Déterminants du remodelage atrial et de son effet pro-arythmique dans la fibrillation atriale

Rational and objective - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Atrial remodeling, whether electrical or structural, leads to the development of atrial cardiomyopathy. The atrial cardiomyopathy results in various complications: on one hand, mechanical with an increased thromboembolic risk and heart failure, and on the other hand electrical prdeisposing to atrial arrhythmias including AF. The aim of the thesis was to characterize the determinants of atrial remodeling, and their proarrhythmic effect in AF.  Main results -  The first part of the thesis focused on the characterization of the atrial remodeling induced by sustained atrial flutter (AFL) in a chronic canine model in order to characterize the interrelationship between AF and AFL. AFL caused electrical remodeling, including increased AF vulnerability and decreased effective refractory periods (ERPs). However, failed to influence AF duration, atrial conduction velocities and fibrosis. Chronic AF in the presence of an anatomical substrate for AFL led to specific AF characteristics, in terms of cycle length and its variability. In addition, AFL ablation significantly reduced arrhythmia duration but not AF vulnerability.  The second part of the thesis characterized the differential role of atrial arrhythmia and ventricular response in AF-induced atrial remodeling. We characterized the atrial remodeling induced by lone atrial arrhythmia in AF, with AV-block to prevent high ventricular rate: on the one hand electrical via decreased ERP, reduced expression of sodium channels and gap junctions, which increased AF vulnerability; on the other hand, structural fibrosis which contributed to conduction slowing. Lone high-rate ventricular response also induced atrial remodeling involving increased AF vulnerability, decreased atrial conduction velocities, moderate abnormalities of fibrosis and sodium channel downregulation. In addition, there was a synergistic effect on atrial remodeling of combined atrial arrhythmia and high ventricular rate, especially regarding fibrosis. Thus,  atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both can contribute to the arrhythmogenic substrate.  These results provide new insights into the determinants of AF-related remodeling and provide novel considerations for ventricular rate-control.    The third part of the thesis studies the ability of cilnidipine, an N- and L-type calcium channel blocker, to alter autonomic, electrical and structural remodeling associated with chronic AF, in a subacute and chronic dog model. We found that the cilnidipine inhibits the electrophysiological, autonomic and structural consequences of AF-related remodeling and the AF-associated increase in AF-vulnerability and AF-duration; in contrast, the highly selective L-type calcium channel blocker nifedipine had no protective effects. The protective effects of cilnidipine on the remodeling consequences of short-term AF were principally manifested by reductions in AF-induced ERP-abbreviation. With longer-term AF, cilnidipine also attenuated conduction-velocity reductions, protecting against AF-induced fibrosis and downregulation of sodium-channel and connexin subunits. Cilnidipine’s anti-remodeling properties were associated with suppression of the changes in autonomic tone caused by AF.  Conclusion - Thus, we have shown 1) the distinct remodeling phenotypes produced by the closely related atrial re-entrant arrhythmias AFL and AF, as well as the interaction when they co-exist; 2) the specific contributions of the atrial rhythm and ventricular rate consequences of AF and how they interact; and 3) the ability of autonomic outflow inhibition by blocking N-type Ca2+-channels to prevent both electrical and structural components of AF-induced profibrillatory remodeling. This work provides new insights into the mechanisms involved in AF-related atrial remodeling and introduces novel preventive approaches.

Keyphrases: Cardiopathie atriale, Atrial fibrillation, Atrial remodeling, Atrial cardiomyopathy, Fibrosis, Autonomic nervous system, Arrhythmia-induced cardiomyopathy