CALCIUM CYCLING PROTEINS AND FORCE-FREQUENCY-RELATIONSHIP IN HEART-FAILURE

Myocardial function, intracellular calcium and levels of calcium cycli ng proteins were analyzed in failing and nonfailing human myocardium. Myocardial function was evaluated by the isometric force-frequency rel ation, and intracellular calcium was studied by aequorin light emissio n. When stimulation frequency was increased above 30 min(-1), there wa s a continuous increase in isometric tension development in the nonfai ling myocardium. In contrast, in failing myocardium, frequency potenti ation of contractile force was blunted or inverse. As a consequence, a t higher rates of stimulation, twitch tension was reduced significantl y in failing compared to nonfailing human myocardium. Aequorin measure ments indicated that the contractile deficit in the failing myocardium at higher rates of stimulation is associated with decreased free intr acellular calcium concentration. Western blot analysis indicated that in the failing myo cardium protein levels of SR-Ca2+-ATPase are signif icantly reduced and protein levels of Na+-Ca2+-exchanger are significa ntly increased. Levels of phospholamban are slightly reduced in the fa iling myocardium, and ryanodine receptor and calsequestrin protein lev els an unchanged. There was a close positive correlation between the p rotein levels of SR-Ca2+-ATPase and frequency potentiation of contract ile force. From these data, we conclude that in failing compared to no nfailing human myocardium 1) force-frequency relation is blunted or in verse. 2) Frequency-dependence of contractile force is closely correla ted with frequency-dependence of intracellular calcium cycling. 3) Pro tein levels of SR-Ca2+-ATPase may determine frequency-dependence of sa rcoplasmic reticulum calcium release. 4) Calcium elimination by an inc reased number of Na+-Ca2+-exchanger molecules may be a compensatory me chanism to prevent diastolic calcium accumulation in failing myocardiu m with a reduced number of SR calcium pumps.