cardiothoracic surgery because pulmonary hypertension is frequently encountered, and right ventricular function is an important determinant of early and late outcomes.     The next study suggests that the use of point of care hemostatic testing may have a place in the management of patients undergoing cardiac surgery. Dr. Karkouti and colleagues of the Toronto General Hospital hypothesized that point of care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery, thereby reducing blood transfusion. They therefore conducted a pragmatic multi-center stepped-wedge cluster randomized controlled trial of a point of care based transfusion algorithm in 7,402 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They found that the trial intervention reduced rate of red cell transfusion with an adjusted relative risk of 0.91 and a number needed to treat of 24.7.     The intervention also reduced rates of platelet transfusion and major bleeding but had no effect on other blood product transfusions or major complications. These findings that point of care testing improved management of coagulopathy in cardiac surgery support the consideration of their broader adoption in clinical practice.     The next study provides experimental evidence that brings us one step closer to therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis. In this study from first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein and colleagues from LMU Munich, authors focus on cathepsin G, which is stored in neutrophil and azurophil granules and discharged upon neutrophil activation. They studied site-specific myeloid cell behavior after high-fat diet feeding or TNF stimulation in the carotid artery, the jugular vein, and cremasteric arterioles and venules in APOE E and Cathepsin G-deficient mice.     Their studies revealed a crucial role for Cathepsin G in arterial leukocyte adhesion, an effect that was specific for the arteries and not found during venular adhesion. Consequently, Cathepsin G deficiency attenuated atherosclerosis but not acute lung inflammation. Mechanistically, Cathepsin G was immobilized on arterial endothelium, where it activated leukocytes to firmly adhere, engaging endocrine clustering, a process of crucial importance to achieve effective adherence under high-sheer flow.     Therapeutic neutralization of Cathepsin G specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of Cathepsin G-neutralizing antibodies really allowed the inhibition of atherogenesis in the mice. Taken together, these findings presented evidence of an arterial-specific recruitment pattern centered on Cathepsin G adhesion, thus representing a potential novel strategy and target for the treatment of arterial inflammation. Well, that wraps it up for the summary of this week's journal. Now, for our featured discussion.     Our feature paper for today discusses the clinical implications of brief device-detected atrial tachycardias and really novel findings from the RATE registry. I'm so happy to be here with the first and corresponding author, Dr. Steven Swiryn from Feinberg School of Medicine, Northwestern University. Hi, Steven.   Steven: Good morning.   Carolyn: We also have with us Dr. Mark Link, associate editor from UT Southwestern. We all know that prolonged episodes of atrial tachycardia or atrial fibrillation are associated with increased risk and that if we anticoagulate those with a high CHA2DS2–VASc score, we can lower the risk of stroke. Now, the European Society of Cardiology guidelines also say that recent data reinforced the assumption that even brief episodes of silent atrial fibrillation may convey an increased risk of stroke. We also know that prior studies have looked at device-detected atrial fibrillation. Steven, I'd really love if you could start by telling us what makes your study different. What was the main thing you were trying to look at?   Steven: Well, one reason it's attractive to use the device population, patients with pacemakers or defibrillators, to look at these issues is because devices have a very high likelihood of detecting episodes of atrial fibrillation whereas symptoms or single 12 EKGs miss a lot of atrial fibrillation, so the sensitivity is much higher, although not perfect. The problem is that very brief episodes of atrial fibrillation are very poorly detected by devices. The specificity of automatic detection is very low, such that all previous studies until the RATE registry have excluded any episode of atrial fibrillation detected by a device less than 5 minutes in duration because they're unreliable. A lot of them turn out to be false positive detections. Our study was designed to evaluate whether even very brief episodes of an atrial tachyarrhythmia might also be associated with risk of clinical events and might or might not warrant anti-coagulation.   Carolyn: Ah, that's interesting, so you really helped to answer how brief is "brief" when we need to talk about device-detected atrial fibrillation. Could you expand on how you actually defined "short episodes" here?   Steven: Right. A short episode for the purpose of the RATE registry was defined as an episode where the electrogram that we scrutinized had both the onset and the offset of the episode within the same electrogram tracing, so although we can't put a specific time duration on it because that wasn't part of the criterion, it's typically less than 20 seconds or so, although not always, whereas a long episode was defined as an electrogram where either the onset and/or the offset was not captured by the device memory and therefore we don't know the duration. Some of those may not have been very long, and some of those may have been extremely prolonged episodes. That allows us to actually scrutinize the electrogram. We looked at 37,530 individual electrograms using 8 teams of adjudicators, each with a physician and a field clinical engineer from the device company so that we could actually say definitively, "Yes, this was atrial fibrillation," or, "No, it wasn't."   Carolyn: This is the first study to really look under that 5-minute limit of atrial tachycardias. What did you find?   Steven: Well, we found that in contrast to prolonged episodes, short episodes of atrial tachyarrhythmias were not associated with an increased risk compared to those without atrial fibrillation of pre-defined clinical events, including death from any cause, heart failure, stroke, hospitalization for atrial fibrillation, and a few other smaller events.   