© 1999 American Heart Association, Inc.
Original Contribution |
Mechanisms of Altered Excitation-Contraction Coupling in Canine Tachycardia-Induced Heart Failure, I
Experimental Studies
From the Section of Molecular and Cellular Cardiology, Division of Cardiology, Department of Medicine, The Johns Hopkins University, Balti-more, Md.
Correspondence to Brian O'Rourke, PhD, Division of Cardiology, Department of Medicine, The Johns Hopkins University, 844 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205. E-mail bor{at}jhmi.edu
Abstract—Pacing-induced
heart failure in the dog recapitulates many of the
electrophysiological and
hemodynamic abnormalities of the human disease;
however, the mechanisms underlying altered Ca2+ handling
have not been investigated in this model. We now show that left
ventricular midmyocardial myocytes isolated from dogs
subjected to 3 to 4 weeks of rapid pacing have prolonged action
potentials and Ca2+ transients with reduced peaks, but
durations 
3-fold longer than controls. To discriminate between
action potential effects on Ca2+ kinetics and direct
changes in Ca2+ regulatory processes, voltage-clamp steps
were used to examine the time constant for cytosolic Ca2+
removal (
Ca). Ca was prolonged by just
35% in myocytes from failing hearts after fixed voltage steps in
physiological solutions (Ca control,
216±25 ms, n=17; Ca failing, 292±23 ms, n=22;
P<0.05), but this difference was markedly accentuated
when Na+/Ca2+ exchange was eliminated
(Ca control, 282±30 ms, n=13; Ca
failing, 576±83 ms, n=11; P<0.005). Impaired
sarcoplasmic reticular (SR) Ca2+ uptake and a greater
dependence on Na+/Ca2+ exchange for cytosolic
Ca2+ removal was confirmed by inhibiting SR
Ca2+ ATPase with cyclopiazonic acid, which
slowed Ca2+ removal more in control than in failing
myocytes. ß-Adrenergic stimulation of SR Ca2+ uptake in
cells from failing hearts sufficed only to accelerate Ca
to the range of unstimulated controls. Protein levels of SERCA2a,
phospholamban, and Na+/Ca2+ exchanger revealed
a pattern of changes qualitatively similar to the functional
measurements; SERCA2a and phospholamban were both reduced in failing
hearts by 28%, and Na+/Ca2+ exchange protein
was increased 104% relative to controls. Thus, SR Ca2+
uptake is markedly downregulated in failing hearts, but this defect is
partially compensated by enhanced Na+/Ca2+
exchange. The alterations are similar to those reported in human heart
failure, which reinforces the utility of the pacing-induced dog model
as a surrogate for the human disease.
Key Words: excitation-contraction coupling • action potential • sarcoplasmic reticulum • Ca2+ uptake • heart failure
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M. T. Jiang, A. J. Lokuta, E. F. Farrell, M. R. Wolff, R. A. Haworth, and H. H. Valdivia Abnormal Ca2+ Release, but Normal Ryanodine Receptors, in Canine and Human Heart Failure Circ. Res., November 29, 2002; 91(11): 1015 - 1022. [Abstract] [Full Text] [PDF]
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R. Kaprielian, R. Sah, T. Nguyen, A. D. Wickenden, and P. H. Backx Myocardial infarction in rat eliminates regional heterogeneity of AP profiles, Ito K+ currents, and [Ca2+]i transients Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1157 - H1168. [Abstract] [Full Text] [PDF]
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I. Deschenes, D. DiSilvestre, G. J. Juang, R. C. Wu, W. F. An, and G. F. Tomaselli Regulation of Kv4.3 Current by KChIP2 Splice Variants: A Component of Native Cardiac Ito? Circulation, July 23, 2002; 106(4): 423 - 429. [Abstract] [Full Text] [PDF]
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 F. A. Tibayan, D. T. M. Lai, T. A. Timek, P. Dagum, D. Liang, G. T. Daughters, N. B. Ingels, and D. C. Miller Alterations in left ventricular torsion in tachycardia-induced dilated cardiomyopathy J. Thorac. Cardiovasc. Surg., July 1, 2002; 124(1): 43 - 49. [Abstract] [Full Text] [PDF]
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J. Kneller, H. Sun, N. Leblanc, and S. Nattel Remodeling of Ca2+-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation Cardiovasc Res, May 1, 2002; 54(2): 416 - 426. [Abstract] [Full Text] [PDF]
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 E. TAKIMOTO, A. YAO, H. TOKO, H. TAKANO, M. SHIMOYAMA, M. SONODA, K. WAKIMOTO, T. TAKAHASHI, H. AKAZAWA, M. MIZUKAMI, et al. Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload FASEB J, March 1, 2002; 16(3): 373 - 378. [Abstract] [Full Text] [PDF]
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K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]
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R. Sah, R. J. Ramirez, and P. H. Backx Modulation of Ca2+ Release in Cardiac Myocytes by Changes in Repolarization Rate: Role of Phase-1 Action Potential Repolarization in Excitation-Contraction Coupling Circ. Res., February 8, 2002; 90(2): 165 - 173. [Abstract] [Full Text] [PDF]
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C. R. Weber, V. Piacentino III, K. S. Ginsburg, S. R. Houser, and D. M. Bers Na+-Ca2+ Exchange Current and Submembrane [Ca2+] During the Cardiac Action Potential Circ. Res., February 8, 2002; 90(2): 182 - 189. [Abstract] [Full Text] [PDF]
