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1. Natural Course of Electrocardiographic Features in Arrhythmogenic Right Ventricular Cardiomyopathy and Their Relation to Ventricular Arrhythmic Events

Author: Anneli Svensson, Henrik Kjaerulf Jensen, Machteld J. Boonstra, Marianne Tétreault‐Langlois, Pia Dahlberg, Henning Bundgaard, Alex Hørby Christensen, Rebecca T. Rylance, Jesper H. Svendsen, Julia Cadrin‐Tourigny, Anneline S. J. M. te Riele, and Pyotr G. Platonov
Subjects: arrhythmogenic right ventricular cardiomyopathy, electrocardiography, longitudinal follow‐up, natural course, prognosis, ventricular arrhythmia, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Electrocardiographic abnormalities are common in arrhythmogenic right ventricular cardiomyopathy and are included in the 2010 Task Force Criteria. Their time course, however, remains uncertain. In this retrospective observational study, we aimed to assess the long‐term evolution of electrocardiographic characteristics and their relation to ventricular arrhythmias. Methods and Results Three hundred fifty‐three patients with arrhythmogenic right ventricular cardiomyopathy as per the 2010 Task Force Criteria with 6871 automatically processed 12‐lead digital ECGs were included. The relationship between the electrocardiographic parameters and the risk of ventricular arrhythmias was assessed at 10 years from the first ECG. Electrocardiographic parameters were compared between the first contact ECG, the ECG at diagnosis, and the most recent ECG. Median time between the first and the latest ECG was 6 [interquartile range, 1–14] years. Reductions of QRS voltage, R‐ and T‐wave amplitudes between the first, diagnostic, and the latest ECGs were observed across precordial and extremity leads. Mean QRS duration increased from 96 to 102 ms (P
Published: 2024
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2. Rationale and Design of the Randomized Bayesian Multicenter COME-TAVI Trial in Patients With a New Onset Left Bundle Branch Block

Author: Lena Rivard, MD, MSc, Isabelle Nault, MD, Andrew D. Krahn, MD, Benoit Daneault, MD, Jean-Francois Roux, MD, Madhu Natarajan, MD, Jeffrey S. Healey, MD, MSc, Kenneth Quadros, MD, Roopinder K. Sandhu, MD, MPH, Remi Kouz, MD, Isabelle Greiss, MD, Peter Leong-Sit, MD, Jean Baptiste Gourraud, MD, Walid Ben Ali, MD, PhD, Anita Asgar, MD, Msc, Martin Aguilar, MD, PhD, Raoul Bonan, MD, Julia Cadrin-Tourigny, MD, PhD, Raymond Cartier, MD, Jean-Francois Dorval, MD, Marc Dubuc, MD, Nicolas Dürrleman, MD, MSc, Katia Dyrda, MD, Peter Guerra, MD, Marina Ibrahim, MD, MSc, Reda Ibrahim, MD, Laurent Macle, MD, Blandine Mondesert, MD, Emmanuel Moss, MD, MSc, Alexandre Raymond-Paquin, MD, Denis Roy, MD, Rafik Tadros, MD, PhD, Bernard Thibault, MD, Mario Talajic, MD, Anna Nozza, MSc, Marie-Claude Guertin, PhD, and Paul Khairy, MD, PhD
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Patients with new-onset left bundle branch block (LBBB) after transcatheter aortic valve implantation (TAVI) are at risk of developing delayed high-degree atrioventricular block. Management of new-onset LBBB post-TAVI remains controversial. In the Comparison of a Clinical Monitoring Strategy Versus Electrophysiology-Guided Algorithmic Approach in Patients With a New LBBB After TAVI (COME-TAVI) trial, consenting patients with new-onset LBBB that persists on day 2 after TAVI, meeting exclusion/inclusion criteria, are randomized to an electrophysiological study (EPS)-guided approach or 30-day electrocardiographic monitoring. In the EPS-guided approach, patients with a His to ventricle (HV) interval ≥ 65 ms undergo permanent pacemaker implantation. Patients randomized to noninvasive monitoring receive a wearable continuous electrocardiographic recording and transmitting device for 30 days. Follow-up will be performed at 3, 6, and 12 months. The primary endpoint is a composite outcome designed to capture net clinical benefit. The endpoint incorporates major consequences of both strategies in patients with new-onset LBBB after TAVI, as follows: (i) sudden cardiac death; (ii) syncope; (iii) atrioventricular conduction disorder requiring a pacemaker (for a class I or IIa indication); and (iv) complications related to the pacemaker or EPS. The trial incorporates a Bayesian design with a noninformative prior, outcome-adaptive randomization (initially 1:1), and 2 prespecified interim analyses once 25% and 50% of the anticipated number of primary endpoints are reached. The trial is event-driven, with an anticipated upper limit of 452 patients required to reach 77 primary outcome events over 12 months of follow-up. In summary, the aim of this Bayesian multicentre randomized trial is to compare 2 management strategies in patients with new-onset LBBB post-TAVI—an EPS-guided approach vs noninvasive 30-day monitoring. Trial registration number: NCT03303612. Résumé: Les patients chez qui un bloc de branche gauche (BBG) est récemment apparu à la suite de l’implantation valvulaire aortique par cathéter (IVAC) présentent un risque de bloc auriculoventriculaire de haut degré tardif. La prise en charge d’un BBG récemment apparu après une IVAC demeure controversée. Dans le cadre de l’essai COME-TAVI (Comparison of a Clinical Monitoring Strategy Versus Electrophysiology-Guided Algorithmic Approach in Patients With a New LBBB After TAVI, ou comparaison d’une stratégie de surveillance clinique, par rapport à une approche guidée par étude électrophysiologique et fondée sur un algorithme, chez des patients présentant un BBG d’apparition récente à la suite d’une IVAC), des patients qui présentent un BBG d’apparition récente persistant le 2e jour après une IVAC, qui répondent aux critères d’admissibilité et qui ont donné leur consentement sont répartis aléatoirement pour être suivis à l’aide d’une approche guidée par une étude électrophysiologique (EEP) ou faire l’objet d’une surveillance électrocardiographique d’une durée de 30 jours. Un stimulateur cardiaque est implanté chez les patients du groupe de l’EEP dont l’intervalle HV (temps de conduction dans le tronc du faisceau de His jusqu’aux ventricules) est ≥ 65 ms. Les patients du groupe de surveillance non invasive reçoivent un dispositif portable d’enregistrement et de transmission continue de données électrocardiographiques pour une période de 30 jours. Le suivi sera réalisé aux 3e, 6e et 12e mois. Le critère d’évaluation principal est un paramètre composite conçu afin de saisir le bienfait clinique net. Il comprend les conséquences majeures des deux stratégies chez les patients présentant un BBG d’apparition récente après une IVAC, comme suit : (i) mort subite d’origine cardiaque; (ii) syncope; (iii) trouble de la conduction auriculoventriculaire nécessitant la pose d’un stimulateur cardiaque (pour une indication de classe I ou IIa); et (iv) complications relatives au stimulateur cardiaque ou à l’EEP. L’essai intègre une conception bayésienne avec une répartition aléatoire (dans un rapport initial de 1:1) antérieure non informative adaptée aux résultats et deux analyses intermédiaires définies au préalable lorsque 25 % et 50 % du nombre anticipé des critères d’évaluation principaux seront atteints. L’essai est axé sur les événements, et la limite supérieure anticipée pour atteindre 77 événements relatifs aux critères d’évaluation principaux sur 12 mois de suivi est de 452 patients. En résumé, l’objectif de cet essai bayésien multicentrique à répartition aléatoire est de comparer deux stratégies de prise en charge de patients présentant un BBG d’apparition récente après une IVAC, soit une approche guidée par une EEP, par rapport à une surveillance non invasive de 30 jours. Trial registration number: NCT03303612.
Published: 2023
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3. Management of Inherited Arrhythmia Syndromes: A HiRO Consensus Handbook on Process of Care

Author: Mikyla L. Janzen, MSc, Brianna Davies, MSc, Zachary W.M. Laksman, MD, Jason D. Roberts, MD, Shubhayan Sanatani, MD, Christian Steinberg, MD, Rafik Tadros, MD, Julia Cadrin-Tourigny, MD, Ciorsti MacIntyre, MD, Joseph Atallah, MD, Anne Fournier, MD, Martin S. Green, MD, Robert Hamilton, MD, Habib R. Khan, MBBS, PhD, Shane Kimber, MD, Steven White, MD, PhD, Jacqueline Joza, MD, Bhavanesh Makanjee, MD, Erkan Ilhan, MD, David Lee, MD, Simon Hansom, MD, Alexios Hadjis, MD, Laura Arbour, MD, Richard Leather, MD, Colette Seifer, MD, Paul Angaran, MD, Christopher S. Simpson, MD, Jeffrey S. Healey, MD, Martin Gardner, MD, Mario Talajic, MD, and Andrew D. Krahn, MD
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Inherited arrhythmia syndromes are rare genetic conditions that predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that confer predisposition to arrhythmia and sudden cardiac arrest and/or death. The field is rapidly evolving as research discoveries increase. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions. This review provides consensus care pathways for 7 conditions, including the 4 most common inherited cardiac conditions that confer predisposition to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These conditions include Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies, and catecholaminergic polymorphic ventricular tachycardia. In addition, an approach to investigating and managing sudden cardiac arrest, sudden unexpected death, and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and nonexperts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high-quality, multidisciplinary, standardized care. Résumé: Les syndromes d’arythmie héréditaires sont des troubles génétiques rares qui prédisposent des personnes en apparence en bonne santé à un arrêt cardiaque soudain et à la mort. L’organisation Hearts in Rhythm Organization est un réseau multidisciplinaire canadien qui regroupe des cliniciens, des chercheurs ainsi que des patients et leurs proches dans le but d’améliorer les soins prodigués aux patients atteints de maladies cardiaques héréditaires et à leur famille, en particulier dans le cas des maladies qui entraînent une prédisposition à l’arythmie et à un arrêt cardiaque soudain et/ou à la mort. Puisque ce champ de recherche évolue rapidement, la mise au point d’un guide pratique et simple à l’intention des professionnels de la santé pour le diagnostic et le suivi des patients enfants et adultes présentant une maladie cardiaque héréditaire serait donc un outil intéressant pour améliorer l’utilisation du système de santé et la prise en charge clinique de ces maladies tout en orientant la recherche à ce propos. La présente synthèse expose les trajectoires de soins faisant l’objet d’un consensus pour sept maladies, dont les quatre maladies cardiaques héréditaires les plus courantes qui prédisposent à l’arythmie. Elle présente aussi des scénarios pour orienter les examens, le diagnostic, la stratification du risque et la prise en charge des patients. Ces maladies sont le syndrome de Brugada, le syndrome du QT long, la cardiomyopathie arythmogénique du ventricule droit et les cardiomyopathies arythmogènes associées, et la tachycardie ventriculaire polymorphe catécholaminergique. En outre, une approche pour la prise en charge de l’arrêt cardiaque soudain, de mort subite inattendue et des membres de la famille immédiate de la personne touchée est proposée. L’orientation vers des cliniques spécialisées en cardiogénétique doit être envisagée dans la plupart des cas. L’objectif est d'établir un cadre de soins qui soit utile pour les experts et les non-experts ainsi que pour les professionnels des domaines connexes, par exemple le personnel de l’administration hospitalière et des services diagnostiques, les coroners et les pathologistes, en vue d’offrir des soins multidisciplinaires normalisés de grande qualité.
Published: 2023
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4. Sex Differences and Utility of Treadmill Testing in Long‐QT Syndrome

Author: Lauren A. Yee, Hui‐Chen Han, Brianna Davies, Charles M. Pearman, Zachary W. M. Laksman, Jason D. Roberts, Christian Steinberg, Rafik Tadros, Julia Cadrin‐Tourigny, Christopher S. Simpson, Martin Gardner, Ciorsti MacIntyre, Laura Arbour, Richard Leather, Anne Fournier, Martin S. Green, Shane Kimber, Paul Angaran, Shubhayan Sanatani, Jacqueline Joza, Habib Khan, Jeffrey S. Healey, Joseph Atallah, Colette Seifer, and Andrew D. Krahn
Subjects: diagnosis, exercise treadmill test, genetics, long‐QT syndrome, LQTS, sex, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Diagnosis of congenital long‐QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal‐to‐borderline resting QT interval. A 3‐step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3‐step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex‐specific cutoffs beyond the resting QTc. Methods and Results We identified 208 LQTS likely pathogenic or pathogenic KCNQ1 or KCNH2 variant carriers in the Canadian NLQTS (National Long‐QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal‐to‐borderline range. The 4‐minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4‐minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1‐minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1‐minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions The 3‐step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.
Published: 2022
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5. The Hearts in Rhythm Organization: A Canadian National Cardiogenetics Network

