Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release

Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca transient. Synchronization of Ca release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca release slows the rise of the cytosolic Ca transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca transients were measured in ventricular myocytes using confocal line scan imaging. Ca transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca release was significantly less well spatially and temporally synchronized in field-stimulated HF versus control or LVH myocytes. Surprisingly, depolarization of HF cells to potentials where Ca currents (ICa) were maximal resynchronized SR Ca release. Correspondingly, decreases in the amplitude of ICa desynchronized SR Ca release in control, LVH, and HF myocytes to the same extent. HF myocytes had significant loss of phase 1 AP repolarization and smaller ICa density, which should both reduce Ca influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca release was desynchronized. SR Ca release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca influx induced in part by alterations in early repolarization of the AP. Therefore, therapies that restore normal early repolarization should improve the contractility of the failing heart.