Carolyn: This was over a 2-year follow-up period, is that right?   Steven: The median follow-up was slightly less than 2 years, that's right.   Carolyn: What I really was struck with was also the second finding, the propensity to develop longer episodes. Could you expand on that?   Steven: We reasoned that in the clinic, one might be faced with a short episode was we defined them, and then you don't know what's going to happen for the next 2 years to bring to bear the results of our study. We looked at if your first episode was short, what was your likelihood over the full follow-up of the study of progressing to longer episodes. About 50% of patients who had their first episode as only a short episode progressed to a longer episode over the full follow-up and therefore were in the long category for the rest of the results. Half of them never got a longer episode.     It was, as one might imagine, if you had your first short episode very early in the study and had a longer follow-up, you were more likely to end up in the long category, and if you had very frequent short episodes, you were also more likely to end up in the long category by the time the full follow-up was over with. Having an initial short episode is not a guarantee that you're never going to get a long episode and that you'll never acquire a consideration of anti-coagulation.   Carolyn: That was a very important message to me as well because it meant that although I can be secure or reassured by these data for very short episodes, I needed to look out for the development of longer episodes, at least that's what your registry showed over 2 years of follow-up. I'm curious, Mark, what were your take-home messages because that leaves us with a bit of a conundrum. What do we do about anti-coagulation in these patients?   Mark: I think this study is a big help to the practicing electrophysiologist and practicing cardiologists. It's a very ledger number of patients with a lot of episodes of afib. It's reassuring to me that the shorter episodes of afib as defined by the study, the individuals did not have a higher incidence of stroke compared to those with no episodes, so it's reassuring and very important clinically as I go through my practice.     I do look forward to more analyses and more data from this study because although now we know that episodes less than 20 seconds are in all likelihood not going to need anti-coagulation, we still don't know about those from 20 seconds to 5 minutes. Hopefully with more analysis of this study we'll get that answer also.   Carolyn: Steven, do you agree with that?   Steven: We would love to have that. At first glance, you would think that devices would give you all of the data you needed because after all, they're monitoring the patient 100% of the time, but there are difficulties with that because device memory is limited, and you don't get electrograms that go on until the termination of atrial fibrillation even if the device were accurate in determining when that termination was because depending on how the device was programmed and depending on whether it was a more modern device later in the trial or earlier and had more or less memory, it cuts off after a limited amount of time, and you don't see necessarily how long the duration is.     Now, you can use device-based data. The device gives you its estimate of how long the episode is, but those are not as reliable as adjudicating the electrograms and actually looking at them. Those data would be a little softer than the main results if we get there.   Mark: That was the data that was used for all of the other studies, was [transassert 00:14:51]. It would be comparable to those other studies. I still think it would be very important data that I'd love to see.   Steven: Okay, well, I agree. I think it would be very interesting to look at that and a number of other things. We have a number of other things we could do with this database. There are a number of substudies that are in progress. For example, one interesting one is there were some instances we found, because we actually looked at these electrograms, there's something that we termed "competitive atrial pacing," where the device will pace at times when we as clinicians would not want to pace. For example, pacemaker-mediated tachycardia would be an instance of that, but then you can pace in the atrium inappropriately. There's a rhythm called repetitive non-reentrant ventricular atrial systole, which, although it's exotic to all of us, actually turned out to be fairly common where there's pacing in the atrium that occurs for various reasons when we want it to.     We actually saw instances where the device itself induced atrial fibrillation. It wasn't that common, but we did see it. We have a substudy that we're working on about the subjective competitive atrial pacing to see how much of that there was and of what, if any, consequence that was. That's one of the things that's been done. Because we scrutinized these so carefully, we tracked morphology and atrial rate at least as a crude estimate, and we have those data, so we could actually evaluate whether if something looks very, very rapid and disorganized as opposed to more organized electrograms at a slower rate, did that make any difference. We don't have any results for those analyses yet. I agree with Mark that the intermediate durations would be interesting to look at.   Carolyn: I agree too, and I'm really grateful for you sharing those thoughts. Very grateful for both of you for your time today. I just have to congratulate you. I completely agree this paper fills an important knowledge gap, and congratulations once again.   Steven: Thank you very much.   Mark: Thank you.   Carolyn: Thank you for listening. You've been listening to Circulation on the Run. Please tune in next week.      

Audio Summary of the August 2, 2016 Issue of JACC, by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Den nye risikoskåren CHA2DS2-VASc-skår er bedre enn CHADS2-skår til å identifisere atrieflimmerpasienter med reell lav risiko for hjerneinfarkt, som da ikke trenger antitrombotisk behandling. Les artikkelen her: https://tidsskriftet.no/2013/08/oversiktsartikkel/atrieflimmer-og-hjerneslag

A summary of the CHa2DS2-VASc score when choosing anticoagulant for a patient with atrial fibrillation