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Heijman J.,University of Duisburg - Essen | Voigt N.,University of Duisburg - Essen | Nattel S.,Montreal Heart Institute | Nattel S.,McGill University | Dobrev D.,University of Duisburg - Essen
Circulation Research | Year: 2014

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca-handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management. © 2014 American Heart Association, Inc. Source


Rouleau J.L.,Montreal Heart Institute
Canadian Journal of Cardiology | Year: 2011

Chronic heart failure remains a common end product of cardiovascular diseases and, despite significant advances in therapy, continues to be accompanied by significant morbidity and mortality. Attenuation of neurohumoral overactivation with blockers of the renin-angiotensinaldosterone system and ß-blockers has improved outcome and helped reverse or halt disease progression in many patients; however, despite this, morbidity and mortality have remained elevated, and only marginal advances have occurred over the last few years. How best to combine these various agents continue to be tested but, apart from the addition of aldosterone receptor blockers and reduction of heart rate with ivabradine, advances have been few. Implantable defibrillators and cardiac resynchronization devices have proved to be very beneficial, and the limits of their use are presently still being tested. How best to handle atrial fibrillation in patients with heart failure remains unanswered, but for now, rate control appears to be appropriate in many patients. Surgical ventricular restoration of the left ventricle has not proved to generally be useful, and although the role of coronary artery bypass graft surgery (CABG) is well established in some patients, its use in others is being reevaluated. The use of biomarkers in patients with heart failure has stimulated great interest; however, much work remains before its full potential can be realized. As the complexity of the use of pharmacogenomics in clinical practice becomes clearer, research in the area is intensifying, but much work remains to be done before its use can be clearly outlined in patients with heart failure. © 2011 Canadian Cardiovascular Society. Source


Dobrev D.,TU Dresden | Nattel S.,Montreal Heart Institute
The Lancet | Year: 2010

Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation. © 2010 Elsevier Ltd. All rights reserved. Source


Asgar A.W.,Montreal Heart Institute | Mack M.J.,Heart Hospital Baylor Plano | Stone G.W.,Columbia University
Journal of the American College of Cardiology | Year: 2015

The development of secondary mitral regurgitation (MR) due to left ventricular dysfunction, also known as functional MR, is strongly associated with a poor prognosis in patients with heart failure. The mechanisms underlying secondary MR are multifactorial; accurate imaging assessment of secondary MR may be challenging and nuanced; and the appropriate roles of medical, surgical, and interventional therapies for management of secondary MR are controversial and evolving. In this review, the pathophysiology, evaluation, and prognosis of secondary MR in patients with heart failure are discussed, and we evaluate in detail the evidence for the various therapeutic approaches for secondary MR, including guideline-directed medication for left ventricular dysfunction, cardiac resynchronization therapy and revascularization when appropriate, and mitral valve surgery and transcatheter interventions. The role of a multidisciplinary heart team in determining the optimal management strategy for secondary MR is also discussed. © 2015 American College of Cardiology Foundation. Source


Nattel S.,Montreal Heart Institute | Harada M.,Montreal Heart Institute | Harada M.,Hamamatsu Medical Center
Journal of the American College of Cardiology | Year: 2014

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. AF and its complications are responsible for important population morbidity and mortality. Presently available therapeutic approaches have limited efficacy and nontrivial potential to cause adverse effects. Thus, new mechanistic knowledge is essential for therapeutic innovation. Atrial arrhythmogenic remodeling, defined as any change in atrial structure or function that promotes atrial arrhythmias, is central to AF. Remodeling can be due to underlying cardiac conditions, systemic processes and conditions such as aging, or AF itself. Recent work has underlined the importance of remodeling in AF, provided new insights into basic mechanisms, and identified new biomarker/imaging approaches to follow remodeling processes. The importance of intracellular Ca2+ handling abnormalities has been highlighted, both for the induction of triggered ectopic activity and for the activation of Ca2+-related cell signaling that mediates profibrillatory remodeling. The importance of microRNAs, which are a new class of small noncoding sequences that regulate gene expression, has emerged in both electrical and structural remodeling. Remodeling related to aging, cardiac disease, and AF itself is believed to underlie the progressive nature of the arrhythmia, which contributes to the complexities of long-term management. New tools that are being developed to quantify remodeling processes and monitor their progression include novel biomarkers, imaging modalities to quantify/localize fibrosis, and noninvasive monitoring/mapping to better characterize the burden of AF and identify arrhythmic sources. This report reviews recent advances in the understanding of the basic pathophysiology of atrial remodeling and potential therapeutic implications. © 2014 by the American College of Cardiology Foundation Published by Elsevier Inc. Source

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