This Article Full Text Full Text (PDF) All Versions of this Article: 94/5/650    most recent 01.RES.0000119923.64774.72v1 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 Díaz, M. E. Articles by Eisner, D. A. Search for Related Content PubMed PubMed Citation Articles by Díaz, M. E. Articles by Eisner, D. A. Related Collections Calcium cycling/excitation-contraction coupling

Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans

From the Unit of Cardiac Physiology, School of Medicine, University of Manchester, Manchester, UK.

Correspondence to David A. Eisner and Mary E. Díaz, Unit of Cardiac Physiology, School of Medicine, University of Manchester, 1.524 Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail eisner{at}man.ac.uk and mary.e.diaz@man.ac.uk

The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca²⁺ transient (Ca²⁺ alternans) is due to changes of sarcoplasmic reticulum (SR) Ca²⁺ content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca²⁺ content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca²⁺ transient. Confocal measurements showed that the larger transients resulted from propagation of Ca²⁺ waves. SR Ca²⁺ content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca²⁺ transient amplitude. After a large transient, if SR Ca²⁺ content was elevated by brief exposure of the cell to a Na⁺-free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca²⁺ content are sufficient to produce alternans. The dependence of Ca²⁺ transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca²⁺ efflux from the cell was also a steeper function of SR Ca²⁺ content than under control. We attribute these steeper relationships to the fact that the larger responses in alternans depend on wave propagation and that wave propagation is a steep function of SR Ca²⁺ content. In conclusion, alternans of systolic Ca²⁺ appears to depend on alternation of SR Ca²⁺ content. This, in turn results from the steep dependence on SR Ca²⁺ content of Ca²⁺ release and therefore Ca²⁺ efflux from the cell as a consequence of wave propagation.

Key Words: calcium • excitation-contraction coupling • alternans • sarcoplasmic reticulum

This article has been cited by other articles:

				L.-H. Xie, D. Sato, A. Garfinkel, Z. Qu, and J. N. Weiss Intracellular Ca Alternans: Coordinated Regulation by Sarcoplasmic Reticulum Release, Uptake, and Leak Biophys. J., September 15, 2008; 95(6): 3100 - 3110. [Abstract] [Full Text] [PDF]

				T. Tao, S. C. O'Neill, M. E. Diaz, Y. T. Li, D. A. Eisner, and H. Zhang Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H598 - H609. [Abstract] [Full Text] [PDF]

				F. R. Heinzel, V. Bito, L. Biesmans, M. Wu, E. Detre, F. von Wegner, P. Claus, S. Dymarkowski, F. Maes, J. Bogaert, et al. Remodeling of T-Tubules and Reduced Synchrony of Ca2+ Release in Myocytes From Chronically Ischemic Myocardium Circ. Res., February 15, 2008; 102(3): 338 - 346. [Abstract] [Full Text] [PDF]

				A. Mahajan, Y. Shiferaw, D. Sato, A. Baher, R. Olcese, L.-H. Xie, M.-J. Yang, P.-S. Chen, J. G. Restrepo, A. Karma, et al. A Rabbit Ventricular Action Potential Model Replicating Cardiac Dynamics at Rapid Heart Rates Biophys. J., January 15, 2008; 94(2): 392 - 410. [Abstract] [Full Text] [PDF]

				N. Liu and S. G. Priori Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin Cardiovasc Res, January 15, 2008; 77(2): 293 - 301. [Abstract] [Full Text] [PDF]

				W. T. Clusin Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H1 - H10. [Abstract] [Full Text] [PDF]

				J. M. Cordeiro, J. E. Malone, J. M. Di Diego, F. S. Scornik, G. L. Aistrup, C. Antzelevitch, and J. A. Wasserstrom Cellular and subcellular alternans in the canine left ventricle Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3506 - H3516. [Abstract] [Full Text] [PDF]

				D. Jiang, W. Chen, R. Wang, L. Zhang, and S. R. W. Chen Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death PNAS, November 13, 2007; 104(46): 18309 - 18314. [Abstract] [Full Text] [PDF]

				A. A. Fossa, T. Wisialowski, J. N. Duncan, S. Deng, and M. Dunne Azithromycin/Chloroquine Combination Does Not Increase Cardiac Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig Am J Trop Med Hyg, November 1, 2007; 77(5): 929 - 938. [Abstract] [Full Text] [PDF]

