title: Alterations in early action potential repolarization causes localized failure of sarcoplasmic reticulum Ca2+ release.
abstract: Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca2+ transient. Synchronization of Ca2+ release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca2+ transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca2+ release slows the rise of the cytosolic Ca2+ transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca2+ transients were measured in ventricular myocytes using confocal line scan imaging. Ca2+ transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca2+ 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 Ca2+ currents (ICa) were maximal resynchronized SR Ca2+ release. Correspondingly, decreases in the amplitude of ICa desynchronized SR Ca2+ 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 Ca2+ influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca2+ release was desynchronized. SR Ca2+ release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca2+ 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.
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Temple University, School of Medicine, Philadelphia, Pa 19140, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Harris
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Mills
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Remus M
authors.initials: RM
authors.lastname: Berretta
authors.forename: V Scott
authors.initials: VS
authors.lastname: Votaw
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001018:Aortic Diseases / Q000150:complications; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002415:Cats; D003251:Constriction, Pathologic / Q000150:complications; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000473:pathology; D017136:Ion Transport; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D002118:Calcium