In human ventricular myocytes from failing hearts, Ca2+ release from the sarcoplasmic reticulum decreased at stimulation frequencies ≥0.5 Hz, contributing to the negative force-frequency relation.
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 (nhearts = 5 ncells = 15) or dilated cardiomyopathy (nhearts = 6, ncells = 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 (APD90) 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 > or = 0.5 Hz, more pronounced in dilated than in ischemic cardiomyopathy. Inhibition of ICaL 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.
Karin R. Sipido (Sun,) conducted a other in End-stage heart failure (ischemic or dilated cardiomyopathy) (n=11). Stimulation frequencies ≥0.5 Hz vs. Lower stimulation frequencies was evaluated on Amplitude of Ca2+ release from the sarcoplasmic reticulum and L-type Ca2+ current. In human ventricular myocytes from failing hearts, Ca2+ release from the sarcoplasmic reticulum decreased at stimulation frequencies ≥0.5 Hz, contributing to the negative force-frequency relation.