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

JUAN IGNACIO ELIO MARIÁNGELO; CECILIA MUNDIÑA-WEILENMANN; LUIS GONANO; MATILDE SAID; LUIS GONANO; MATILDE SAID; LETICIA VITTONE; LETICIA VITTONE; JUAN IGNACIO ELIO MARIÁNGELO; CECILIA MUNDIÑA-WEILENMANN

Rosario

Congreso; REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE FISIOLOGÍA; 2019

Sociedad Argentina de Fisiología

One of the earliest cardiovascular alterations produced by hypertension is the left ventricular hypertrophy (LVH). This abnormal increase in the LV mass is now recognized as an independent risk factor for poorer cardiovascular outcome. Among other complications, LVH shows an increased propensity to alternans. At the cellular level, alternans is a cyclic beat-to-beat oscillation in contraction amplitude (mechanical alternans), action potential duration (APD alternans), or cytosolic Ca2+ transient amplitude (Ca2+ alternans) at a constant heart rate. Clinically, these alterations are causally linked to severe arrhythmias. Evidence suggests an important role of a defective sarcoplasmic reticulum (SR) Ca2+ cycling in the genesis of alternans. In previous studies we demonstrated that the hypertrophied myocardium of spontaneously hypertensive rats (SHR) showed an increased propensity to mechanical alternans vs. normotensive rats (W). The aim of the present work was to establish whether Ca2+ alternans were involved in the genesis of the mechanical alternans detected in ex vivo hearts. To this purpose, isolated cardiac myocytes from 12 months-SHR and W rats, loaded with FURA2-AM, were paced from 0.5 to 5Hz to induce alternans and Ca2+ signal was analyzed by IonOptix system. Ca2+ alternans appeared in W myocytes at 4.25±0.48Hz (n=4) and in SHR myocytes at a significantly lower frequency (2.96±0.14Hz, n=7). 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) suggesting a slowed down recovery from refractoriness in SHR myocytes. Confocal microscopy studies confirmed Ca2+ alternans in SHR myocytes. Our results indicate that the increased susceptibility to alternans in SHR rats depends on a defective SR Ca2+ cycling, based on a re-lengthening of refractoriness of SR Ca2+ release, without alteration in SR Ca2+ uptake.