Altered Ca Homeostasis and Ca Alternans in Left Atrial Myocytes of Spontaneously Hypertensive Rats

Abstract

Chronic hypertension can cause atrial fibrillation. The cellular mechanisms responsible for hypertension-induced atrial tachyarrhythmias, however, are unknown. Here we tested the hypothesis that, in spontaneously hypertensive rats (SHR), altered atrial Ca homeostasis may induce atrial tachyarrhythmias.At 6-8 months of age, SHR had significantly increased systolic blood pressure (185±6 mmHg, N=18; vs WKY: 129±4 mmHg, N=16, P<0.01), accompanied by compensatory left ventricular hypertrophy, but left atrial (LA) hypotrophy. At the cellular level, the area of the ventricular myocytes was increased in SHR, while LA myocytes were not different in size. Basal Ca transients (CaTs) of LA myocytes (1 Hz stimulation) showed no major differences between WKY and SHR. Further evaluation, however, revealed increased SR Ca load in SHR (amplitude of caffeine-induced CaT, Fura-2 ratio: 1.07±0.13, n=10; vs WKY: 0.72±0.04, n=18, P<0.01), reduced fractional SR Ca release (SHR: 0.20±0.03, n=10; vs WKY: 0.29±0.03, n=18, P<0.05) and reduced L-type Ca current (SHR: −4.3±0.2 pA/pF, n=12; vs WKY: −5.2±0.1 pA/pF, n=10, P<0.05) accompanied by reduced expression (−33%; P<0.01) of the alpha 1C subunit of the L-type calcium channel. Experimental simulation of tachycardia by increasing stimulation frequency (1-2-4 Hz) induced significantly more arrhythmogenic Ca alternans in SHR (2 Hz: 41%, 4 Hz: 72% of cells) than in WKY (2 Hz: 7%, 4 Hz 37% of cells; both P<0.05 vs SHR) LA myocytes.These data indicate that, at 6-8 months of age, SHR hearts display morphological changes at the ventricular but not at the atrial level. Subcellular changes in Ca homeostasis occur in LA myocytes at the sarcolemma and the SR, which are associated with a much higher incidence of arrhythmogenic Ca alternans. This may explain the increased propensity of SHR to develop atrial tachyarrhythmias.