Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation

Abstract

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6 -8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 ϫ 16 photodiode array from 2 ϫ 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD 80) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD80 may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility. atrial conduction; optical mapping ATRIAL FIBRILLATION (AF) is a frequently occurring arrhythmia, present in ϳ5% of people over 65 yr old (5). Among the risk factors predisposing to AF are congestive heart failure (CHF), hypertension, and mitral valve disease, including both stenosis and insufficiency (reviewed in Ref. 5). In general, atrial dilatation is associated with an increased occurrence of AF (17,28).Prevailing theory suggests that inducibility of sustained AF requires either a shortening of refractoriness, increased dispersion of refractoriness, or conduction slowing (1). Other factors that have been implicated in the stabilization of AF include increased conduction heterogeneity and anisotropy (23). The presence of one or more of these proarrhythmic factors would thus represent a "substrate for AF," contributing to increased AF stability. Various animal models of AF have been developed to study AF substrate. Parasympathetic stimulation (either with direct vagal nerve stimulation or circulating cholinergic agents) results in shortening of atrial refractoriness and sustained AF (10, 16). Prolonged rapid atrial pacing (RAP) leads to shortening of refractoriness and sustained AF (18,30). In a dog model of CHF due to rapid ventricular pacing, no changes in refractoriness were found, but increased con...

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

“…There are many causes of AF and although patients generally show multiple predisposing risk factors, Ͼ70% of patients have some form of underlying structural heart disease (2, 3). Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained (10,13,22,29,30,32,34,48). In addition to atrial enlargement, fibrosis and conduction abnormalities that establish a substrate for reentry, cellular remodeling involving cellular hypertrophy, changes in membrane structure, and abnormal expression and function of ion channels and transporters are also likely to contribute to the genesis of AF (4,10,13,15,16,18,22,26,29,30,32,34,35,38,48,51).…”

“…Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained (10,13,22,29,30,32,34,48). In addition to atrial enlargement, fibrosis and conduction abnormalities that establish a substrate for reentry, cellular remodeling involving cellular hypertrophy, changes in membrane structure, and abnormal expression and function of ion channels and transporters are also likely to contribute to the genesis of AF (4,10,13,15,16,18,22,26,29,30,32,34,35,38,48,51).Atrial L-type Ca 2ϩ current (I CaL ) is reduced in heart disease, both in animal models (4,13,29,38) and in myocytes from human dilated atria (19,33). The loss of I CaL has been suggested to have a number of sequelae that contribute to the genesis of AF, including 1) changes in action potential configuration and the rate dependence of refractoriness, 2) abnormalities in Ca 2ϩ handling and the triggering of episodes of AF, and 3) hypocontractility and dilatation of the atria (15,29,33,35,42).…”

Regional left atrial voltage in patients with atrial fibrillation

“…18 After intravenous injection of 5,000 units of heparin, mongrel dogs were euthanized by injection of 50 mg/kg pentobarbital sodium, and the heart rapidly excised and immersed in and perfused with cold cardioplegic solution, as previously described. 18 The right and left coronary arteries were cannulated for perfusion. Once the preparation was completed, the coronary arteries were perfused with an oxygenated modified Tyrode's solution, and the preparation was placed in a temperature-controlled chamber.…”

Stem cell therapy for cardiac disease

“…Optical mapping not only maps membrane depolarization but also the repolarization process. Verheule and coworkers utilized highresolution optical mapping to study atrial conduction in canine models of chronic atrial dilatation and chronic rapid atrial pacing to determine whether the underlying mechanisms of atrial fibrillation inducibility are similar (101). Based on the conduction profiles obtained, they found that the underlying substrate for atrial fibrillation in the chronic atrial dilatation model is distinctly different from that of the chronic rapid atrial pacing model.…”