Influence of pyruvate on contractile performance and Ca2+ cycling in isolated failing human myocardium

Abstract

Background-Application of pyruvate was shown to improve contractile function in isolated animal myocardium and hemodynamics in patients with congestive heart failure. We assessed the influence of pyruvate on systolic and diastolic myocardial function and its subcellular mode of action in isolated myocardium. from end-stage failing human hearts. Methods and Results-In muscle strip preparations, concentration-dependent effects of pyruvate on developed and diastolic force (n=6), aequorin light emission reflecting intracellular Ca2+ transients (n=6), and rapid cooling contractures reflecting sarcoplasmic reticulum (SR) Ca2+ content (n=11) were measured. Pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force, with a maximum effect of 155% and 21%, respectively, at 20 mmol/L pyruvate (P<0.05). This was associated with a dose-dependent prolongation of time to peak tension and relaxation time. Pyruvate increased rapid cooling contractures by 51% and aequorin light signals by 85% (at 15 and 20 mmol/L; P<0.05). This indicates increased SR Ca2+ content and increased intracellular Ca2+ transients. The inotropic effect of pyruvate was still present after elimination of SR Ca2+ storage function with 10 mumol/L cyclopiazonic acid and I mumol/L ryanodine (n=8). Pyruvate significantly increased intracellular pH from 7.31+/-0.03 to 7.40+/-0.04 by BCECF fluorescence (n=6). Conclusions-The present findings indicate that pyruvate improves contractile performance of failing human myocardium by increasing a intracellular Ca2+ transients as well as myofilament Ca2+ sensitivity. The former seem to result from increased SR Ca2+ accumulation and release, the latter from increased intracellular pH.