A defective sarcoplasmic reticulum Ca2+ cycling is linked to the increased susceptibility to Ca2+ alternans of the hypertrophied myocardium.

MARIÁNGELO JIE; GONANO L; VITTONE L.; MUNDIÑA - WEILENMANN C; SAID M

Rosario

Congreso; Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS); 2019

Sociedad Argentina de Fisiologia

One of the earliest cardiovascular alterations produced by hypertension is the left ventricular hypertrophy (LVH).This abnormal increase in LV mass is recognized as an independent risk factor for poorer cardiovascular outcome. Among other complications, LVH shows an increased propensity to cardiac alternans. Clinically, these alterations create a highly arrhythmogenic substrate. At the cellular level, alternans is a cyclic beat-to-beat oscillation in contraction amplitude (mechanical alternans), action potential duration (APD alternans) and/or cytosolic Ca2+ transient amplitude (Ca2+ alternans) at a constant heart rate. The emerging consensus is that cardiac alternans is ultimately linked to a defective sarcoplasmic reticulum (SR) Ca2+ cycling. In previous studies in ex vivo hearts, we demonstrated an increased propensity to mechanical alternans in the hypertrophied myocardium of spontaneously hypertensive rats (SHR) vs. normotensive rats (W). To further characterize these beat-to-beat fluctuations, isolated cardiac myocytes from SHR and W rats were loaded with the fluorescent Ca2+ probe FURA2-AM and paced between 0.5 and 5Hz to induce alternans. The threshold frequency for Ca2+alternans was significantly lower in SHR myocytes than in W myocytes (3.19±0.29Hz, n=8 vs 4.03±0.22Hz, n=8). SR Ca2+ uptake, indirectly evaluated by the frequency-dependent relaxant effect (half time for Ca2+ decline), was not different between both strains. The refractoriness of SR Ca2+ release was evaluated by the Ca2+ transient restitution at different time interval (Ti) between electrical stimulation. Ti at 50% restitution was significantly prolonged in SHR vs W myocytes (in msec:339.0±6.7, n=14 vs 311.1±5.9, n=8). Confocal microscopy studies confirmed Ca2+ alternans in SHR myocytes. Our results indicate that the increased susceptibility to cardiac alternans in SHR rats was associated to a defective SR Ca2+ cycling, based on a slowed down recovery from refractoriness of SR Ca2+ release, without alteration in SR Ca2+ uptake.