Author: Brianna Davies, MSc, CGC, Jason D. Roberts, MD, Rafik Tadros, MD, PhD, Martin S. Green, MD, Jeffrey S. Healey, MD, Christopher S. Simpson, MD, Shubhayan Sanatani, MD, Christian Steinberg, MD, Ciorsti MacIntyre, MD, Paul Angaran, MD, Henry Duff, MD, Robert Hamilton, MD, Laura Arbour, MD, Richard Leather, MD, Colette Seifer, MD, Anne Fournier, MD, Joseph Atallah, MD, Shane Kimber, MD, Bhavanesh Makanjee, MD, Wael Alqarawi, MD, Julia Cadrin-Tourigny, MD, Jacqueline Joza, MD, Jimmy McKinney, MD, Stephanie Clarke, MSc, CGC, CCGC, Zachary W.M. Laksman, MD, Karen Gibbs, RN, CCRP, Vuk Vuksanovic, PhD, Martin Gardner, MD, Mario Talajic, MD, and Andrew D. Krahn, MD
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background: The Hearts in Rhythm Organization (HiRO) is a team of Canadian inherited heart rhythm and cardiomyopathy experts, genetic counsellors, nurses, researchers, patients, and families dedicated to the detection of inherited arrhythmias and cardiomyopathies, provision of best therapies, and protection from the tragedy of sudden cardiac arrest. Methods: Recently, existing disease-specific registries were merged into the expanded National HiRO Registry, creating a single common data set for patients and families with inherited conditions that put them at risk for sudden death in Canada. Eligible patients are invited to participate in the registry and optional biobank from 20 specialized cardiogenetics clinics across Canada. Results: Currently, there are 4700 participants enrolled in the National HiRO Registry, with an average of 593 participants enrolled annually over the past 5 years. The capacity to enable knowledge translation of research findings is built into HiRO’s organizational infrastructure, with 3 additional working groups (HiRO Clinical Care Committee, HiRO Active Communities Committee, and HiRO Annual Symposium Committee), supporting the organization’s current goals and priorities as set alongside patient partners. Conclusion: The National HiRO Registry aims to be an integrated research platform to which researchers can pose novel research questions leading to a better understanding, detection, and clinical care of those living with inherited heart rhythm and cardiomyopathy conditions and ultimately to prevent sudden cardiac death. Résumé: Contexte: La Hearts in Rhythm Organization (HiRO) est une équipe d’experts canadiens en matière de rythmes cardiaques et de cardiomyopathies héréditaires, de conseillers en génétique, d’infirmières, de chercheurs, de patients et de familles qui se consacrent à la détection des arythmies et des cardiomyopathies héréditaires, à la mise en place des meilleures thérapies et à la protection contre la tragédie que représente une mort subite d’origine cardiaque. Méthodes: Récemment, les registres existants relatifs à des maladies spécifiques ont été fusionnés en un registre national élargi de l’HiRO, créant ainsi un ensemble de données commun unique à destination des patients et leurs familles, atteints de maladies héréditaires, qui sont à risque de mort subite au Canada. Les patients admissibles sont invités à s’associer au registre et à la biobanque facultative regroupant 20 cliniques spécialisées en cardiogénétique au Canada. Résultats: Actuellement, 4 700 participants sont inscrits au registre national de l’HiRO, avec une moyenne de 593 participants inscrits chaque année au cours des cinq dernières années. La capacité à favoriser l’application des connaissances issues de la recherche fait partie de la structure organisationnelle de l’HiRO, avec trois groupes de travail supplémentaires (comité des soins cliniques de l’HiRO, comité des communautés cctives de l’HiRO et comité du symposium annuel de l’HiRO), soutenant les objectifs et les priorités actuels de l’organisation tels qu’ils ont été fixés en partenariat avec les patients. Conclusion: Le registre national de l’HiRO vise à devenir une plateforme de recherche intégrée au sein de laquelle les chercheurs peuvent exposer des questions de recherche inédites permettant de mieux comprendre, détecter et soigner les personnes atteintes de troubles du rythme cardiaque et de cardiomyopathie héréditaires et, à terme, de prévenir la mort subite d’origine cardiaque.
Published: 2020
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6. Subcutaneous Implantable Cardioverter‐Defibrillator in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: A Transatlantic Experience

Author: Gabriela M. Orgeron, Aditya Bhonsale, Federico Migliore, Cynthia A. James, Crystal Tichnell, Brittney Murray, Emanuele Bertaglia, Julia Cadrin‐Tourigny, Pietro De Franceschi, Jane Crosson, Harikrishna Tandri, Domenico Corrado, and Hugh Calkins
Subjects: arrhythmogenic right ventricular cardiomyopathy, implanted cardioverter defibrillator, long‐term follow‐up, ventricular tachycardia, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Despite growing use of the subcutaneous implantable cardioverter‐defibrillator (S‐ICD), its clinical role in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients remains undefined. We aim to elucidate the cardiac phenotype, implant characteristics, and long‐term efficacy regarding appropriate therapy and complications in ARVC/D patients with an S‐ICD implant. Methods and Results A transatlantic cohort of ARVC/D patients who underwent S‐ICD implantation was analyzed for clinical characteristics, S‐ICD therapy, and long‐term outcome including device‐related complications. The cohort included 29 patients (52% male, 76% probands, 59% with ARVC/D‐associated mutation, 59% primary prevention [no prior sustained ventricular arrhythmias], and 45% first‐generation S‐ICD devices). At implant, all inducible patients (27/29) had conversion of induced ventricular fibrillation. Two patients (7%) had superficial infections of the incision site that were treated conservatively. Over a median follow‐up of 3.16 years (interquartile range: 2.21–4.51 years), all episodes (6 patients, 4% per year) of sustained ventricular arrhythmias were appropriately detected and treated. Six patients (21%) experienced 39 inappropriate shocks, with 3 requiring device explantation. Oversensing of noncardiac signal (n=4; especially myopotentials) and cardiac signal (n=4) was the most frequent etiology. No lead or device dislodgement, infection, skin erosion, or explantation related to need for antitachycardia pacing was noted. Conclusions S‐ICD can effectively treat both induced and spontaneous ventricular arrhythmias in patients with ARVC/D. The rate of inappropriate shocks, although considerable, is comparable to that in ARVC/D patients treated with transvenous ICDs. When they occurred, inappropriate shocks were primarily due to cardiac and, uniquely, noncardiac oversensing. We suggest potential strategies for minimizing inappropriate therapy.
Published: 2018
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7. Impact of Exercise Restriction on Arrhythmic Risk Among Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

Author: Weijia Wang, Gabriela Orgeron, Crystal Tichnell, Brittney Murray, Jane Crosson, Oliver Monfredi, Julia Cadrin‐Tourigny, Harikrishna Tandri, Hugh Calkins, and Cynthia A. James
Subjects: arrhythmogenic right ventricular cardiomyopathy, exercise, implantable cardioverter‐defibrillator, ventricular tachycardia, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Prior studies have shown a close link between exercise and development of arrhythmogenic right ventricular cardiomyopathy. How much exercise restriction reduces ventricular arrhythmia (VA), how genotype modifies its benefit, and whether it reduces risk sufficiently to defer implantable cardioverter‐defibrillator (ICD) placement in arrhythmogenic right ventricular cardiomyopathy are unknown. Methods and Results We interviewed 129 arrhythmogenic right ventricular cardiomyopathy patients (age: 34.0±14.8 years; male: 60%) with ICDs (36% primary prevention) about exercise participation. Exercise change was defined as annual exercise duration and dose in the 3 years before clinical presentation minus that after presentation. The primary outcome was appropriate ICD therapy for VA. During the 5.1 years (interquartile range: 2.7–10.8 years) after presentation, 74% (95/129) patients reduced exercise dose and 85 (66%) patients experienced the primary outcome. In multivariate analyses, top tertile reduction in exercise duration and dose were both associated with less VA (duration: hazard ratio: 0.23 [95% confidence interval, 0.07–0.81]; dose: hazard ratio: 0.14 [95% confidence interval, 0.04–0.44]). Greater reduction in exercise dose conferred greater reduction in VA (P=0.01 for trend). Patients without desmosomal mutations and those with primary‐prevention ICDs benefited more from exercise reduction (P=0.16 and P=0.06 for interaction); however, 58% (18/31) of athletes who reduced exercise dose by >80% still experienced VA. Conclusions Exercise restriction should be recommended to all arrhythmogenic right ventricular cardiomyopathy patients with ICDs. Patients who are “gene‐elusive” and those with primary‐prevention devices may particularly benefit. Exercise reduction is unlikely to reduce arrhythmia sufficiently in high‐risk patients to alter decision‐making regarding ICD implantation.
Published: 2018
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8. Bioresorbable Vascular Scaffold Use in a Case of In-stent Restenosis

Author: Julia Cadrin-Tourigny, Liang Dong, Akiko Maehara, Erick Schampaert, and Philippe Genereux
Subjects: Stents, Doença da Artéria Coronariana, Cateterismo Cardíaco, Dispositivos Vasculares Biorreabsorvíveis, Diseases of the circulatory (Cardiovascular) system, RC666-701
Published: 2014
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9. Incremental value of the signal-averaged ECG for diagnosing arrhythmogenic cardiomyopathy

Author: Charles Michael Pearman, David Lee, Brianna Davies, Habib Khan, Rafik Tadros, Julia Cadrin-Tourigny, Jason D. Roberts, Shubhayan Sanatani, Christopher Simpson, Paul Angaran, Simon Hansom, Erkan Ilhan, Colette Seifer, Martin Green, Martin Gardner, Mario Talajic, Zachary Laksman, Jeff S. Healey, and Andrew D. Krahn
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is currently diagnosed using a combination of clinical features, imaging, electrocardiography, and genetic investigations. An abnormal signal-averaged electrocardiogram (SAECG) is defined as a minor diagnostic criterion by the 2010 Task Force Criteria, but doubts remain about the value of this investigation.We evaluated the utility of the SAECG in diagnosing ARVC using the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry, a population representative registry of probands with ARVC and relatives, less influenced by referral bias.Probands with ARVC and family members from the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry underwent phenotype review. SAECG parameters were compared individually and in combination between those with varying degrees of ARVC severity and healthy controls (family members of probands with ARVC and unexplained sudden death, free of evidence of cardiac disease).A total of 196 patients with ARVC and 205 controls were included (mean age 44 ± 15 years; 186 of 401 men [46%]). SAECG abnormalities were seen in 83 of 205 controls (40%), 33 of 68 patients with ARVC and mild disease (51%), and 31 of 42 with severe disease (74%). The SAECG associated strongly with imaging abnormalities (major: odds ratio 3.0, 95% confidence interval 1.3-6.9; minor: odds ratio 3.5, 95% confidence interval 0.7-16.5) but not with other aspects of phenotype. Patients carrying pathogenic variants but with minimal phenotype had similar SAECGs to healthy controls (filtered QRS duration 111.2 ± 11.2 ms vs 111 ± 7.6 ms, P = .93; duration of low amplitude signals40 μV 32.3 ± 8.9 ms vs 34.2 ± 7.2 ms, P = .32; root mean square of the terminal 40 ms of the filtered QRS complex 43.1 ± 25.2 ms vs 38.2 ± 20.2 ms, P = .38).The SAECG appears to be a surrogate marker for structural abnormalities seen on imaging in those with ARVC. Great caution is required in interpreting SAECG findings in those without other corroborating evidence of an ARVC phenotype.
Published: 2023

10. Programmed Ventricular Stimulation as an Additional Primary Prevention Risk Stratification Tool in Arrhythmogenic Right Ventricular Cardiomyopathy

Author: Alessio Gasperetti, Richard T. Carrick, Sarah Costa, Paolo Compagnucci, Laurens P. Bosman, Monica Chivulescu, Crystal Tichnell, Brittney Murray, Harikrishna Tandri, Rafik Tadros, Lena Rivard, Maarten P. van den Berg, Katja Zeppenfeld, Arthur A.M. Wilde, Giulio Pompilio, Corrado Carbucicchio, Antonio Dello Russo, Michela Casella, Anneli Svensson, Corinna B. Brunckhorst, J. Peter van Tintelen, Pyotr G. Platonov, Kristina H. Haugaa, Firat Duru, Anneline S.J.M. te Riele, Paul Khairy, Claudio Tondo, Hugh Calkins, Cynthia A. James, Ardan M. Saguner, Julia Cadrin-Tourigny, Cardiology, ACS - Heart failure & arrhythmias, and Cardiovascular Centre (CVC)
Subjects: Male, Adult, implantable, cardiac, defibrillator, implantable, arrhythmogenic right ventricular cardiomyopathy, electrophysiological techniques, cardiac, risk assessment, sudden cardiac death, defibrillator, Risk Factors, Physiology (medical), Humans, Cardiac and Cardiovascular Systems, Arrhythmogenic Right Ventricular Dysplasia, Kardiologi, electrophysiological techniques, Settore MED/23 - Chirurgia Cardiaca, Arrhythmias, Cardiac, Stroke Volume, Middle Aged, Defibrillators, Implantable, Primary Prevention, Death, Sudden, Cardiac, Tachycardia, Ventricular, Ventricular Function, Right, Female, Cardiology and Cardiovascular Medicine
Abstract: Background: A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. Methods: All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. Results: Two hundred eighty-eight patients (41.0 +/- 14.5 years, 55.9% male, right ventricular ejection fraction 42.5 +/- 11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (PFunding Agencies|Leonie-Wild Foundation; Leyla Erkan Family Fund for ARVD Research; Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; Dr. Francis P. Chiramonte Private Foundation; Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; Fondation Leducq; National Center for Advancing Translational Sciences [UL1TR001079]; Philippa and Marvin Carsley cardiology research chair; Montreal Heart Institute Foundation; Georg und Bertha Schwyzer-Winiker Foundation; Baugarten Foundation; Swiss Heart Foundation [FF17019, FF21073]; Swiss National Science Foundation [160327]; Swedish Heart Lung Foundation [20200674]; Swedish state under the Avtal om lakarutbildning och forsknin (ALF)-agreement; Netherlands Cardiovascular Research Initiative; Dutch Heart Foundation [CVON201512/2018-30]
Published: 2022

11. Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator

Author: Paloma Jordà, Laurens P Bosman, Alessio Gasperetti, Andrea Mazzanti, Jean Baptiste Gourraud, Brianna Davies, Tanja Charlotte Frederiksen, Zoraida Moreno Weidmann, Andrea Di Marco, Jason D Roberts, Ciorsti MacIntyre, Colette Seifer, Antoine Delinière, Wael Alqarawi, Deni Kukavica, Damien Minois, Alessandro Trancuccio, Marine Arnaud, Mattia Targetti, Annamaria Martino, Giada Oliviero, Daniel C Pipilas, Corrado Carbucicchio, Paolo Compagnucci, Antonio Dello Russo, Iacopo Olivotto, Leonardo Calò, Steven A Lubitz, Michael J Cutler, Philippe Chevalier, Elena Arbelo, Silvia Giuliana Priori, Jeffrey S Healey, Hugh Calkins, Michela Casella, Henrik Kjærulf Jensen, Claudio Tondo, Rafik Tadros, Cynthia A James, Andrew D Krahn, Julia Cadrin-Tourigny, Sociedad Española de Cardiología, Novo Nordisk Foundation, American Heart Association, and Canada Research Chairs
Subjects: Defibrillators, Implantable/adverse effects, Settore MED/11 - Malattie dell'Apparato Cardiovascolare, Arrhythmias, Cardiac, Arrhythmias, Cardiac/etiology, Implantable cardioverter-defibrillator, Defibrillators, Implantable, Sudden cardiac death, Ventricular arrhythmias, Death, Sudden, Cardiac, Arrhythmogenic right ventricular cardiomyopathy, Genetic cardiomyopathies, Risk stratification, Risk Factors, Arrhythmogenic Right Ventricular Dysplasia/complications, Humans, Cardiology and Cardiovascular Medicine, Death, Sudden, Cardiac/epidemiology, Arrhythmogenic Right Ventricular Dysplasia, Retrospective Studies
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC. P.J. is supported by the Daniel Bravo Foundation grant and Spanish Society of Cardiology Magda Heras mobility grant, A.G. by the Wilton W. Webster Fellow of Heart Rhythm Society, The Johns Hopkins ARVD/C Programme by the Leonie-Wild Foundation, Leyla Erkan Family Fund for ARVD Research, The Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center, Dr Francis P. Chiramonte Private Foundation, Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, Bogle Foundation, Campanella Family, Patrick J. Harrison Family, Peter French Memorial Foundation, and Wilmerding Endowments, H.K.J. by grants from Novo Nordisk Foundation, Denmark (NNF18OC0031258 and NNF20OC0065151), S.A.L. by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007, R.T. by the Canada Research Chairs programme, J.C.T. by the Philippa and Marvin Carsley Cardiology Research Chair. S.G.P. receives support from Ricerca Corrente funding scheme of the Italian Ministry of Health and Italian Ministry of Research and University Dipartimenti di Eccellenza 2018 to 2022 grant to the Molecular Medicine Department (University of Pavia). Sí
Published: 2022

12. FDG-PET/CT and rest myocardial perfusion imaging to predict high-degree atrioventricular block recovery in cardiac sarcoidosis

Author: Yousif A. Lucinian, Patrick Martineau, Raluca Poenaru, Maxime Tremblay-Gravel, Julia Cadrin-Tourigny, Francois Harel, and Matthieu Pelletier-Galarneau
Subjects: Radiology, Nuclear Medicine and imaging, Cardiology and Cardiovascular Medicine
Published: 2023

13. Anti-tachycardia pacing in ARVC: should a transvenous or subcutaneous system be used?

Author: Julia Cadrin-Tourigny, Andrew D Krahn, and Magdi Saba
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023

14. Comparing clinical performance of current implantable cardioverter-defibrillator implantation recommendations in arrhythmogenic right ventricular cardiomyopathy

Author: Anneline S.J.M. te Riele, Cynthia A. James, Julia Cadrin-Tourigny, Folkert W. Asselbergs, Laurens P Bosman, Claire L Nielsen Gerlach, Sing-Chien Yap, Katja Zeppenfeld, Brittney Murray, Gabriela M. Orgeron, Hariskrishna Tandri, Arthur A.M. Wilde, Hugh Calkins, Mimount Bourfiss, Crystal Tichnell, Maarten P. van den Berg, J. Peter van Tintelen, Jeroen F. van der Heijden, Cardiovascular Centre (CVC), Cardiology, ACS - Heart failure & arrhythmias, and Neurosciences
Subjects: Male, medicine.medical_specialty, Consensus, medicine.medical_treatment, DYSPLASIA/CARDIOMYOPATHY, DIAGNOSIS, Right ventricular cardiomyopathy, Implantable cardioverter-defibrillator, Ventricular arrhythmias, Physiology (medical), Internal medicine, medicine, Humans, Arrhythmogenic Right Ventricular Dysplasia, Risk stratification, RISK, HYPERTROPHIC CARDIOMYOPATHY, business.industry, Task force, Clinical performance, Expert consensus, Arrhythmias, Cardiac, Guideline, Prognosis, Defibrillators, Implantable, Increased risk, Death, Sudden, Cardiac, Decision curve analysis, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Arrhythmogenic right ventricular cardiomyopathy, TASK-FORCE
Abstract: Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have an increased risk of ventricular arrhythmias (VA). Four implantable cardioverter-defibrillator (ICD) recommendation algorithms are available The International Task Force Consensus (‘ITFC’), an ITFC modification by Orgeron et al. (‘mITFC’), the AHA/HRS/ACC guideline for VA management (‘AHA’), and the HRS expert consensus statement (‘HRS’). This study aims to validate and compare the performance of these algorithms in ARVC. Methods and results We classified 617 definite ARVC patients (38.5 ± 15.1 years, 52.4% male, 39.2% prior sustained VA) according to four algorithms. Clinical performance was evaluated by sensitivity, specificity, ROC-analysis, and decision curve analysis for any sustained VA and for fast VA (>250 b.p.m.). During 6.4 [2.8–11.5] years follow-up, 282 (45.7%) patients experienced any sustained VA, and 63 (10.2%) fast VA. For any sustained VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (94.0–97.8% vs. 76.7–83.5%), but lower specificity (15.9–32.0% vs. 42.7%-60.1%). Similarly, for fast VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (95.2–97.1% vs. 76.7–78.4%) but lower specificity (42.7–43.1 vs. 76.7–78.4%). Decision curve analysis showed ITFC and mITFC to be superior for a 5-year sustained VA risk ICD indication threshold between 5–25% or 2–9% for fast VA. Conclusion The ITFC and mITFC provide the highest protection rates, whereas AHA and HRS decrease unnecessary ICD placements. ITFC or mITFC should be used if we consider the 5-year threshold for ICD indication to lie within 5–25% for sustained VA or 2–9% for fast VA. These data will inform decision-making for ICD placement in ARVC.
Published: 2022

15. PO-04-190 LONG TERM OUTCOMES OF VENTRICULAR TACHYCARDIA ABLATION IN DESMOPLAKIN ARRHYTHMOGENIC CARDIOMYOPATHY – A MULTICENTER STUDY

Author: Alessio Gasperetti, Richard Carrick, Giovanni Peretto, Steven Muller, Anneline Te Riele, Kanae Hasegawa, Paolo Compagnucci, Michela Casella, Antonio Dello Russo, Brittney A. Murray, Crystal Tichnell, Cynthia A. James, Arthur A. Wilde, Claudio Tondo, Firat Duru, Ardan Saguner, Charles Massie, JULIA CADRIN-TOURIGNY, Paolo Della Bella, Hugh Calkins, and Harikrishna Tandri
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023

16. CE-452775-4 LONG-TERM ARRHYTHMIC FOLLOW-UP AND PERFORMANCE OF MODERN RISK STRATIFICATION TOOLS IN LARGE COHORT OF PATIENTS WITH DESMOPLAKIN ARRHYTHMOGENIC CARDIOMYOPATHY

Author: Alessio Gasperetti, Richard Carrick, Alexander Protonotarios, Mikael Laredo, Iris van der Schaaf, Petros Syrris, Brittney Murray, Crystal Tichnell, Chiara Cappelletto, Marta Gigli, Kristen Medo, Peter Crabtree, Ardan Saguner, Firat Duru, Robyn Hylind, Dominic J. Abrams, Neal Lakdawala, Charles Massie, Julia Cadrin-Tourigny, Mattia Targetti, Iacopo Olivotto, Maddalena Graziosi, Moniek Cox, Elena Biagini, Philippe Charron, Michela Casella, Claudio Tondo, Momina Yazdani, James S. Ware, Sanjay Prasad, Leonardo Caló, Eric D. Smith, Adam Helms, Sophie Hespe, Jodie Ingles, Harikrishna Tandri, Flavie Ader, Luisa Mestroni, Arthur A. Wilde, Marco Merlo, Estelle Gandjbakhch, Hugh Calkins, Anneline te Riele, Peter van Tintelen, Perry Elliott, and Cynthia A. James
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023

17. PO-02-125 EVALUATION OF A GENOME-WIDE AND POLYGENIC RISK SCORE FOR THE PREDICTION OF ATRIAL FIBRILLATION RECURRENCE AFTER PULMONARY VEIN ISOLATION

Author: Adrian Petzl, Paloma Jorda, Amélie Jeuken, Martin Aguilar, Julia Cadrin-Tourigny, Marc Dubuc, Katia Dyrda, Peter G. Guerra, Paul Khairy, Blandine A. Mondesert, Alexandre Raymond-Paquin, Lena Rivard, Denis Roy, Mario Talajic, Bernard Thibault, Jean-Claude Tardif, Laurent Macle, and Rafik Tadros
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023

18. MP-453089-11 DIFFERENCES IN UTILIZATION OF PRIMARY PREVENTION IMPLANTABLE CARDIOVERTER DEFIBRILLATORS IN ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY ACROSS NORTH AMERICA AND EUROPE

Author: Richard Carrick, Corrado De Marco, Alessio Gasperetti, Laurens P. Bosman, JEAN BAPTISTE GOURRAUD, Andrea Mazzanti, Brittney A. Murray, Catherine Pendleton, Crystal Tichnell, Harikrishna Tandri, Katja Zeppenfeld, Arthur A. Wilde, Brianna Davies, Colette M. Seifer, Jason D. Roberts, Jeffrey S. Healey, Ciorsti MacIntyre, Wael Alqarawi, Rafik Tadros, Michael J. Cutler, Mattia Targetti, Leonardo Caló, Francesco Vitali, Matteo Bertini, Paolo Compagnucci, Michela Casella, Antonio Dello Russo, Chiara Cappelletto, Antonio De Luca, Davide Stolfo, Firat Duru, Henrik K. Jensen, Anneli Svensson, Pia Dahlberg, Nina Hasselberg, Andrea Di Marco, Paloma Jorda, Elena Arbelo, Zoraida Moreno weidmann, Karolina Borowiec, Antoine Deliniere, Elzbieta K. Biernacka, Peter van Tintelen, Pyotr G. Platonov, Iacopo Olivotto, Ardan Saguner, Kristina H. Haugaa, Moniek Cox, Claudio Tondo, Marco Merlo, Andrew D. Krahn, Anneline te Riele, Katherine C. Wu, Hugh Calkins, Cynthia A. James, and JULIA CADRIN-TOURIGNY
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023

19. Progression of Atrial Fibrillation after Cryoablation or Drug Therapy

Author: Jason G. Andrade, Marc W. Deyell, Laurent Macle, George A. Wells, Matthew Bennett, Vidal Essebag, Jean Champagne, Jean-Francois Roux, Derek Yung, Allan Skanes, Yaariv Khaykin, Carlos Morillo, Umjeet Jolly, Paul Novak, Evan Lockwood, Guy Amit, Paul Angaran, John Sapp, Stephan Wardell, Sandra Lauck, Julia Cadrin-Tourigny, Simon Kochhäuser, and Atul Verma
Subjects: General Medicine
Abstract: Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation.We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected.A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group.Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).
Published: 2022

20. Longitudinal prediction of ventricular arrhythmic risk in patients with arrhythmogenic right ventricular cardiomyopathy

