Cellular Mechanisms of Contractile Impairment in Human Chronic Atrial Fibrillation

Abstract

Chronic Atrial Fibrillation (cAF) is associated with contractile impairment. Down regulation of L-Type Ca2+current plays a major role in determining contractile dysfunction. However, additional EC-Coupling changes could be involved in human cAF. We dissected atrial trabeculae from left atrial appendages of cAF patients undergoing cardiac surgery and used them for simultaneous force and action potential recordings. Cells isolated from the same samples were used for Ca2+current, Ca2+transients, and reticular Ca2+content(caffeine) measurements. Samples from sinus rhythm (SR) patients were used as controls. Despite 75%reduction in basal force, positive inotropic responses to isoproterenol, stimulation pauses, and high [Ca2+]e were preserved in cAF. Basal Ca2+current and Ca2+transients were decreased (30%of SR) but showed a greater increase upon inotropic stimuli, reducing the difference with SR. No difference was found in time-course of mechanical restitution, suggesting no major impairment of Ryanodine Receptor function. The finding that sarcoplasmic reticulum Ca2+ content was not reduced in cAF suggests that Ca2+release impairment could be due to a change from synchronous EC Coupling to propagated Ca2+-induced Ca2+-release (CICR), in which a fast subsarcolemmal Ca2+rise is followed by Ca2+diffusion-mediated signal propagation toward the cell core. The following observations in cAF preaparations supports this idea: 1)Ca2+transients showed a fast monophasic rise(subsarcolemmal Ca2+-release only) but exhibited a biphasic, dome-shaped aspect (peripheral rise followed by inward Ca2+-wave spread) upon inotropic stimulations; 2)Ca2+recirculation fraction decreased, suggesting an increased role of NCXvs.SERCA, consistent with a non-propagated peripheral Ca2+rise; 3)twitch force transitorily increased after abrupt reduction of intracellular Ca2+ buffering by the SERCA blocker CPA. Reduction in T-tubules density and/or increased cytosolic Ca2+buffering (e.g.increased myofilament Ca2+sensitivity) could be crucial in cAF for transition to propagated-CICR and Ca2+-wave spread impairment. Ca2+trigger enhancement or Ca2+diffusion improvement could promote recruitment of deeper myofibril layers and increase twitch force.