© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure
aLaboratory of Experimental Cardiology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
bCenter for Experimental Surgery and Anesthesiology, University of Leuven, Leuven, Belgium
cInterdisciplinary Research Center, University of Leuven-Kortrijk, Leuven, Belgium
* Corresponding author. Tel. (+32-16) 34 71 53; Fax (+32-16) 34 58 44; E-mail: karin.sipido@med.kuleuven.ac.be
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°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 
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.
KEYWORDS Heart failure; Humans; Single cells; Calcium; Calcium channel; Sarcoplasmic reticulum; Frequency potentiation
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