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 cardiom yopathy may be attributed to alterations in intracellular calcium hand ling. Methods and Results The force-frequency relation was investigate d in isometrically contracting ventricular muscle strip preparations f rom 5 nonfailing human hearts and 7 hearts with end-stage failing dila ted cardiomyopathy. Intracellular calcium cycling was measured simulta neously by use of the bioluminescent photoprotein aequorin. Stimulatio n frequency was increased stepwise from 15 to 180 beats per minute (37 degrees C). In nonfailing myocardium, twitch tension and aequorin lig ht 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 low est 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 myo cardium, there was a close correlation between the frequencies at whic h aequorin light emission and isometric tension were maximum (r=.92; n =19; P<.001). Action potential duration decreased similarly with incre asing stimulation frequencies in nonfailing and end-stage failing myoc ardium. Sarcoplasmic reticulum Ca-45(2+) uptake, measured in homogenat es from the same hearts, was significantly reduced in failing myocardi um (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-freq uency relation of the failing human myocardium results from disturbed excitation-contraction coupling with decreased calcium cycling at high er rates of stimulation.