Circulation Research. 2003
Published online before print February 20, 2003, doi: 10.1161/01.RES.0000062469.83985.9B
Published online before print February 20, 2003, doi: 10.1161/01.RES.0000062469.83985.9B
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Submitted on August 6, 2002
Revised on January 29, 2003
Accepted on January 30, 2003
Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes
Valentino Piacentino III ;
From Molecular and Cellular Cardiology Laboratories (V.P., X.C., J.W.-T., K.B.M., S.R.H.), Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pa; and the Department of Physiology (C.R.W., D.M.B.), Loyola University Chicago, Stritch School of Medicine, Maywood, Ill.
* To whom correspondence should be addressed. E-mail: srhouser{at}unix.temple.edu.
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 Vm and measure Im, 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.
Key words: excitation-contraction coupling • sarcoplasmic reticulum • Na+-Ca2+ exchanger • congestive heart failure
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