Excitation–contraction coupling in human heart failure examined by action potential clamp in rat cardiac myocytes

The effect of the loss of the notch in the human action potential (AP) during heart failure was examined by voltage clamping rat ventricular myocytes with human APs and recording intracellular Ca2+ with fluorescent dyes. Loss of the notch resulted in about a 50% reduction in the initial phase of the Ca2+ transient due to reduced ability of the l-type Ca2+ channel to trigger release. The failing human AP increased non-uniformity of cytosolic Ca2+, with some cellular regions failing to elicit Ca2+-induced Ca2+ release from the sarcoplasmic reticulum. In addition, there was an increase in the occurrence of late Ca2+ sparks. Monte-Carlo simulations of spark activation by l-type Ca2+ current supported the idea that the decreased synchrony of Ca2+ spark production associated with the loss of the notch could be explained by reduced Ca2+ influx from open Ca2+ channels. We conclude that the notch of the AP is critical for efficient and synchronous EC coupling and that the loss of the notch will reduce the SR Ca2+ release in heart failure, without changes in (for example) SR Ca2+-ATPase uptake.