title: Cellular basis of abnormal calcium transients of failing human ventricular myocytes.
abstract: Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca2+]i. This study examined the respective roles of the L-type Ca2+ current (ICa), SR Ca2+ uptake, storage and release, Ca2+ transport via the Na+-Ca2+ exchanger (NCX), and Ca2+ buffering in the altered Ca2+ transients of failing human ventricular myocytes. Electrophysiological techniques were used to measure and control V(m) and measure I(m), respectively, and Fluo-3 was used to measure [Ca2+]i in myocytes from nonfailing (NF) and failing (F) human hearts. Ca2+ transients from F myocytes were significantly smaller and decayed more slowly than those from NF hearts. Ca2+ uptake rates by the SR and the amount of Ca2+ stored in the SR were significantly reduced in F myocytes. There were no significant changes in the rate of Ca2+ removal from F myocytes by the NCX, in the density of NCX current as a function of [Ca2+]i, ICa density, or cellular Ca2+ buffering. However, Ca2+ influx during the late portions of the action potential seems able to elevate [Ca2+]i in F but not in NF myocytes. A reduction in the rate of net Ca2+ uptake by the SR slows the decay of the Ca2+ transient and reduces SR Ca2+ stores. This leads to reduced SR Ca2+ release, which induces additional Ca2+ influx during the plateau phase of the action potential, further slowing the decay of the Ca2+ transient. These changes can explain the defective Ca2+ transients of the failing human ventricular myocyte.
authors.affiliation: Molecular and Cellular Cardiology Laboratories, Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pa 19140, USA.
authors.forename: Valentino
authors.initials: V
authors.lastname: Piacentino
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Jutta
authors.initials: J
authors.lastname: Weisser-Thomas
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000200:Action Potentials; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000502:physiology; D004553:Electric Conductivity; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D017136:Ion Transport; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000502:physiology
chemical_list: D019831:Sodium-Calcium Exchanger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium