Relation between myocardial function and expression of sarcoplasmic reticulum Ca²⁺-ATPase in failing and nonfailing human myocardium

Expression of sarcoplasmic reticulum (SR) Ca²⁺-ATPase was shown to be reduced in failing human myocardium. The functional relevance of this finding, however, is not known. We investigated the relation between myocardial function and protein levels of SR Ca²⁺-ATPase in nonfailing human myocardium (8 muscle strips from 4 hearts) and in myocardium from end-stage failing hearts with dilated (10 muscle strips from 9 hearts) or ischemic (7 muscle strips from 5 hearts) cardiomyopathy. Myocardial function was evaluated by the force-frequency relation in isometrically contracting muscle strip preparations (37°C, 30 to 180 min^-1). In nonfailing myocardium, twitch tension rose with increasing rates of stimulation and was 76% higher at 120 min^-1 compared with 30 min^-1 (P<.02). In failing myocardium, there was no significant increase in average tension at stimulation rates above 30 min^-1. At 120 min^-1, twitch tension was decreased by 59% (P<.05) in dilated cardiomyopathy and 76% (P<.05) in ischemic cardiomyopathy compared with nonfailing myocardium. Protein levels of SR Ca²⁺-ATPase, normalized per total protein or per myosin, were reduced by 36% (P<.02) or 32% (P<.05), respectively, in failing compared with nonfailing myocardium. SR Ca²⁺-ATPase protein levels were closely related to SR Ca²⁺ uptake, measured in homogenates from the same hearts (r=.70, n=16, and P<.005). For all types of myocardium, there was a significant correlation between SR Ca²⁺-ATPase protein levels and the frequency at which twitch tension was maximum (r=.74, n=18, and P<.001 in the case of normalization per total protein). Similarly, SR Ca²⁺-ATPase protein levels were correlated with the potentiation of twitch tension after an increase in stimulation frequency from 30 to 120 min^-1 (r=.80, n=18, and P<.001). These data show that the protein levels of SR Ca²⁺-ATPase are closely related to the force-frequency behavior of human myocardium. This may suggest that protein levels of SR Ca²⁺-ATPase determine the systolic contractile reserve with respect to frequency potentiation of contractile force in the human myocardium.