Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice.

Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca(2+) homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals ( approximately 2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 +/- 0.1 vs. 1.9 +/- 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca(2+) transient time to peak values were prolonged in chronic CHF (115 +/- 6 and 158 +/- 11% sham values, respectively). Surprisingly, contraction and Ca(2+) transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca(2+) content and greater Ca(2+) influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca(2+) transients suggest that slowing of Ca(2+) release is a critical mediator of CHF progression.