Author: Richard T. Carrick, Anneline S.J.M. te Riele, Alessio Gasperetti, Laurens Bosman, Steven A. Muller, Catherine Pendleton, Crystal Tichnell, Brittney Murray, Sing-Chien Yap, Maarten P. van den Berg, Arthur Wilde, Katja Zeppenfeld, Allison Hays, Stefan L. Zimmerman, Harikrishna Tandri, Julia Cadrin-Tourigny, Peter van Tintelen, Hugh Calkins, Cynthia A. James, Katherine C. Wu, Cardiovascular Centre (CVC), Cardiology, and ACS - Heart failure & arrhythmias
Subjects: sudden, implantable, cardiac, Arrhythmias, Cardiac, tachycardia, Electrocardiography, defibrillator, Physiology (medical), death, Tachycardia, Ventricular, Humans, risk factors, Cardiology and Cardiovascular Medicine, cardiomyopathy, Arrhythmogenic Right Ventricular Dysplasia, Retrospective Studies
Abstract: Background: The arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator stratifies risk for incident sustained ventricular arrhythmias (VA) at the time of ARVC diagnosis. However, included risk factors change over time, and how well the ARVC risk calculator performs at follow-up is unknown. Methods: This was a retrospective analysis of patients with definite ARVC and without prior sustained VA. Risk factors for VA including age, nonsustained ventricular tachycardia, premature ventricular complex burden, T-wave inversions on electrocardiogram, cardiac syncope, right ventricular function, therapeutic medication use, and exercise intensity were assessed at the time of 2010 Task Force Criteria based ARVC diagnosis and upon repeat evaluations. Changes in these risk factors were analyzed over 5-year follow-up. The 5-year risk of VA was predicted longitudinally using (1) the baseline ARVC risk calculator prediction, (2) the ARVC risk prediction calculated using updated risk factors, and (3) time-varying Cox regression. Discrimination and calibration were assessed in comparison to observed VA event rates. Results: Four hundred eight patients with ARVC experiencing 132 primary VA events were included. Matched comparison of risk factors at baseline versus at 5 years of follow-up revealed decreased burdens of premature ventricular complexes (−1200/day) and nonsustained ventricular tachycardia (−14%). Presence of significant right ventricular dysfunction and number of T-wave inversions on electrocardiogram were unchanged. Observed risk for VA decreased by 13% by 5 years follow-up. The baseline ARVC risk calculator’s ability to predict 5-year VA risk worsened during follow-up (C statistics, 0.83 at diagnosis versus 0.68 at 5 years). Both the updated ARVC risk calculator (C statistics of 0.77) and time-varying Cox regression model (C statistics, 0.77) had strong discrimination. The updated ARVC risk calculator overestimated 5-year VA risk by an average of +6%. ConclusionS: Risk factors for VA in ARVC are dynamic, and overall risk for incident sustained VA decreases during follow-up. Up-to-date risk factor assessment improves VA risk stratification.
Published: 2022

21. Sudden cardiac death risk prediction in arrhythmogenic right ventricular cardiomyopathy: a practical approach to navigating the challenges of prediction models

Author: Julia Cadrin-Tourigny, Laurens P Bosman, and Cynthia A James
Subjects: Cardiology and Cardiovascular Medicine
Published: 2022

22. International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework

Author: Cynthia A. James, Ray E. Hershberger, Kalliopi Pilichou, Ana Morales, Jan D. H. Jongbloed, Argelia Medeiros Domingo, Jennifer McGlaughon, Alexandros Protonotarios, Courtney Thaxton, Elizabeth Jordan, Emily Brown, Ronald H. Lekanne Deprez, C. Lisa Kurtz, Brittney Murray, Petros Syrris, Babken Asatryan, Daniel P. Judge, J. Peter van Tintelen, Julia Cadrin-Tourigny, Rudy Celeghin, Cardiovascular Centre (CVC), Human Genetics, ACS - Pulmonary hypertension & thrombosis, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, Tachycardia, Male, medicine.medical_specialty, Evidence-based practice, GENETICS, diagnosis, VARIANT, 610 Medicine & health, 030204 cardiovascular system & hematology, tachycardia, Genome, Right ventricular cardiomyopathy, DISEASE, genetic testing, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Humans, desmosomes, Genetic Predisposition to Disease, genes, Gene, MUTATION, Arrhythmogenic Right Ventricular Dysplasia, Genetic testing, medicine.diagnostic_test, IDENTIFICATION, business.industry, Arrhythmias, Cardiac, General Medicine, Original Articles, 030104 developmental biology, Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, Inherited disease, medicine.symptom, business
Abstract: Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes. Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. Results: Of 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.
Published: 2021

23. PO-02-106 GENERAL ANESTHESIA VERSUS CONSCIOUS SEDATION WITH LOCOREGIONAL ANESTHESIA IN S-ICD IMPLANTATION: A MONOCENTRIC RETROSPECTIVE ANALYSIS

Author: Corrado De Marco, Jean-Sébastien Lebon, Nicolas Rousseau-Saine, Marc Dubuc, Bernard Thibault, JULIA CADRIN-TOURIGNY, Alexandre Raymond-Paquin, Malorie Chabot-Blanchet, Annik Fortier, and Blandine A. Mondesert
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023

24. The Hearts in Rhythm Organization: A Canadian National Cardiogenetics Network

Author: Martin S. Green, Joseph Atallah, Rafik Tadros, Julia Cadrin-Tourigny, Shane Kimber, Christian Steinberg, Bhavanesh Makanjee, Wael Alqarawi, Laura Arbour, Vuk Vuksanovic, Christopher S. Simpson, Zachary Laksman, Jeff S. Healey, Henry J. Duff, Jacqueline Joza, Stephanie Clarke, Anne Fournier, Ciorsti MacIntyre, Brianna Davies, Colette M. Seifer, Karen Gibbs, Shubhayan Sanatani, James McKinney, Paul Angaran, Richard Leather, Mario Talajic, Andrew D. Krahn, Robert J. Hamilton, Martin J. Gardner, and Jason D. Roberts
Subjects: medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Study Design, business.industry, MEDLINE, Cardiomyopathy, Sudden cardiac arrest, 030204 cardiovascular system & hematology, medicine.disease, Sudden death, Biobank, 3. Good health, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, lcsh:RC666-701, Family medicine, Knowledge translation, medicine, 030212 general & internal medicine, medicine.symptom, Cardiology and Cardiovascular Medicine, Working group, business
Abstract: Background: The Hearts in Rhythm Organization (HiRO) is a team of Canadian inherited heart rhythm and cardiomyopathy experts, genetic counsellors, nurses, researchers, patients, and families dedicated to the detection of inherited arrhythmias and cardiomyopathies, provision of best therapies, and protection from the tragedy of sudden cardiac arrest. Methods: Recently, existing disease-specific registries were merged into the expanded National HiRO Registry, creating a single common data set for patients and families with inherited conditions that put them at risk for sudden death in Canada. Eligible patients are invited to participate in the registry and optional biobank from 20 specialized cardiogenetics clinics across Canada. Results: Currently, there are 4700 participants enrolled in the National HiRO Registry, with an average of 593 participants enrolled annually over the past 5 years. The capacity to enable knowledge translation of research findings is built into HiRO’s organizational infrastructure, with 3 additional working groups (HiRO Clinical Care Committee, HiRO Active Communities Committee, and HiRO Annual Symposium Committee), supporting the organization’s current goals and priorities as set alongside patient partners. Conclusion: The National HiRO Registry aims to be an integrated research platform to which researchers can pose novel research questions leading to a better understanding, detection, and clinical care of those living with inherited heart rhythm and cardiomyopathy conditions and ultimately to prevent sudden cardiac death. Résumé: Contexte: La Hearts in Rhythm Organization (HiRO) est une équipe d’experts canadiens en matière de rythmes cardiaques et de cardiomyopathies héréditaires, de conseillers en génétique, d’infirmières, de chercheurs, de patients et de familles qui se consacrent à la détection des arythmies et des cardiomyopathies héréditaires, à la mise en place des meilleures thérapies et à la protection contre la tragédie que représente une mort subite d’origine cardiaque. Méthodes: Récemment, les registres existants relatifs à des maladies spécifiques ont été fusionnés en un registre national élargi de l’HiRO, créant ainsi un ensemble de données commun unique à destination des patients et leurs familles, atteints de maladies héréditaires, qui sont à risque de mort subite au Canada. Les patients admissibles sont invités à s’associer au registre et à la biobanque facultative regroupant 20 cliniques spécialisées en cardiogénétique au Canada. Résultats: Actuellement, 4 700 participants sont inscrits au registre national de l’HiRO, avec une moyenne de 593 participants inscrits chaque année au cours des cinq dernières années. La capacité à favoriser l’application des connaissances issues de la recherche fait partie de la structure organisationnelle de l’HiRO, avec trois groupes de travail supplémentaires (comité des soins cliniques de l’HiRO, comité des communautés cctives de l’HiRO et comité du symposium annuel de l’HiRO), soutenant les objectifs et les priorités actuels de l’organisation tels qu’ils ont été fixés en partenariat avec les patients. Conclusion: Le registre national de l’HiRO vise à devenir une plateforme de recherche intégrée au sein de laquelle les chercheurs peuvent exposer des questions de recherche inédites permettant de mieux comprendre, détecter et soigner les personnes atteintes de troubles du rythme cardiaque et de cardiomyopathie héréditaires et, à terme, de prévenir la mort subite d’origine cardiaque.
Published: 2020

25. Exercise restriction is protective for genotype-positive family members of arrhythmogenic right ventricular cardiomyopathy patients

Author: Weijia Wang, Hugh Calkins, Harikrishna Tandri, Cynthia A. James, Julia Cadrin-Tourigny, Crystal Tichnell, Stephen P. Chelko, Julia Agafonova, and Brittney Murray
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Genotype, Disease, 030204 cardiovascular system & hematology, Ventricular tachycardia, Metabolic equivalent, Right ventricular cardiomyopathy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, medicine, Humans, Family, 030212 general & internal medicine, Child, Exercise, Arrhythmogenic Right Ventricular Dysplasia, business.industry, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Arrhythmogenic right ventricular dysplasia, Mutation, Female, Cardiology and Cardiovascular Medicine, business, Plakophilins
Abstract: Aims In arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, exercise worsens disease course, so exercise restriction is recommended. However, recommendations for genotype-positive ARVC family members is incompletely resolved. We aimed to provide evidence for exercise recommendations for genotype-positive ARVC family members. Methods and results Arrhythmogenic right ventricular cardiomyopathy family members inheriting a pathogenic desmosomal variant were interviewed about exercise history from age 10. Exercise was characterized by duration, intensity, and dose (duration*intensity). Associations between exercise and (i) diagnosis by 2010 Task Force Criteria and (ii) development of sustained ventricular arrhythmias were examined. The study included 101 family members (age: 40.5 ± 19.3 years, male: 41%, Plakophilin-2 variant: 81%). Forty-four individuals (44%) met diagnostic criteria and 16 (16%) experienced sustained ventricular arrhythmia. Individuals who met diagnostic criteria had significantly higher average exercise duration and dose, but not peak intensity than those who did not. Only one individual who exercised below the American Heart Association recommended minimum (650 metabolic equivalent of task-hours/year) met diagnostic criteria or experienced sustained ventricular arrhythmia as opposed to 50% of individuals who exceeded it (adjusted odds ratio = 0.03, 95% confidence interval 0.003–0.26). The difference in exercise exposure between affected and unaffected individuals was more striking in females than in males. Females who had done high-dose exercise in adolescence had the worst survival free from diagnosis (P Conclusions In phenotype-negative ARVC family members with a pathogenic desmosomal variant, athletic activities should be limited, particularly exercise dose. Exercise may play a greater role in promoting disease in female family members.
Published: 2020

26. Infections Associated with Resterilized Pacemakers and Defibrillators

Author: Thomas F Khairy, Santiago Nava, Laurent Macle, Frank Valdez Baez, Lena Rivard, Richard Cartier, Marie-Andrée Lupien, Nery E Linarez Ochoa, Mario Talajic, Fernando Solares Ovalle, Cesar A Carrazco, Denis Roy, Paul Khairy, Christine Villemaire, Gerardo Sosa Mendoza, Katia Dyrda, Rafik Tadros, Julia Cadrin-Tourigny, Bernard Thibault, Marc Dubuc, Blandine Mondésert, and Peter G. Guerra
Subjects: medicine.medical_specialty, business.industry, MEDLINE, Follow up studies, General Medicine, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Multicenter study, Emergency medicine, Medicine, 030212 general & internal medicine, Equipment Reuse, business, Limited resources
Abstract: Background Access to pacemakers and defibrillators is problematic in places with limited resources. Resterilization and reuse of implantable cardiac devices obtained post mortem from patie...
Published: 2020

27. Diagnosing arrhythmogenic right ventricular cardiomyopathy by 2010 Task Force Criteria: clinical performance and simplified practical implementation

Author: Cynthia A. James, Mimount Bourfiss, Harikrishna Tandri, Crystal Tichnell, Julia Cadrin-Tourigny, Brittney Murray, Rob W Roudijk, Johannes B. Reitsma, Hugh Calkins, J. Peter van Tintelen, Jeroen F. van der Heijden, Apurva Sharma, Anneline S.J.M. te Riele, Folkert W. Asselbergs, Mounes Aliyari Ghasabeh, Stefan L. Zimmerman, Paul Khairy, Richard N.W. Hauer, Laurens P Bosman, Ihab R. Kamel, and Human Genetics
Subjects: medicine.medical_specialty, Channelopathies and Cardiomyopathies, Cardiomyopathy, 030204 cardiovascular system & hematology, Ventricular tachycardia, Right ventricular cardiomyopathy, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Physiology (medical), Internal medicine, Diagnosis, False positive paradox, Medicine, 030212 general & internal medicine, Family history, business.industry, medicine.disease, Signal-averaged electrocardiogram, Arrhythmogenic right ventricular dysplasia, Cardiology, Ventricular arrhythmia, Cardiology and Cardiovascular Medicine, business, Arrhythmogenic right ventricular cardiomyopathy
Abstract: Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is diagnosed by a complex set of clinical tests as per 2010 Task Force Criteria (TFC). Avoiding misdiagnosis is crucial to prevent sudden cardiac death as well as unnecessary implantable cardioverter-defibrillator implantations. This study aims to validate the overall performance of the TFC in a real-world cohort of patients referred for ARVC evaluation. Methods and results We included patients consecutively referred to our centres for ARVC evaluation. Patients were diagnosed by consensus of three independent clinical experts. Using this as a reference standard, diagnostic performance was measured for each individual criterion as well as the overall TFC classification. Of 407 evaluated patients (age 38 ± 17 years, 51% male), the expert panel diagnosed 66 (16%) with ARVC. The clinically observed TFC was false negative in 7/66 (11%) patients and false positive in 10/69 (14%) patients. Idiopathic outflow tract ventricular tachycardia was the most common alternative diagnosis. While the TFC performed well overall (sensitivity and specificity 92%), signal-averaged electrocardiogram (SAECG, P = 0.43), and several family history criteria (P ≥ 0.17) failed to discriminate. Eliminating these criteria reduced false positives without increasing false negatives (net reclassification improvement 4.3%, P = 0.019). Furthermore, all ARVC patients met at least one electrocardiogram (ECG) or arrhythmia criterion (sensitivity 100%). Conclusion The TFC perform well but are complex and can lead to misdiagnosis. Simplification by eliminating SAECG and several family history criteria improves diagnostic accuracy. Arrhythmogenic right ventricular cardiomyopathy can be ruled out using ECG and arrhythmia criteria alone, hence these tests may serve as a first-line screening strategy among at-risk individuals.
Published: 2020

28. Association of Premature Ventricular Contraction Burden on Serial Holter Monitoring With Arrhythmic Risk in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

Author: Alessio Gasperetti, Chiara Cappelletto, Richard Carrick, Mattia Targetti, Crystal Tichnell, Annamaria Martino, Brittney Murray, Paolo Compagnucci, Davide Stolfo, Jasmine Bisson, Nisha Gilotra, Corrado Carbucicchio, Iacopo Olivotto, Harikrishna Tandri, Antonio Dello Russo, Julia Cadrin-Tourigny, Leonardo Calò, Claudio Tondo, Gianfranco Sinagra, Cynthia A. James, Michela Casella, Hugh Calkins, Gasperetti, A., Cappelletto, C., Carrick, R., Targetti, M., Tichnell, C., Martino, A., Murray, B., Compagnucci, P., Stolfo, D., Bisson, J., Gilotra, N., Carbucicchio, C., Olivotto, I., Tandri, H., Dello Russo, A., Cadrin-Tourigny, J., Calo, L., Tondo, C., Sinagra, G., James, C. A., Casella, M., and Calkins, H.
Subjects: Adult, Cohort Studies, Male, ARVC, Electrocardiography, Ambulatory, Tachycardia, Ventricular, Humans, Female, Cardiology and Cardiovascular Medicine, Polyvinyl Chloride, Ventricular Premature Complexes, Arrhythmogenic Right Ventricular Dysplasia, Original Investigation
Abstract: IMPORTANCE: A high burden of premature ventricular contractions (PVCs) at disease diagnosis has been associated with an overall higher risk of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC). Data regarding dynamic modification of PVC burden at follow-up with Holter monitoring and its impact on arrhythmic risk in ARVC are scarce. OBJECTIVE: To describe changes in the PVC burden and to assess whether serial Holter monitoring is dynamically associated with sustained ventricular arrhythmias during follow-up in patients with ARVC. DESIGN, SETTINGS, AND PARTICIPANTS: In this cohort study, patients with a definite ARVC diagnosis, available Holter monitoring results at disease diagnosis, and at least 2 additional results of Holter monitoring during follow-up were enrolled from 6 ARVC registries in North America and Europe. Data were collected from June 1 to September 15, 2021. MAIN OUTCOMES AND MEASURES: The association between prespecified variables retrieved at each Holter monitoring follow-up (ie, overall PVC burden; presence of sudden PVC spikes, defined as absolute increase in PVC burden ≥5000 per 24 hours or a relative ≥75% increase, with an absolute increase of ≥1000 PVCs; presence of nonsustained ventricular tachycardia [NSVT]; and use of β-blockers and class III antiarrhythmic drugs) and sustained ventricular arrhythmias occurring within 12 months after that Holter examination was assessed using a mixed logistical model. RESULTS: In 169 enrolled patients with ARVC (mean [SD] age, 36.3 [15.0] years; 95 men [56.2%]), a total of 723 Holter examinations (median, 4 [IQR, 4-5] per patient) were performed during a median follow-up of 54 (IQR, 42-63) months and detected 75 PVC spikes and 67 sustained ventricular arrhythmias. The PVC burden decreased significantly from the first to the second Holter examination (mean, 2906 [95% CI, 1581-4231] PVCs per 24 hours; P
Published: 2022

29. Integrating Exercise Into Personalized Ventricular Arrhythmia Risk Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy

Author: Laurens P. Bosman, Weijia Wang, Øyvind H. Lie, Freyja H.M. van Lint, Christine Rootwelt-Norberg, Brittney Murray, Crystal Tichnell, Julia Cadrin-Tourigny, J. Peter van Tintelen, Folkert W. Asselbergs, Hugh Calkins, Anneline S.J.M. te Riele, Kristina H. Haugaa, Cynthia A. James, Graduate School, ACS - Heart failure & arrhythmias, and ARD - Amsterdam Reproduction and Development
Subjects: Adult, Male, arrhythmogenic right ventricular dysplasia, Time Factors, exercise, Norway, Incidence, Arrhythmias, Cardiac, Middle Aged, Risk Assessment, Decision Support Techniques, Young Adult, Predictive Value of Tests, Risk Factors, Physiology (medical), Baltimore, Humans, Female, Longitudinal Studies, prognosis, Cardiology and Cardiovascular Medicine, Netherlands, Retrospective Studies
Abstract: Background: Exercise is associated with sustained ventricular arrhythmias (VA) in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) but is not included in the ARVC risk calculator ( arvcrisk.com ). The objective of this study is to quantify the influence of exercise at diagnosis on incident VA risk and evaluate whether the risk calculator needs adjustment for exercise. Methods: We interviewed ARVC patients without sustained VA at diagnosis about their exercise history. The relationship between exercise dose 3 years preceding diagnosis (average METh/wk) and incident VA during follow-up was analyzed with time-to-event analysis. The incremental prognostic value of exercise to the risk calculator was evaluated by Cox models. Results: We included 176 patients (male, 43.2%; age, 37.6±16.1 years) from 3 ARVC centers, of whom 53 (30.1%) developed sustained VA during 5.4 (2.7–9.7) years of follow-up. Exercise at diagnosis showed a dose-dependent nonlinear relationship with VA, with no significant risk increase 18, >24, and >36 METh/wk), was significantly associated with VA (hazard ratios, 2.53–2.91) but was also correlated with risk factors currently in the risk calculator model. Thus, adding athlete status to the model did not change the C index of 0.77 (0.71–0.84) and showed no significant improvement (Akaike information criterion change, Conclusions: Exercise at diagnosis was dose dependently associated with risk of sustained VA in ARVC patients but only above 15 to 30 METh/wk. Exercise does not appear to have incremental prognostic value over the risk calculator. The ARVC risk calculator can be used accurately in athletic patients without modification.
Published: 2022

30. Acute myocarditis associated with desmosomal gene variants

Author: Enrico Ammirati, Francesca Raimondi, Nicolas Piriou, Loren Sardo Infirri, Saidi A. Mohiddin, Andrea Mazzanti, Chetan Shenoy, Ugo A. Cavallari, Massimo Imazio, Giovanni Donato Aquaro, Iacopo Olivotto, Patrizia Pedrotti, Neha Sekhri, Caroline M. Van de Heyning, Glenn Broeckx, Giovanni Peretto, Oliver Guttmann, Santo Dellegrottaglie, Alessandra Scatteia, Piero Gentile, Marco Merlo, Randal I. Goldberg, Alex Reyentovich, Christopher Sciamanna, Sabine Klaassen, Wolfgang Poller, Cory R. Trankle, Antonio Abbate, Andre Keren, Smadar Horowitz-Cederboim, Julia Cadrin-Tourigny, Rafik Tadros, Giuseppe A. Annoni, Emanuela Bonoldi, Claire Toquet, Lara Marteau, Vincent Probst, Jean Noël Trochu, Antheia Kissopoulou, Aurelia Grosu, Deni Kukavica, Alessandro Trancuccio, Cristina Gil, Giacomo Tini, Matteo Pedrazzini, Margherita Torchio, Gianfranco Sinagra, Juan Ramón Gimeno, Davide Bernasconi, Maria Grazia Valsecchi, Karin Klingel, Eric D. Adler, Paolo G. Camici, Leslie T. Cooper, Ammirati, Enrico, Raimondi, Francesca, Piriou, Nicola, Sardo Infirri, Loren, Mohiddin, Saidi A, Mazzanti, Andrea, Shenoy, Chetan, Cavallari, Ugo A, Imazio, Massimo, Aquaro, Giovanni Donato, Olivotto, Iacopo, Pedrotti, Patrizia, Sekhri, Neha, Van de Heyning, Caroline M, Broeckx, Glenn, Peretto, Giovanni, Guttmann, Oliver, Dellegrottaglie, Santo, Scatteia, Alessandra, Gentile, Piero, Merlo, Marco, Goldberg, Randal I, Reyentovich, Alex, Sciamanna, Christopher, Klaassen, Sabine, Poller, Wolfgang, Trankle, Cory R, Abbate, Antonio, Keren, Andre, Horowitz-Cederboim, Smadar, Cadrin-Tourigny, Julia, Tadros, Rafik, Annoni, Giuseppe A, Bonoldi, Emanuela, Toquet, Claire, Marteau, Lara, Probst, Vincent, Trochu, Jean Noël, Kissopoulou, Antheia, Grosu, Aurelia, Kukavica, Deni, Trancuccio, Alessandro, Gil, Cristina, Tini, Giacomo, Pedrazzini, Matteo, Torchio, Margherita, Sinagra, Gianfranco, Gimeno, Juan Ramón, Bernasconi, Davide, Valsecchi, Maria Grazia, Klingel, Karin, Adler, Eric D, Camici, Paolo G, and Cooper, Leslie T
Subjects: acute myocarditi, acute myocarditis, desmoplakin, desmosomal gene variant, desmosomal gene variants, cardiac magnetic resonance, prognosis, Human medicine, Cardiology and Cardiovascular Medicine
Abstract: BACKGROUND The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown.OBJECTIVES The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV.METHODS In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up.RESULTS In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM. CONCLUSIONS Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk. (J Am Coll Cardiol HF 2022;10:714-727) (c) 2022 by the American College of Cardiology Foundation.
Published: 2022

31. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study

Author: Jonathan P Piccini, Valeria Caso, Stuart J Connolly, Keith A A Fox, Jonas Oldgren, W Schuyler Jones, Diana A Gorog, Václav Durdil, Thomas Viethen, Christoph Neumann, Hardi Mundl, Manesh R Patel, Johann Auer, Martin Hubauer, Sead Pandzic, Eva Preishuber, Carina Primus-Grabscheit, Dietmar Reitgruber, Florian Schmalzer, Christopher Adlbrecht, Andreas Schober, Johannes Hajos, Christoph Keil, Alexandra Schratter, Matthias Frick, Magdalena Anna Benda, Maximilian Mächler, Beatrix Mutschlechner, Christoph Saely, Lukas Sprenger, Michael Lichtenauer, Miriam Eber, Uta Hoppe, Tobias Kolbitsch, Peter Michael Jirak, Moritz Mirna, Robert Schönbauer, Jutta Bergler-Klein, Christian Hengstenberg, Stefan Stojkovic, Daniel Scherr, Martin Manninger-Wünscher, Ursula Rohrer, Markus Stühlinger, Wilfried Schgoer, Jana Schwarzl, Helmut Pürerfellner, Michael Derndorfer, Christian Ebner, Veronika Eder, Georgios Kollias, Thomas Sturmberger, Stefan Sieghartsleitner, Johan Vijgen, Peter Koopman, Karl Dujardin, Wim Anné, Michel De Ceuninck, Rene Tavernier, Mattias Duytschaever, Sébastien Knecht, Luc Missault, Yves Vandekerckhove, Tom Rossenbacker, Bavo Ector, Filip Charlier, Philippe Debruyne, Willem Dewilde, Luc Janssens, John Roosen, Bart Vankelecom, Hein Heidbuchel, Michiel Delesie, Gert Vervoort, Hans Rombouts, Thomas Vanassche, Matthias Engelen, Peter Verhamme, Rik Willems, Christian Constance, Nicolas Pranno, Jafna Cox, Iqbal Bata, Laurent Macle, Martin Aguilar, Julia Cadrin Tourigny, Marc Dubuc, Katia Dyrda, Peter Guerra, Paul Khairy, Blandine Mondésert, Léna Rivard, Denis Roy, Rafik Tadros, Mario Talajic, Bernard Thibault, Isabelle Nault, Louis Blier, Jean Champagne, Franck Molin, Gilles O'Hara, François Philippon, Benoit Plourde, Jean-François Sarrazin, Christian Steinberg, Zdenek Coufal, David Balazsik, Michal Mikulica, Jakub Zapeca, Ondrej Cermak, Tomas Drasnar, Matej Falc, Josef Hornof, Blazej Racz, Danica Weissova, Hana Linkova, Eva Paskova, Robert Petr, Andrea Sirakova, Jiri Kettner, Ales Benak, Martin Holek, Ivo Podpera, Monika Podperova, Vlastimil Vancura, Tomas Jandik, Jiri Smid, Vratislav Dedek, Jan Banik, Vaclav Durdil, Tomas Hnat, Nicolas Lellouche, Ségolène Rouffiac, Guillaume Taldir, Valentin Bridonneau, Philippe Couffon, Magalie Daudin, Cécile Hamon, Jonathan Lacaze, Anne Quentin, Christophe Thebault, Emmanuel Boiffard, Olivier Billon, Fabien Miette, Hervé Pouliquen, Guillaume Turlotte, Hervé Gorka, Franck Albert, Sandrine Bayle, Reda Bensaid, Madalina Dasoveanu, Thibaud Demichili, Teodora Dutoiu, Cliff Khalil, Caterina Loghin, Grégoire Range, Laurent Roussel, Pierre Socié, Christophe Thuaire, Fabrice Extramiana, Vincent Algalarrondo, Haten Boughanmi, Noreddine El Mansour, Usman Mohammad, Romain Sellier, Meyer Elbaz, Clémence Laperche, Philippe Maury, Robert Kiss, Tunde Borsanyi, Zoltan Gingl, Balaza Polgar, Bela Benczur, Alexandra Bodor, Tamas Hepp, Eva Malati, Laszlo Nagy, Norbert Erdei, Jozsef Kapus, Katalin Kapus, Brigitta Toth, Andras Matoltsy, Tunde Kiss, Bela Merkely, Szilvia Herczeg, Orsolya Kiss, Zoltan Sallo, Kalman Toth, Tamas Habon, Miklos Rabai, Kinga Totsimon, Zsolt Zilahi, Gabriella Bencze, Janos Santa, Daniel Aradi, Barbara Kelemen, Leonardo Bolognese, Martina Nesti, Pasquale Giovanni Notarstefano, Simona D'Orazio, Franco Cosmi, Cecilia Becattini, Giancarlo Agnelli, Belinda Broccatelli, Maria Giulia Mosconi, Maurizio Paciaroni, Chiara Urbini, Vito Maurizio Parato, Camilla Notaristefani, Michele Scarano, Pietro Ameri, Giorgio Ghigliotti, Giulia Guglielmi, Roberta Lotti, Andrea Carlo Merlo, Maria Lorenza Muiesan, Andrea Abondio, Caterina Berasi, Elena Mattiuzzo, Claudio Mutti, Massimo Salvetti, Pasquale Pignatelli, Danilo Menichelli, Daniele Pastori, Eiji Tamiya, Takahiro Matsumoto, Tomosato Takabe, Shoichi Yamamoto, Haruyo Yamashita, Shinichi Higashiue, Onichi Furuya, Norihiko Hiramatsu, Kensuke Kasuga, Saburo Kojima, Masatoshi Komooka, Satoshi Kuroyanagi, Makoto Matsuura, Tetsushi Takemoto, Shuji Yamamoto, Katusmi Saito, Takuro Abe, Issei Ishida, Yuji Iwanami, Shohei Kataoka, Tetsu Moriyama, Akira Murohashi, Akihito Sasaki, Yuichiro Nakamura, Tetsuya Ueno, Akira Shimane, Tomoyo Hamana, Hirotoshi Ichibori, Tomohiro Inoue, Mitsuaki Itoh, Seigo Iwane, Hiroya Kawai, Tatsuya Kokawa, Akiko Masumoto, Koki Matsuo, Taishi Miyata, Shinsuke Nakano, Shogo Oishi, Tetsuari Onishi, Takahiro Sawada, Takayuki Saito, Mitsuhiko Shoda, Nobuyuki Takahashi, Tomofumi Takaya, Yasuyo Taniguchi, Shota Tsukamoto, Yasue Tsukishiro, Yoshiro Tsukiyama, Hiroshi Tsunamoto, Kenzo Uzu, Hiroyuki Yamamoto, Tetsuya Yamamoto, Kiminobu Yokoi, Chiaki Yoshida, Nobuhiro Watanabe, Tetsuo Betsuyaku, Kumiko Adachi, Kouichi Awane, Daisuke Goto, Mamoru Sakakibara, Masashi Watanabe, Hideki Ueno, Yoshitaka Hiroe, Koshi Matsuo, Kenji Ayata, Ko Fukuda, Yoshiki Hata, Katsushi Hashimoto, Hiroaki Matsumi, Akira Nikaido, Shuichi Okamoto, Iveta Sime, Valters Stirna, Ilze Reinholde, Silvija Hansone, Anita Kozlovska, Janina Romanova, Dace Klincare, Natalja Pontaga, Igors Dirmans, Artis Kalnins, Dana Upite, Arcils Gersamija, Arturs Teleznikovs, Nadezda Rozkova, Jelena Safro, Ignasi Anguera Camós, Paolo Domenico Dallaglio, Rafael Salguero Bodes, Fernando Arnbas, Luis Borrego, Alvaro Marco, Javier Ramos Jimenez, Juan José Gómez-Doblas, Alejandro Pérez Cabeza, Ignacio Ferreira Gonzålez, Javier Limeres Freire, Merce Lopez Grau, Xavier Viñolas Prat, Zoraida Moreno Weidmann, Jose Maria Guerra Ramos, Maria Concepcion Alonso Martin, Bieito Campos Garcia, Javier Mauricio Mogro Carranza, Francisco Javier Mendez Zurita, Enrique Rodriguez Font, Carlos Eduardo Gonzales Matos, Víctor García Hernando, Carl-Johan Lindholm, Jörgen Thulin, Håkan Wallén, Kristina Hagwall, Ken Eliasson, Martin Lundvall, Jens Olsson, Björn Kjellman, Markus Lind, Lars Johansson, Niclas Svedberg, Stefan Berglund, Julia Söderberg, Christer Zedigh, Thomas Mooe, Mattias Axelsson, Emil Binsell, Daniel Huber, Christian Müller, Isabelle Danier, Michael Kühne, Bernhard Okamura, Hadrien Schoepfer, Cornelia Simmen, Tobias Reichlin, Laurève Chollet, Anna Lam, Severin Wittmer, Hans Rickli, Christian Gall, Greta Hametner, Stephanie Intorp, Daniel Luescher, Laurent Haegeli, Jan Christopher Berg, Ramin Ebrahimi, Angelo Auricchio, Carmela Crljenica, Tizziano Moccetti, Cristina Monti, Elena Pasotti, Iveta Petrova, Mariagrazia Rossi, François Mach, Mehdi Namdar, Joris de Groot, Virginnio Proost, Joline Neefs, Dominik Linz, Twan van Stipdonk, Dennis den Uijl, Marco Alings, Jeroen Schaap, Dolf Segers, Noemi Wouters, Louis Bartels, Robert Tieleman, Ron Pisters, Tim de Vries, Jaap Selig, Aaf Kuijper, Pieter Bot, Mitran Keijzers, Gerardus Verdel, Raymond Tukkie, Ewout van den Bos, Floris Kauer, Rohit Oemrawsingh, Jeroen Stevenhagen, Jan van Es, Gregory Lip, Dhiraj Gupta, Agnieszka Kotalczyk, Anthony Gunstone, Richard David Brixey, Diana Gorog, Danial Dinarvand, Ying Gue, Rahim Kanji, Vassilios Memtsas, Roxy Senior, Gabriel Bioh, Yuk-Ki Wong, Nick Child, Cardiology, and ACS - Heart failure & arrhythmias
Subjects: anticoagulants, factor xa inhibitors, General Medicine, aged, double-blind method, female, hemorrhage, humans, male, pyrazoles, pyridones, treatment outcome, atrial fibrillation, 610 Medicine & health
Abstract: BACKGROUND Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. METHODS In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. FINDINGS Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. INTERPRETATION The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. FUNDING Bayer.
Published: 2022

32. Myocarditis

Author: Geneviève Giraldeau, Julia Cadrin-Tourigny, Patrick Martineau, and Matthieu Pelletier-Galarneau
Published: 2022

33. Predicting Sudden Cardiac Death in Genetic Heart Disease

Author: Julia Cadrin-Tourigny and Rafik Tadros
Subjects: Death, Sudden, Cardiac, Heart Diseases, Risk Factors, Humans, Arrhythmias, Cardiac, Cardiomyopathy, Hypertrophic, Cardiology and Cardiovascular Medicine, Risk Assessment, Arrhythmogenic Right Ventricular Dysplasia, Defibrillators, Implantable
Abstract: Genetic heart diseases are common causes of sudden cardiac death (SCD) in the young and are typically divided into inherited cardiomyopathies and primary electrical heart diseases. Cardiomyopathies associated with risk of SCD include hypertrophic cardiomyopathy (HCM) and arrhythmogenic cardiomyopathy (ACM). The latter includes arrhythmogenic right ventricular cardiomyopathy (ARVC) as well as ACM primarily affecting the left ventricle, such as lamin cardiomyopathy. Primary electrical diseases more commonly seen in clinical practice include Brugada syndrome (BrS) and long QT syndrome (LQTS). Risk stratification of SCD is a central component of the management of patients with these genetic heart diseases. Numerous risk factors have been identified with variable degrees of scientific evidence. More recently, risk prediction models have been developed to estimate the absolute risk of sustained arrhythmias and SCD, to support clinicians and patients in decision making regarding prophylactic implantable cardioverter-defibrillators (ICDs). This paper provides a practical review of the current literature on risk stratification in ARVC and other ACMs, HCM, BrS, and LQTS, and summarises current recommendations for ICD use.
Published: 2021

34. Importance of genetic testing in unexplained cardiac arrest

Author: Steffany Grondin, Brianna Davies, Julia Cadrin-Tourigny, Christian Steinberg, Christopher C Cheung, Paloma Jorda, Jeffrey S Healey, Martin S Green, Shubhayan Sanatani, Wael Alqarawi, Paul Angaran, Laura Arbour, Pavel Antiperovitch, Habib Khan, Richard Leather, Peter G Guerra, Lena Rivard, Christopher S Simpson, Martin Gardner, Ciorsti MacIntyre, Colette Seifer, Anne Fournier, Jacqueline Joza, Michael H Gollob, Guillaume Lettre, Mario Talajic, Zachary W Laksman, Jason D Roberts, Andrew D Krahn, and Rafik Tadros
Subjects: Male, Humans, Arrhythmias, Cardiac, Female, Heart, Genetic Testing, Cardiology and Cardiovascular Medicine, Cardiomyopathies, Heart Arrest
Abstract: Aims Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). Methods and results Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of ‘explained’ cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. Conclusions Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.
Published: 2021

35. PO-648-05 PREDICTORS FOR TEMPORARY PACEMAKER USE IN PATIENTS WITH NEW LEFT BUNDLE BRANCH BLOCK AFTER TRANSCATHETER AORTIC VALVE IMPLANTATION

Author: Antoine NOEL, William Rémillard, Michelle Samuel, Walid Ben Ali, Paul Khairy, Laurent Macle, Blandine Mondesert, Katia Dyrda, Rafik Tadros, Peter Guerra, Bernard Thibault, JULIA CADRIN-TOURIGNY, Martin Aguilar, Marc Dubuc, Alexandre Raymond-Paquin, Anita Asgar, Reda Ibrahim, Jean-Francois Dorval, Nicolas DURRLEMAN, Marina Ibrahim, Denis Roy, and Lena Rivard
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2022

36. CE-522-03 LONGITUDINAL PREDICTION OF VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Author: Richard Carrick, Anneline Te Riele, Alessio Gasperetti, Laurens P. Bosman, Julia Cadrin-Tourigny, Fabrizio Tundo, Kristin Pendleton, Crystal Tichnell, nicoline P. van den berg, Jeroen F. van der Heijden, Peter van Tintelen, Arthur A.M. Wilde, Sing-Chien Yap, Katja Zeppenfeld, Hugh Calkins, Cynthia A. James, and Katherine C. Wu
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2022

37. PE-565-01 PROGRAMMED VENTRICULAR STIMULATION AS AN ADDITIONAL PRIMARY PREVENTION RISK STRATIFICATION TOOL IN ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY: A MULTINATIONAL STUDY

Author: Alessio Gasperetti, Richard T. Carrick, Fabrizio Tundo, Paolo Compagnucci, Laurens P. Bosman, Crystal Tichnell, Brittney A. Murray, Harikrishna Tandri, Rafik Tadros, Lena Rivard, Paul Van Der Bergh, Katja Zeppenfeld, Arthur A.M. Wilde, Corrado Carbucicchio, Antonio Dello Russo, Michela Casella, Anneli Svensson, Corinna B. Brunckhorst, Peter van Tintelen, Pyotr G. Platonov, Kristina H. Haugaa, Firat Duru, Anneline Te Riele, Paul Khairy, Claudio Tondo, Hugh Calkins, Cynthia A. James, Ardan Saguner, and JULIA CADRIN-TOURIGNY
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2022

