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°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 ⁴⁵Ca²⁺ 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.