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(Circulation Research. 1999;85:1009.)
© 1999 American Heart Association, Inc.

Cellular Biology

Upregulation of Na⁺/Ca²⁺ Exchanger Expression and Function in an Arrhythmogenic Rabbit Model of Heart Failure

Steven M. Pogwizd, Ming Qi, Weilong Yuan, Allen M. Samarel, Donald M. Bers

From the University of Illinois at Chicago (S.M.P.), Section of Cardiology, Chicago, and Loyola University Chicago, Department of Physiology and Cardiovascular Institute (M.Q., W.Y., A.M.S., D.M.B.), Maywood, Ill.

Correspondence to Steven M. Pogwizd, MD, Section of Cardiology, University of Illinois at Chicago, 840 S Wood Street, M/C 787, Chicago, IL 60612-7323.

Abstract—Three-dimensional cardiac mapping in rabbits with nonischemic cardiomyopathy has shown that ventricular arrhythmias initiate by a nonreentrant mechanism that may be due to triggered activity from delayed afterdepolarizations. Delayed afterdepolarizations are thought to be due to spontaneous release of Ca²⁺ from the sarcoplasmic reticulum (SR) and consequent activation of an inward Na⁺/Ca²⁺ exchange (NaCaX) current. The goal of this study was to determine whether there is enhanced NaCaX gene expression and functional activity that may contribute to nonreentrant activation. Heart failure (HF) was induced in rabbits by combined aortic insufficiency and aortic constriction. HF rabbits had left ventricular enlargement (left ventricular end-diastolic dimension increased from 1.43±0.03 to 1.97±0.05 cm) and severely depressed function (fractional shortening reduced from 37% to 26%, P<0.02). Heart-to-body weight was increased by 79% in HF. Western blots showed a 93% increase in NaCaX protein in HF (P<0.04). NaCaX mRNA (7-kb transcript) was increased by 104% relative to the 18S rRNA in HF. A 14-kb NaCaX transcript was also seen in the HF rabbits, raising total NaCaX mRNA to 2.7-fold compared with controls. The amplitude of caffeine-induced contractures, used to assess SR Ca²⁺ load, was not significantly different in HF. Relaxation and [Ca²⁺]_i decline during caffeine-induced contractures is attributable to Ca²⁺ transport by NaCaX and was 61% and 45% faster in HF (P<0.05), respectively. NaCaX current measured under controlled voltage clamp conditions was also 2-fold higher in HF cells. SR Ca²⁺-ATPase mRNA and protein levels and Ca²⁺ current density were not significantly altered in HF. Twitch amplitudes from HF myocytes were 26% smaller compared with control (P<0.02), but twitch relaxation and [Ca²⁺]_i decline (due largely to SR Ca²⁺-ATPase) were not altered. Thus myocytes and myocardium from HF rabbits exhibit enhanced NaCaX expression and function. The enhanced NaCaX activity may contribute to depressed contractions, increased transient inward current (for a given SR Ca²⁺ release), delayed afterdepolarizations, and nonreentrant initiation of ventricular tachycardia in this arrhythmogenic model of HF.

Key Words: heart failure • Na⁺/Ca²⁺ exchange • ventricular tachycardia • delayed afterdepolarization • Ca²⁺

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				R. Shenoy, I. Klein, and K. Ojamaa Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1690 - H1696. [Abstract] [Full Text] [PDF]

				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]

				J. Meszaros, D. Khananshvili, and G. Hart Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricular myocytes of rats Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H903 - H914. [Abstract] [Full Text] [PDF]

				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]

				M. Shigekawa and T. Iwamoto Cardiac Na+-Ca2+ Exchange : Molecular and Pharmacological Aspects Circ. Res., May 11, 2001; 88(9): 864 - 876. [Abstract] [Full Text] [PDF]

				J. Yamashita, M. Itoh, T. Kuro, Y. Kobayashi, M. Ogata, M. Takaoka, and Y. Matsumura Pre- or Post-Ischemic Treatment with a Novel Na+/Ca2+ Exchange Inhibitor, KB-R7943, Shows Renal Protective Effects in Rats with Ischemic Acute Renal Failure J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 412 - 419. [Abstract] [Full Text]

				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]

				K. L. Golden, J. Ren, J. O'Connor, A. Dean, S. E. DiCarlo, and J. D. Marsh In vivo regulation of Na/Ca exchanger expression by adrenergic effectors Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1376 - H1382. [Abstract] [Full Text] [PDF]

				C. R. Weber, K. S. Ginsburg, K. D. Philipson, T. R. Shannon, and D. M. Bers Allosteric Regulation of Na/Ca Exchange Current by Cytosolic Ca in Intact Cardiac Myocytes J. Gen. Physiol., February 1, 2001; 117(2): 119 - 132. [Abstract] [Full Text] [PDF]

				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]

				K. R. Sipido Local Ca2+ Release in Heart Failure : Timing Is Important Circ. Res., November 24, 2000; 87(11): 966 - 968. [Full Text] [PDF]

				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]

				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]

				S. R. Houser When Does Spontaneous Sarcoplasmic Reticulum CA2+ Release Cause a Triggered Arrythmia? Cellular Versus Tissue Requirements Circ. Res., October 27, 2000; 87(9): 725 - 727. [Full Text] [PDF]

				K. Schlotthauer and D. M. Bers Sarcoplasmic Reticulum Ca2+ Release Causes Myocyte Depolarization : Underlying Mechanism and Threshold for Triggered Action Potentials Circ. Res., October 27, 2000; 87(9): 774 - 780. [Abstract] [Full Text] [PDF]

				K. R. Sipido, P. G. A. Volders, S. H. M. de Groot, F. Verdonck, F. Van de Werf, H. J. J. Wellens, and M. A. Vos Enhanced Ca2+ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes : Potential Link Between Contractile Adaptation and Arrhythmogenesis Circulation, October 24, 2000; 102(17): 2137 - 2144. [Abstract] [Full Text] [PDF]

				S. M. Pogwizd Increased Na+-Ca2+ Exchanger in the Failing Heart Circ. Res., October 13, 2000; 87(8): 641 - 643. [Full Text] [PDF]

				I. A. Hobai and B. O'Rourke Enhanced Ca2+-Activated Na+-Ca2+ Exchange Activity in Canine Pacing-Induced Heart Failure Circ. Res., October 13, 2000; 87(8): 690 - 698. [Abstract] [Full Text] [PDF]

				P. Trouve, F. Carre, I. Belikova, C. Leclercq, T. Dakhli, L. Soufir, I. Coquard, J. Ramirez-Gil, and D. Charlemagne Na+-K+-ATPase alpha 2-isoform expression in guinea pig hearts during transition from compensation to decompensation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1972 - H1981. [Abstract] [Full Text] [PDF]

				W. H. Barry Na+-Ca2+ Exchange in Failing Myocardium : Friend or Foe? Circ. Res., September 29, 2000; 87(7): 529 - 531. [Full Text] [PDF]

				S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]

				D. M. Bers Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction Circ. Res., August 18, 2000; 87(4): 275 - 281. [Full Text] [PDF]