38. Arrhythmogenic Right Ventricular Cardiomyopathy

Author: Andrew D. Krahn, Arthur A.M. Wilde, Hugh Calkins, Andre La Gerche, Julia Cadrin-Tourigny, Jason D. Roberts, and Hui-Chen Han
Subjects: Male, Death, Sudden, Cardiac, cardiovascular system, Catheter Ablation, Tachycardia, Ventricular, sudden death, Humans, Female, cardiomyopathy, inherited, Arrhythmogenic Right Ventricular Dysplasia, ventricular arrhythmia, Defibrillators, Implantable
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) encompasses a group of conditions characterized by right ventricular fibrofatty infiltration, with a predominant arrhythmic presentation. First described in the late 1970s and early 1980s, it is now frequently recognized to have biventricular involvement. The prevalence is ∼1:2,000 to 1:5,000, depending on geographic location, and it has a slight male predominance. The diagnosis of ARVC is determined on the basis of fulfillment of task force criteria incorporating electrophysiological parameters, cardiac imaging findings, genetic factors, and histopathologic features. Risk stratification of patients with ARVC aims to identify those who are at increased risk of sudden cardiac death or sustained ventricular tachycardia. Factors including age, sex, electrophysiological features, and cardiac imaging investigations all contribute to risk stratification. The current management of ARVC includes exercise restriction, β-blocker therapy, consideration for implantable cardioverter-defibrillator insertion, and catheter ablation. This review summarizes our current understanding of ARVC and provides clinicians with a practical approach to diagnosis and management.
Published: 2021

39. Return of Results Policies for Genomic Research: Current Practices and the Hearts in Rhythm Organization (HiRO) Approach

Author: Laura Zahavich, Wael Alqarawi, Christopher S. Simpson, Julia Cadrin-Tourigny, Richard Leather, Paul Angaran, Zachary Laksman, Shane Kimber, Henry J. Duff, Laura Arbour, Alice Virani, Robert J. Hamilton, Laura Robb, Martin J. Gardner, Jeff S. Healey, Joseph Atallah, Anna Lehman, Drake A. Comber, Colette M. Seifer, Mario Talajic, Brianna Davies, Jason D. Roberts, Andrew D. Krahn, Anne Fournier, Martin S. Green, Rafik Tadros, Karen Gibbs, Bhavanesh Makanjee, Jacqueline Joza, Shubhayan Sanatani, Ciorsti MacIntyre, and Christian Steinberg
Subjects: Team composition, 0303 health sciences, Research program, Knowledge management, Informed Consent, business.industry, Genomic research, 030305 genetics & heredity, Disclosure, Genomics, Biobank, Genomic databases, Research Personnel, 3. Good health, 03 medical and health sciences, Resource (project management), Policy, Informed consent, Medicine, Humans, Cardiology and Cardiovascular Medicine, business, Return of results, 030304 developmental biology
Abstract: Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for non-disclosure of research results while others follow clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals are discussed. Lastly, the National Hearts in Rhythm Organization (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition and availability of clinical resources.
Published: 2021

40. Retracted and Republished: A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy

Author: Jeroen F. van der Heijden, Mimount Bourfiss, Pyotr G. Platonov, Jane E. Crosson, Crystal Tichnell, Maarten P. van den Berg, Laurens P Bosman, Ardan M. Saguner, Stephen P. Chelko, Aditya Bhonsale, Annik Fortier, Mario Talajic, Anna Nozza, Andrew D. Krahn, Stefan L. Zimmerman, Arthur A.M. Wilde, Cynthia A. James, Daniel P. Judge, Paul Khairy, Øyvind H. Lie, Sing Chien Yap, Harikrishna Tandri, Ihab R. Kamel, J. Peter van Tintelen, Jan D. H. Jongbloed, Antoine Andorin, Katja Zeppenfeld, Brittney Murray, Anneli Svensson, Hugh Calkins, Julia Cadrin-Tourigny, Firat Duru, Folkert W. Asselbergs, Kristina H. Haugaa, Richard N.W. Hauer, Marie Claude Guertin, Anneline S.J.M. te Riele, Rafik Tadros, Weijia Wang, and Lena Rivard
Subjects: medicine.medical_specialty, Ejection fraction, business.industry, Cardiomyopathy, Hypertrophic cardiomyopathy, 030229 sport sciences, 030204 cardiovascular system & hematology, medicine.disease, Ventricular tachycardia, Right ventricular cardiomyopathy, 3. Good health, Arrhythmogenic right ventricular dysplasia, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Cardiology, cardiovascular diseases, Cardiology and Cardiovascular Medicine, business
Abstract: AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P
Published: 2019

41. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

Author: Antonio de Marvao, Roddy Walsh, Jean-Claude Tardif, R. Thomas Lumbers, Eric Villard, Rafik Tadros, Peter Lichtner, Catherine Francis, Julie Amyot, Michelle Michels, Hugh Watkins, Julia Cadrin-Tourigny, Najim Lahrouchi, Rudolf A. de Boer, Patrick Garceau, Karin J. H. Verweij, Paul M. Matthews, Paul Elliott, S. Matthijs Boekholdt, Folkert W. Asselbergs, Declan P. O'Regan, Benjamin Meder, Joost A. Offerhaus, Nicola Whiffin, Jacco C. Karper, Jason D. Roberts, Marie-Pierre Dubé, Hideaki Suzuki, James S. Ware, Yigal M. Pinto, Thomas Meitinger, Guillaume Lettre, Hannah G. van Velzen, Arthur A.M. Wilde, Marjon van Slegtenhorst, Francesco Mazzarotto, Wouter P. te Rijdt, Paul J.R. Barton, Sanjay K Prasad, A. John Baksi, Michael W.T. Tanck, Mario Talajic, Roy Huurman, J. Peter van Tintelen, Connie R. Bezzina, Antonis Pantazis, Robert A. Hegele, Jentien M Vermeulen, Rachel Buchan, Imke Christiaans, Jan H. Veldink, Edgar T. Hoorntje, Elham Kayvanpour, Pascale Richard, Geneviève Giraldeau, Flavie Ader, Andrew Thain, Philippe L. L’Allier, Xiao Xu, Leander Beekman, David McCarty, Alexa M.C. Vermeer, Geraldine Sloane, Wenjia Bai, Andrew R. Harper, Jolanda van der Velden, Stuart A. Cook, Ken Kelu Bisabu, Philippe Charron, Deborah Schneider-Luftman, Human Genetics, ACS - Heart failure & arrhythmias, Cardiology, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Compulsivity, Impulsivity & Attention, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, ACS - Amsterdam Cardiovascular Sciences, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Human genetics, Physiology, Cardiovascular Centre (CVC), Clinical Genetics, Wellcome Trust, Department of Health, British Heart Foundation, Engineering & Physical Science Research Council (EPSRC), UK DRI Ltd, The Academy of Medical Sciences, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: Linkage disequilibrium, Cardiomyopathy, Dilated/genetics, Left, Cardiomyopathy, Genome-wide association study, Kaplan-Meier Estimate, VARIANTS, Ventricular Function, Left, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Dilated, Ventricular Function, 11 Medical and Health Sciences, Cardiomyopathy, Hypertrophic/genetics, Genetics & Heredity, 0303 health sciences, HERITABILITY, Single Nucleotide, MENDELIAN RANDOMIZATION, Cardiology, cardiovascular system, HEART, Life Sciences & Biomedicine, Ventricular Function, Left/genetics, Cardiomyopathy, Dilated, medicine.medical_specialty, Heart Ventricles, Quantitative Trait Loci, Biology, Quantitative trait locus, Sudden death, Polymorphism, Single Nucleotide, Article, Heart Ventricles/physiopathology, 03 medical and health sciences, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, 030304 developmental biology, Genetic association, Science & Technology, Hypertrophic/genetics, Left/genetics, Case-control study, CONTRACTILITY, 06 Biological Sciences, Cardiomyopathy, Hypertrophic, medicine.disease, Hypertrophic, Dilated/genetics, Case-Control Studies, Genome-Wide Association Study, 030217 neurology & neurosurgery, Developmental Biology
Abstract: The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
Published: 2021

42. Sudden cardiac death prediction in arrhythmogenic right ventricular cardiomyopathy

Author: Aditya Bhonsale, Mimount Bourfiss, Crystal Tichnell, Maarten P. van den Berg, Stephen P. Chelko, Brittney Murray, Folkert W. Asselbergs, Arthur A.M. Wilde, Laurens P Bosman, Mario Talajic, Andrew D. Krahn, Ihab R. Kamel, Hugh Calkins, Daniel P. Judge, Ardan M. Saguner, Rafik Tadros, J. Peter van Tintelen, Jane E. Crosson, Cynthia A. James, Paul Khairy, Øyvind H. Lie, Kristina H. Haugaa, Julia Cadrin-Tourigny, Richard N.W. Hauer, Katja Zeppenfeld, Anneline S.J.M. te Riele, Anneli Svensson, Firat Duru, Weijia Wang, Lena Rivard, Sing Chien Yap, Stefan L. Zimmerman, Jeroen F. van der Heijden, Pyotr G. Platonov, Jan D. H. Jongbloed, Antoine Andorin, Harikrishna Tandri, Human Genetics, Cardiology, ACS - Heart failure & arrhythmias, and Cardiovascular Centre (CVC)
Subjects: arrhythmogenic right ventricular dysplasia, medicine.medical_specialty, Ventricular Ejection Fraction, Heart disease, Global Health, Ventricular tachycardia, Right ventricular cardiomyopathy, sudden cardiac death, Sudden cardiac death, Electrocardiography, Risk Factors, Interquartile range, Physiology (medical), Internal medicine, calibration, syncope, ventricular tachycardia, medicine, Humans, Cardiac and Cardiovascular Systems, cardiovascular diseases, Retrospective Studies, Kardiologi, business.industry, Incidence, Stroke Volume, Retrospective cohort study, Original Articles, medicine.disease, Defibrillators, Implantable, Arrhythmogenic right ventricular dysplasia, Death, Sudden, Cardiac, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Ventricular Function, Right, Cardiology, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77–10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69–0.80) and calibration slope of 0.95 (95% CI, 0.94–0.98) indicating minimal over-optimism. Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.
Published: 2021

43. Novel Gain-of-Function Variant in CACNA1C Associated With Timothy Syndrome, Multiple Accessory Pathways, and Noncompaction Cardiomyopathy

Author: Ken Kelu Bisabu, Evelyne Naas, Alla-Eddine Mokrane, Steffany Grondin, Rafik Tadros, Martin Aguilar, Mireille Marsolais, Julia Cadrin-Tourigny, Juan Zhao, Lucie Parent, Mario Talajic, Johannie Gagnon, Emilie Segura, and François-Pierre Mongeon
Subjects: medicine.medical_specialty, Noncompaction cardiomyopathy, Gain of function, Voltage-dependent calcium channel, business.industry, Long QT syndrome, Internal medicine, Cardiology, medicine, Timothy syndrome, General Medicine, business, medicine.disease
Published: 2020

44. Pulmonary Vein Stenosis After Atrial Fibrillation Ablation: Insights From the ADVICE Trial

Author: Marc Dubuc, Michelle Samuel, Jean-Claude Tardif, François Pierre Mongeon, Jason G. Andrade, George D. Veenhuyzen, Rafik Tadros, Christophe Scavée, Syamkumar M. Divakara Menon, Julia Cadrin-Tourigny, Rukshen Weerasooriya, Stanley Nattel, Peter G. Guerra, Denis Roy, Lena Rivard, Blandine Mondésert, Pierre Jaïs, Ratika Parkash, Isabelle Nault, Mario Talajic, Helmut Puererfellner, Sylvie Levesque, Paul Khairy, Atul Verma, Katia Dyrda, Zurine Galvan, Martin Aguilar, Bernard Thibault, Paul Novak, Thomas Arentz, Isabel Deisenhofer, Sophie Gomes, Laurent Macle, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Service de pathologie cardiovasculaire
Subjects: Male, medicine.medical_specialty, Canada, Radiofrequency ablation, Computed Tomography Angiography, medicine.medical_treatment, Catheter ablation, 030204 cardiovascular system & hematology, Severity of Illness Index, law.invention, Pulmonary vein, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, law, Risk Factors, Internal medicine, Atrial Fibrillation, Outcome Assessment, Health Care, Medicine, Humans, 030212 general & internal medicine, Pulmonary vein stenosis, medicine.diagnostic_test, business.industry, Incidence, Atrial fibrillation, Organ Size, Middle Aged, medicine.disease, Ablation, 3. Good health, Stenosis, Stenosis, Pulmonary Vein, Pulmonary Veins, Angiography, Cardiology, Catheter Ablation, Female, Cardiology and Cardiovascular Medicine, business, Magnetic Resonance Angiography
Abstract: BACKGROUND: Pulmonary vein (PV) stenosis is a complication of atrial fibrillation (AF) ablation. The incidence of PV stenosis after routine post-ablation imaging remains unclear and is limited to single-centre studies. Our objective was to determine the incidence and predictors of PV stenosis following circumferential radiofrequency ablation in the multicentre Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) trial. METHODS: Patients with symptomatic AF underwent circumferential radiofrequency ablation in one of 13 trial centres. Computed tomographic (CTA) or magnetic resonance (MRA) angiography was performed before ablation and 90 days after ablation. Two blinded reviewers measured PV diameters and areas. PVs with stenosis were classified as severe (> 70%), moderate (50%-70%), or mild (< 50%). Predictors of PV stenosis were identified by means of multivariable logistic regression. RESULTS: A total of 197 patients (median age 59.5 years, 29.4% women) were included in this substudy. PV stenosis was identified in 41 patients (20.8%) and 47 (8.2%) of 573 ablated PVs. PV stenosis was classified as mild in 42 PVs (7.3%) and moderate in 5 PVs (0.9%). No PVs had severe stenosis. Both cross-sectional area and diameter yielded similar classifications for severity of PV stenosis. Diabetes was associated with a statistically significant increased risk of PV stenosis (OR 4.91, 95% CI 1.45-16.66). CONCLUSIONS: In the first systematic multicentre evaluation of post-ablation PV stenosis, no patient acquired severe PV stenosis. Although the results are encouraging for the safety of AF ablation, 20.8% of patients had mild or moderate PV stenosis, in which the long-term effects are unknown.
Published: 2020

