Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure

Objectives: Human cardiac muscle from failing heart shows a decrease in active tension development and a rise in diastolic tension at stimulation frequencies above 50-60 beats/min due to both systolic and diastolic dysfunction. We have investigated underlying changes in cellular [Ca2+](i) regulation. Methods: Single ventricular myocytes were isolated enzymatically from the explanted hearts of transplant recipients with ischemic cardiomyopathy (n(hearts) = 5, n(cells) = 15) or dilated cardiomyopathy (n(hearts) = 6, n(cells) = 19). Cells were studied during whole-cell patch clamp with fluo-3 and fura-red as [Ca2+](i) indicators (36 +/- 1 degrees C). Results: In current clamp mode (action potential recording), the amplitude of Ca2+ release from the sarcoplasmic reticulum (SR) decreased at stimulation frequencies above 0.5 Hz: this decrease was more pronounced for cells from dilated cardiomyopathy. Diastolic [Ca2+](i) increased at 1 and 2 Hz for both groups. Action potential duration (APD(90)) decreased with frequency in all cells; in addition there was a drop in plateau potential of 10 +/- 1 mV for cells from ischemic cardiomyopathy and of 13 +/- 2 mV for cells from dilated cardiomyopathy. In voltage clamp mode the L-type Ca2+ current showed reversible decrease during stimulation at 1 and 2 Hz. Recovery from inactivation during a double pulse protocol was slow (75 +/- 3% at 500 ms, 89 +/- 3% at 1000 ms) and followed the decay of the [Ca2+](i) transient. Conclusions: The negative force-frequency relation of the failing human heart is due to a decrease in Ca2+ release of the cardiac myocytes at frequencies greater than or equal to 0.5 Hz, more pronounced in dilated than in ischemic cardiomyopathy. Inhibition of I-CaL at higher frequencies. at least partially related to an increase in diastolic [Ca2+](i), will contribute to this negative staircase because of a decrease in the trigger for Ca2+ release, and of decreased loading of the SR. (C) 1998 Elsevier Science B.V.