Increased cardiomyocyte function and Ca²⁺ transients in mice during early congestive heart failure

Abstract 

End-stage heart failure is believed to involve depressed cardiomyocyte contractility and Ca²⁺ transients. However, the time course of these alterations is poorly understood. We examined alterations in myocyte excitation–contraction coupling in a mouse model of early congestive heart failure (CHF) following myocardial infarction. One week after myocardial infarction was induced by ligation of the left coronary artery, CHF mice were selected based on established criteria (increased left atrial diameter, increased lung weight). Sham-operated animals (SHAM) served as controls. Echocardiographic measurements showed decreased global function in early CHF relative to SHAM, but increased local function in viable regions of the myocardium which deteriorated with time. Cardiomyocytes isolated from the non-infarcted septum also exhibited larger contractions in early CHF than SHAM (CHF=219.6±15.3% of SHAM values, P<0.05; 1 Hz field stimulation), and relaxation was more rapid (time to 50% relaxation=82.9±5.5% of SHAM values, P<0.05). Ca²⁺ transients (fluo-4 AM) were larger and decayed more rapidly in CHF than SHAM during both field stimulation (1 Hz) and voltage-clamp steps. Sarcoplasmic reticulum (SR) Ca²⁺ content was increased. Western blots showed that while SR Ca²⁺ ATPase (SERCA) expression was unaltered in CHF, phospholamban (PLB) was downregulated (60±11% of SHAM values, P<0.05). Thus, an increased SERCA/PLB ratio in CHF may promote SR Ca²⁺ re-uptake. Additionally, peak L-type Ca²⁺ current and Na⁺/Ca²⁺ exchanger expression were increased in CHF, suggesting increased sarcolemmal Ca²⁺ flux. Thus, in early CHF, alterations in Ca²⁺ homeostasis improve cardiomyocyte contractility which may compensate for loss of function in the infarction area.

Keywords: Calcium, e–c coupling, Heart failure, Ventricular function, Sarcoplasmic reticulum function