45. An International Multi-Center Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2- Catecholaminergic Polymorphic Ventricular Tachycardia

Author: Antoine Leenhardt, Shubhayan Sanatani, Susan P. Etheridge, Caitlin Brateng, Tomas Robyns, Isabelle Denjoy, Christopher Semsarian, Allan C. Skanes, Andrea Mazzanti, Jaimie Manlucu, Natalia Jura, Rahul C. Deo, Sean Connors, Andrew D. Krahn, Seshadri Balaji, Benjamin Pang, Michael J. Ackerman, Robert M. Hamilton, Julia Cadrin-Tourigny, Jason D. Roberts, Craig T. January, Arthur A.M. Wilde, Anthony Tang, Alice Maltret, Erron W. Titus, J. Martijn Bos, Silvia G. Priori, Dominic Abrams, Jeremy Wu, Martin S. Green, Frederick H. Deiter, Julie Rutberg, Jodie Ingles, Kevin Ng, Jeff S. Healey, Jan Till, Krystien V.V. Lieve, Lee L. Eckhardt, Christian van der Werf, Stephen A. Duffett, Peter S. Fischbach, Kathryn K. Collins, Kathleen R. Maginot, Kate M. Orland, Thomas M. Roston, Ferran Rosés I. Noguer, Linda M. Knight, Michael H. Gollob, Melvin M. Scheinman, Christian Steinberg, Graduate School, ACS - Heart failure & arrhythmias, Cardiology, CIC Hôpital Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, [SDV]Life Sciences [q-bio], Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, Bioinformatics, 0302 clinical medicine, Risk Factors, Tachycardia, 2.1 Biological and endogenous factors, Inheritance Patterns, Medicine, genetics, Aetiology, Death sudden cardiac, 0303 health sciences, catecholaminergic polymorphic ventricular tachycardia, Homozygote, 3. Good health, Heart Disease, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, arrhythmias, Heterozygote, cardiac, Clinical Sciences, Mutation, Missense, Catecholaminergic polymorphic ventricular tachycardia, Article, 03 medical and health sciences, Clinical Research, death, Physiology (medical), Genetics, Calsequestrin, Humans, 030304 developmental biology, sudden, business.industry, death, sudden, cardiac, Ventricular, Genetic variants, arrhythmias, cardiac, medicine.disease, Cardiovascular System & Hematology, Mutation, Tachycardia, Ventricular, Missense, Autosomal recessive form, business
Abstract: Background:Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms ofCASQ2-CPVT was sought through an international multicenter collaboration.Methods:Genotype-phenotype segregation inCASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominantCASQ2missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.Results:A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenicCASQ2variant, were identified. AmongCASQ2homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66CASQ2heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative toCASQ2heterozygotes,CASQ2homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0;P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1;PCASQ2missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.Conclusions:This international multicenter study ofCASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygousCASQ2variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
Published: 2020

46. 668Principal component analysis can identify ventricular regions with highest variability in the arrhythmogenic substrate of ventricular tachycardia patients

Author: Kyungmoo Ryu, François Harel, Marc Dubuc, Paul Khairy, Bernard Thibault, Luke C. McSpadden, Jean Grégoire, Julia Cadrin-Tourigny, Blandine Mondésert, Laurent Macle, Katia Dyrda, Rafik Tadros, J Relan, L P Richer, and Lena Rivard
Subjects: medicine.medical_specialty, Component analysis, business.industry, Physiology (medical), Internal medicine, Cardiology, Medicine, Cardiology and Cardiovascular Medicine, business, Ventricular tachycardia, medicine.disease, Arrhythmogenic substrate
Abstract: Introduction Left ventricle (LV) substrate can be characterized by imaging modalities providing physiological variables (tissue perfusion, ischemia, etc.) grouped in a complex dataset. Principal Component Analysis (PCA) can identify the dataset variables that best explain its variance. Variables linked to substrate arrhythmogenicity will lead PCA to identify LV regions most influenced by the variables on a LV 3D geometry. Purpose To evaluate whether regions identified by PCA correspond to regions targeted by physicians in a ventricular tachycardia (VT) ablation procedure. Methods Ischemic VT subjects underwent SPECT/CT perfusion imaging (rest and stress) prior to LV voltage mapping with the cardiac mapping system. Co-registration allowed projection of ablation sites onto SPECT/CT geometries. PCA retrospectively analyzed the following dataset: tissue perfusion (rest and stress), tissue ischemia and the local (1cm2 sub-regions) stress-rest difference for: 1) standard deviation (STD) and 2) skewness (Skew). PCA components (PCAc) explaining ≥85% of the total variance were plotted on the LV 3D geometry to display regions highly influenced by the dataset variables (see figure below). Results Ten subjects (9 males, 66 ± 8 years old, LVEF 37 ± 11%) underwent co-registration. In 7/10 subjects, tissue perfusion (in PCAc#1) and ischemia (in PCAc#2) were most influential on LV regions variance. Ischemia and low perfusion (≤40%) areas equaled 32 ± 19 % of the LV with 21 ± 23% of these areas highly involved in the arrhythmogenic substrate (≥75% of explained LV variance). The location of 63 ± 18% of ablation sites were Conclusion Preliminary results showed that PCA can synthesize the influence of different perfusion derived variables, like tissue perfusion and ischemia, used in SPECT/CT imaging of the LV. Further analysis is needed to confirm whether this could be used to select VT ablation targets. Abstract Figure.
Published: 2020

47. Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review

Author: Julie Amyot, Laura Robb, Johannie Gagnon, Julia Cadrin-Tourigny, Donato Gerardo Terrone, Lena Rivard, Sylvain Pagé, Mario Talajic, Steffany Grondin, Rafik Tadros, Paloma Jordà, and Avedis-Christ Wazirian
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Heart Ventricles, Protein domain, Cardiomyopathy, Mutation, Missense, 030105 genetics & heredity, Sudden cardiac death, 03 medical and health sciences, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Genetics (clinical), Loss function, Arrhythmogenic Right Ventricular Dysplasia, biology, Desmoplakin, business.industry, Cardiac arrhythmia, Spectrin repeat, Genetic Variation, Arrhythmias, Cardiac, medicine.disease, 030104 developmental biology, Phenotype, Desmoplakins, biology.protein, Female, business
Abstract: Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life-threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.
Published: 2020

48. An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition

Author: Julia Cadrin-Tourigny, Dan M. Roden, Valentina Kutyifa, Henry J. Duff, Robert M. Gow, Marco V Perez, Eric Vittinghoff, Wataru Shimizu, Birgit Stallmeyer, Linda M. Knight, Lia Crotti, Michael H. Gollob, Silvia G. Priori, Rafik Tadros, Juan Pablo Kaski, Gregory M. Marcus, S. Yukiko Asaki, Thomas M. Roston, Sharmila Udupa, Takeshi Aiba, Deni Kukavica, Peter J. Schwartz, Nikhil Chavali, M. Benjamin Shoemaker, Carla Spazzolini, Christopher S. Simpson, Fabrizio Drago, Yanushi D. Wijeyeratne, J. Martijn Bos, Sven Dittmann, John R. Giudicessi, Eric Schulze-Bahr, Peter S. Fischbach, Anwar Baban, Keiko Shimamoto, Arthur A. M. Wilde, Jonathan R. Skinner, Jason D. Roberts, Brynn E. Dechert, Peter F. Aziz, Andrew P. Landstrom, Andrea Mazzanti, Elijah R. Behr, Jacob Tfelt-Hansen, Dominic Abrams, Elizabeth S. Kaufman, Izabela Tuleta, Alison Muir, Maisoon D. Yousif, Lorne J. Gula, Michael J. Ackerman, Wojciech Zareba, Imane El Hajjaji, Christopher L. Johnsrude, Melvin M. Scheinman, Susan P. Etheridge, Peter Leong-Sit, Luciana Marcondes, Andrew D. Krahn, Cardiology, ACS - Heart failure & arrhythmias, Roberts, J, Asaki, S, Mazzanti, A, Bos, J, Tuleta, I, Muir, A, Crotti, L, Krahn, A, Kutyifa, V, Shoemaker, M, Johnsrude, C, Aiba, T, Marcondes, L, Baban, A, Udupa, S, Dechert, B, Fischbach, P, Knight, L, Vittinghoff, E, Kukavica, D, Stallmeyer, B, Giudicessi, J, Spazzolini, C, Shimamoto, K, Tadros, R, Cadrin-Tourigny, J, Duff, H, Simpson, C, Roston, T, Wijeyeratne, Y, El Hajjaji, I, Yousif, M, Gula, L, Leong-Sit, P, Chavali, N, Landstrom, A, Marcus, G, Dittmann, S, Wilde, A, Behr, E, Tfelt-Hansen, J, Scheinman, M, Perez, M, Kaski, J, Gow, R, Drago, F, Aziz, P, Abrams, D, Gollob, M, Skinner, J, Shimizu, W, Kaufman, E, Roden, D, Zareba, W, Schwartz, P, Schulze-Bahr, E, Etheridge, S, Priori, S, and Ackerman, M
Subjects: Male, Proband, Potassium Channels, Penetrance, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, Sudden cardiac death, Electrocardiography, 0302 clinical medicine, Genotype, 2.1 Biological and endogenous factors, Medicine, genetics, Registries, Aetiology, 0303 health sciences, Hazard ratio, Voltage-Gated, Middle Aged, Death, Heart Disease, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, Cardiac, Adult, medicine.medical_specialty, Adolescent, Long QT syndrome, Clinical Trials and Supportive Activities, Clinical Sciences, Electric Countershock, BIO/18 - GENETICA, arrhythmia, QT interval, Article, sudden cardiac death, 03 medical and health sciences, Clinical Research, Physiology (medical), Internal medicine, Genetics, long QT syndrome, Humans, penetrance, 030304 developmental biology, business.industry, Proportional hazards model, Human Genome, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Sudden, Heart Arrest, Cardiovascular System & Hematology, genetic, business
Abstract: Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.
Published: 2020

49. Hereditary Cardiac Conduction Diseases

Author: Rafik Tadros and Julia Cadrin-Tourigny
Published: 2020

50. Arrhythmic outcome of arrhythmogenic right ventricular cardiomyopathy patients without implantable defibrillators

Author: Aditya Bhonsale, Harikrishna Tandri, Cynthia A. James, Crystal Tichnell, Oliver Monfredi, Julia Cadrin-Tourigny, Hugh Calkins, Jane E. Crosson, Brittney Murray, Jonathan Chrispin, and Weijia Wang
Subjects: Adult, Male, Proband, medicine.medical_specialty, Time Factors, Clinical Decision-Making, Electric Countershock, 030204 cardiovascular system & hematology, Implantable defibrillator, Ventricular tachycardia, Risk Assessment, Sudden death, Right ventricular cardiomyopathy, Young Adult, 03 medical and health sciences, Electrophysiology study, 0302 clinical medicine, Risk Factors, Interquartile range, Physiology (medical), Internal medicine, medicine, Humans, Registries, 030212 general & internal medicine, Arrhythmogenic Right Ventricular Dysplasia, medicine.diagnostic_test, business.industry, Arrhythmias, Cardiac, Middle Aged, medicine.disease, Progression-Free Survival, Defibrillators, Implantable, Heart Arrest, Death, Sudden, Cardiac, Cohort, Disease Progression, cardiovascular system, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: BACKGROUND Implantable defibrillators (ICD) are an important therapy for arrhythmogenic right ventricular cardiomyopathy (ARVC) patients at high risk of sudden death. Given the high appropriate ICD therapy rate, some have argued that the mere act of implanting an ICD inflates the malignant arrhythmia rate in ARVC. OBJECTIVE To report the arrhythmic course of ARVC patients without ICDs at the fulfillment of the 2010 Task Force Criteria and explore predictors of malignant ventricular arrhythmias. METHODS We included 131 definite ARVC patients (age 32 ± 15 years, male 39%, proband 50%) either without ICDs (N = 47) or receiving an ICD at least 6 months after the fulfillment of the diagnostic criteria. The primary outcome was a composite of cardiac arrest (both resuscitated successfully and unsuccessfully) and sustained ventricular tachyarrhythmias (cycle length
Published: 2018

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