Exercise Training Reduces Spontaneous Ca2+ Waves In Cardiomyocytes From Post-myocardial Infarction Heart Failure Rats

Abstract

Arrhythmias cause ∼50% of deaths in heart failure (HF), but no satisfactory treatment exists. An underlying scenario is the impaired control of cardiomyocyte intracellular diastolic Ca2+. Exercise training (ExTr) has the potency to correct abnormal Ca2+ handling in experimental models of HF, but several aspects remain unstudied. We induced myocardial infarctions (MI) by coronary artery ligation in Sprague-Dawley rats, which subsequently resulted in HF. MI was evidenced by echocardiography, indicating that 40±5% infarction of the left ventricle (LV), whereas HF was evidenced by increased LV end-diastolic pressures and decreased contraction-relaxation rates and exercise work capacity. Pathological remodeling was evidenced by increased LV cardiomyocyte lengths and widths. Spontaneous Ca2+ waves were measured by confocal linescanning after 488nm excitation and recording emission at 505-530nm in intact Fluo-3-loaded cardiomyocytes (2uM) at 37°C and at [Ca2+] 1.2mM and 5.0mM. These studies showed that spontaneous wave frequency was higher at 5.0mM than 1.2mM Ca2+. Post-MI HF cardiomyocytes had ∼twice the wave frequency compared to sham-operated controls. Regular ExTr post-MI improved exercise capacity and induced reverse remodeling. ExTr also reduced the frequency of spontaneous waves at both Ca2+ 1.2mM and 5.0mM, although it did not completely normalize spontaneous Ca2+ waves. ExTr also increased the ratio between aborted and complete waves at Ca2+ 1.2mM, but not Ca2+ 5.0mM. No effects were found on spontaneous wave velocity. This suggests that ExTr partly improved the control of diastolic Ca2+ by reducing the frequency of spontaneous Ca2+ waves and by improving the ability of the cardiomyocyte to eliminate a spontaneous wave after its generation, but before its propagation. Finally, we repeated these studies in the presence of the nitric oxide synthase inhibitor L-NAME, to study the contribution of nitric oxide. This did not have any effects.