This Article Full Text Full Text (PDF) All Versions of this Article: 108/21/2704    most recent 01.CIR.0000093276.10885.5Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Walker, M. L. Articles by Rosenbaum, D. S. Search for Related Content PubMed PubMed Citation Articles by Walker, M. L. Articles by Rosenbaum, D. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Electrophysiology Arrythmias-basic studies

(Circulation. 2003;108:2704.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Hysteresis Effect Implicates Calcium Cycling as a Mechanism of Repolarization Alternans

From The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio.

Correspondence to David S. Rosenbaum, MD, Director, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamman 330, Cleveland, OH 44109-1998. E-mail drosenbaum{at}metrohealth.org

Received May 27, 2003; revision received July 18, 2003; accepted July 21, 2003.

Background— T-wave alternans is due to alternation of membrane repolarization at the cellular level and is a risk factor for sudden cardiac death. Recently, a hysteresis effect has been reported in patients whereby T-wave alternans, once induced by rapid heart rate, persists even when heart rate is subsequently slowed. We hypothesized that alternans hysteresis is an intrinsic property of cardiac myocytes, directly related to an underlying mechanism for repolarization alternans that involves intracellular calcium cycling.

Methods and Results— Stepwise pacing was used to induce alternans in Langendorff-perfused guinea pig hearts from which optical action potentials were recorded simultaneously at 256 ventricular sites with voltage-sensitive dyes and in whole-cell patch-clamped cardiac myocytes treated with or without BAPTA-AM (1,2-bis[2-aminophenoxy]ethane-N,N,N',N'-tetraacetic acid tetrakis [acetoxymethyl ester]). Alternans hysteresis was observed in every isolated heart: threshold heart rate for alternans was 280±12 bpm, but during subsequent deceleration of pacing, alternans persisted to significantly slower heart rates (238±5 bpm, P<0.05). Optical mapping showed that this effect also applied to the threshold for spatially discordant alternans (313±2.2 bpm during acceleration versus 250±6.6 bpm during deceleration, P<0.05). Alternans hysteresis was also observed in isolated cardiac myocytes. Moreover, calcium chelation by BAPTA-AM raised the threshold for alternans and inhibited hysteresis in a dose-dependent manner with no effect on baseline action potential duration.

Conclusions— Alternans hysteresis is an intrinsic property of cardiac myocytes that can lead to persistence of arrhythmogenic discordant alternans even after heart rate is slowed. These results also support an important underlying role of calcium cycling in the mechanism of alternans.

Key Words: electrophysiology • calcium • arrhythmia

This article has been cited by other articles:

				D. Guo, L. Young, C. Patel, Z. Jiao, Y. Wu, T. Liu, P. R. Kowey, and G.-X. Yan Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H97 - H104. [Abstract] [Full Text] [PDF]

				P. N. Jordan and D. J. Christini Characterizing the contribution of voltage- and calcium-dependent coupling to action potential stability: implications for repolarization alternans Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2109 - H2118. [Abstract] [Full Text] [PDF]

				Z. Qu and J. N. Weiss The chicken or the egg? Voltage and calcium dynamics in the heart Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2054 - H2055. [Full Text] [PDF]

				G. A. Ng, K. E. Brack, V. H. Patel, and J. H. Coote Autonomic modulation of electrical restitution, alternans and ventricular fibrillation initiation in the isolated heart Cardiovasc Res, March 1, 2007; 73(4): 750 - 760. [Abstract] [Full Text] [PDF]

				S. M. Narayan T-Wave Alternans and the Susceptibility to Ventricular Arrhythmias J. Am. Coll. Cardiol., January 17, 2006; 47(2): 269 - 281. [Abstract] [Full Text] [PDF]

				J. N. Weiss, Z. Qu, P.-S. Chen, S.-F. Lin, H. S. Karagueuzian, H. Hayashi, A. Garfinkel, and A. Karma The Dynamics of Cardiac Fibrillation Circulation, August 23, 2005; 112(8): 1232 - 1240. [Abstract] [Full Text] [PDF]

				P. A. Boyden and H. E.D.J. ter Keurs An Intimate Relationship: Ca2+ and Cardiac Ion Channels Circ. Res., March 4, 2005; 96(4): 393 - 394. [Full Text] [PDF]

				E. J. Pruvot, R. P. Katra, D. S. Rosenbaum, and K. R. Laurita Role of Calcium Cycling Versus Restitution in the Mechanism of Repolarization Alternans Circ. Res., April 30, 2004; 94(8): 1083 - 1090. [Abstract] [Full Text] [PDF]

				K. R. Sipido Understanding Cardiac Alternans: The Answer Lies in the Ca2+ Store Circ. Res., March 19, 2004; 94(5): 570 - 572. [Full Text] [PDF]