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S.-k. Wei, J. F Quigley, S. U Hanlon, B. O'Rourke, and M. C.P Haigney Cytosolic free magnesium modulates Na/Ca exchange currents in pig myocytes Cardiovasc Res, February 1, 2002; 53(2): 334 - 340. [Abstract] [Full Text] [PDF]
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J. B Sande, I. Sjaastad, I. B Hoen, J. Bokenes, T. Tonnessen, E. Holt, P. K Lunde, and G. Christensen Reduced level of serine16 phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity Cardiovasc Res, February 1, 2002; 53(2): 382 - 391. [Abstract] [Full Text] [PDF]
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U. Schotten, M. Greiser, D. Benke, K. Buerkel, B. Ehrenteidt, C. Stellbrink, J. F Vazquez-Jimenez, F. Schoendube, P. Hanrath, and M. Allessie Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort Cardiovasc Res, January 1, 2002; 53(1): 192 - 201. [Abstract] [Full Text] [PDF]
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C. L. Elias, A. Lukas, S. Shurraw, J. Scott, A. Omelchenko, G. J. Gross, M. Hnatowich, and L. V. Hryshko Inhibition of Na+/Ca2+ exchange by KB-R7943: transport mode selectivity and antiarrhythmic consequences Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1334 - H1345. [Abstract] [Full Text] [PDF]
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 S. Kaab and M. Nabauer Diversity of ion channel expression in health and disease Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K31 - K40. [Abstract] [PDF]
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H. SENZAKI, C. J. SMITH1, G. J. JUANG, T. ISODA, S. P. MAYER, A. OHLER, N. PAOLOCCI, G. F. TOMASELLI, J. M. HARE, and D. A. KASS Cardiac phosphodiesterase 5 (cGMP-specific) modulates {beta}-adrenergic signaling in vivo and is down-regulated in heart failure FASEB J, August 1, 2001; 15(10): 1718 - 1726. [Abstract] [Full Text] [PDF]
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S. Adachi-Akahane and Y. Kurachi New Era for Translational Research in Cardiac Arrhythmias Circ. Res., June 8, 2001; 88(11): 1095 - 1096. [Full Text] [PDF]
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R. Sah, R. J Ramirez, R. Kaprielian, and P. H Backx Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes J. Physiol., May 15, 2001; 533(1): 201 - 214. [Abstract] [Full Text] [PDF]
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P. B. Adamson and E. Vanoli Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: Characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1741 - 1748. [Abstract] [Full Text] [PDF]
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I. A. Hobai and B. O'Rourke Decreased Sarcoplasmic Reticulum Calcium Content Is Responsible for Defective Excitation-Contraction Coupling in Canine Heart Failure Circulation, March 20, 2001; 103(11): 1577 - 1584. [Abstract] [Full Text] [PDF]
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 C.-E. Laurent, R. Cardinal, G. Rousseau, M. Vermeulen, C. Bouchard, M. Wilkinson, J. A. Armour, and M. Bouvier Functional desensitization to isoproterenol without reducing cAMP production in canine failing cardiocytes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2001; 280(2): R355 - R364. [Abstract] [Full Text] [PDF]
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S. R Houser Reduced abundance of transverse tubules and L-type calcium channels: another cause of defective contractility in failing ventricular myocytes Cardiovasc Res, February 1, 2001; 49(2): 253 - 256. [Full Text] [PDF]
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J.-Q. He, M. W Conklin, J. D Foell, M. R Wolff, R. A Haworth, R. Coronado, and T. J Kamp Reduction in density of transverse tubules and L-type Ca2+ channels in canine tachycardia-induced heart failure Cardiovasc Res, February 1, 2001; 49(2): 298 - 307. [Abstract] [Full Text] [PDF]
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C. M.N. Terracciano, K. D. Philipson, and K. T. MacLeod Overexpression of the Na+/Ca2+ exchanger and inhibition of the sarcoplasmic reticulum Ca2+-ATPase in ventricular myocytes from transgenic mice Cardiovasc Res, January 1, 2001; 49(1): 38 - 47. [Abstract] [Full Text] [PDF]
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T. G. Hampton, J.-F. Wang, J. DeAngelis, I. Amende, K. D. Philipson, and J. P. Morgan Enhanced gene expression of Na+/Ca2+ exchanger attenuates ischemic and hypoxic contractile dysfunction Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2846 - H2854. [Abstract] [Full Text] [PDF]
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K. R. Sipido Local Ca2+ Release in Heart Failure : Timing Is Important Circ. Res., November 24, 2000; 87(11): 966 - 968. [Full Text] [PDF]
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S. Nattel Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders Cardiovasc Res, November 1, 2000; 48(2): 188 - 190. [Full Text] [PDF]
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C. M.N Terracciano Sarcoplasmic reticulum calcium release function and FK binding proteins in heart failure: another piece of a complex jigsaw Cardiovasc Res, November 1, 2000; 48(2): 191 - 193. [Full Text] [PDF]
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