Development Of Calcium Handling Defects During Aging In Spontaneously Hypertensive Rats

Several defects in calcium handling have been identified in failing myocytes. We investigated the progression of these defects in the course of development of overt heart failure (HF). Intracellular Ca2+ transients were measured using confocal microscopy in intact hearts from age-matched Wistar-Kyoto (WKY) control rats and Spontaneously Hypertensive Rats (SHR) at 6, 7.5, 9 and >22 months of age. Amplitude of basal Ca2+ transients (cycle length of 700msec) in SHR increased at 7.5 and 9 months, but subsequently decreased at 22 months compared to WKY. SHR myocytes exhibited longer transient duration starting at 9 months compared to WKY. Cell-to-cell variability in transient duration increased at 7.5 months and subsequently decreased at 9 months as defects became more extensive. At 22 months, Ca2+ transients showed further increases in transient duration and intercellular variability. Restitution of Ca2+ release was slowed and was paralleled by increased Ca2+ alternans susceptibility starting at 9 months in SHR. Dyssynchronous alternans incidence increased beginning at 7.5 months in SHR compared to WKY. SHR myocytes also demonstrated an increased incidence of spontaneous Ca2+ waves at all ages, with the greatest difference at 22 months. A separate population of SHR myocytes showed Ca2+ waves that were activated during pacing (“triggered waves”) whose incidence increased at all ages but most profoundly at 22 months. We conclude that well-coupled failing myocytes demonstrate progressively increasing defects in Ca2+ cycling. Biphasic changes in calcium transient magnitude may partially account for a transient inotropic effect during compensation but ultimately reduced cardiac output in HF. The progression of Ca2+ handling defects may also account for the increasing sensitivity to alternans as well as incidence of spontaneous and triggered Ca2+ waves with age, possibly explaining increased arrhythmias during progressive HF.