ALTERATIONS IN INTRACELLULAR CALCIUM HANDLING ASSOCIATED WITH THE INVERSE FORCE-FREQUENCY RELATION IN HUMAN DILATED CARDIOMYOPATHY

Background The present study was performed to test the hypothesis that the altered force-frequency relation in human failing dilated cardiomyopathy may be attributed to alterations in intracellular calcium handling. Methods and Results The force-frequency relation was investigated in isometrically contracting ventricular muscle strip preparations from 5 nonfailing human hearts and 7 hearts with end-stage failing dilated cardiomyopathy. Intracellular calcium cycling was measured simultaneously by use of the bioluminescent photoprotein aequorin. Stimulation frequency was increased stepwise from 15 to 180 beats per minute (37 degrees C). In nonfailing myocardium, twitch tension and aequorin light emission rose with increasing rates of stimulation. Maximum average twitch tension was reached at 150 min(-1) and was increased to 212+/-34% (P<.05) of the value at 15 min(-1) Aequorin light emission was lowest at 15 min(-1) and was maximally increased at 180 min(-1) to 218+/-39% (P<.01). In the failing myocardium, average isometric tension was maximum at 60 min(-1) (106+/-7% of the basal value at 15 min(-1), P=NS) and then decreased continuously to 62+/-9% of the basal value at 180 min(-1) (P<.002). In the failing myocardium, aequorin light emission was highest at 15 min(-1). At 180 min(-1), it was decreased to 71+/-7% of the basal value (P<.01). Including both failing and nonfailing myocardium, there was a close correlation between the frequencies at which aequorin light emission and isometric tension were maximum (r=.92; n=19; P<.001). Action potential duration decreased similarly with increasing stimulation frequencies in nonfailing and end-stage failing myocardium. Sarcoplasmic reticulum Ca-45(2+) uptake, measured in homogenates from the same hearts, was significantly reduced in failing myocardium (3.60+/-0.51 versus 1.94+/-0.18 (nmol/L) . min(-1) . mg protein(-1), P<.005). Conclusions These data indicate that the altered force-frequency relation of the failing human myocardium results from disturbed excitation-contraction coupling with decreased calcium cycling at higher rates of stimulation.