				L. D. Wilson and D. S. Rosenbaum Mechanisms of arrythmogenic cardiac alternans Europace, November 1, 2007; 9(suppl_6): vi77 - vi82. [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]

				J. F. Huizar, M. D. Warren, A. G. Shvedko, J. Kalifa, J. Moreno, S. Mironov, J. Jalife, and A. V. Zaitsev Three distinct phases of VF during global ischemia in the isolated blood-perfused pig heart Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1617 - H1628. [Abstract] [Full Text] [PDF]

				V. E. Bondarenko and R. L. Rasmusson Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1816 - H1832. [Abstract] [Full Text] [PDF]

				T. Y. Kim, S.-J. Woo, S.-m. Hwang, J. H. Hong, and K. J. Lee Cardiac beat-to-beat alternations driven by unusual spiral waves PNAS, July 10, 2007; 104(28): 11639 - 11642. [Abstract] [Full Text] [PDF]

				L. M. Livshitz and Y. Rudy Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2854 - H2866. [Abstract] [Full Text] [PDF]

				H. E. D. J. ter Keurs and P. A. Boyden Calcium and Arrhythmogenesis Physiol Rev, April 1, 2007; 87(2): 457 - 506. [Abstract] [Full Text] [PDF]

				J. Fauconnier, D. C. Andersson, S.-J. Zhang, J. T. Lanner, R. Wibom, A. Katz, J. D. Bruton, and H. Westerblad Effects of Palmitate on Ca2+ Handling in Adult Control and ob/ob Cardiomyocytes: Impact of Mitochondrial Reactive Oxygen Species Diabetes, April 1, 2007; 56(4): 1136 - 1142. [Abstract] [Full Text] [PDF]

				D. Sato, Y. Shiferaw, Z. Qu, A. Garfinkel, J. N. Weiss, and A. Karma Inferring the Cellular Origin of Voltage and Calcium Alternans from the Spatial Scales of Phase Reversal during Discordant Alternans Biophys. J., February 15, 2007; 92(4): L33 - L35. [Abstract] [Full Text] [PDF]

				T. Krogh-Madsen and D. J. Christini Action Potential Duration Dispersion and Alternans in Simulated Heterogeneous Cardiac Tissue with a Structural Barrier Biophys. J., February 15, 2007; 92(4): 1138 - 1149. [Abstract] [Full Text] [PDF]

				H. Hayashi, Y. Shiferaw, D. Sato, M. Nihei, S.-F. Lin, P.-S. Chen, A. Garfinkel, J. N. Weiss, and Z. Qu Dynamic Origin of Spatially Discordant Alternans in Cardiac Tissue Biophys. J., January 15, 2007; 92(2): 448 - 460. [Abstract] [Full Text] [PDF]

				E. Picht, J. DeSantiago, L. A. Blatter, and D. M. Bers Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations Circ. Res., September 29, 2006; 99(7): 740 - 748. [Abstract] [Full Text] [PDF]

				D. Sato, Y. Shiferaw, A. Garfinkel, J. N. Weiss, Z. Qu, and A. Karma Spatially Discordant Alternans in Cardiac Tissue: Role of Calcium Cycling Circ. Res., September 1, 2006; 99(5): 520 - 527. [Abstract] [Full Text] [PDF]

				J. N. Weiss, A. Karma, Y. Shiferaw, P.-S. Chen, A. Garfinkel, and Z. Qu From Pulsus to Pulseless: The Saga of Cardiac Alternans Circ. Res., May 26, 2006; 98(10): 1244 - 1253. [Abstract] [Full Text] [PDF]

				Y. Shiferaw and A. Karma Turing instability mediated by voltage and calcium diffusion in paced cardiac cells PNAS, April 11, 2006; 103(15): 5670 - 5675. [Abstract] [Full Text] [PDF]

				H. Bien, L. Yin, and E. Entcheva Calcium Instabilities in Mammalian Cardiomyocyte Networks Biophys. J., April 1, 2006; 90(7): 2628 - 2640. [Abstract] [Full Text] [PDF]

				L.-S. Song, E. A. Sobie, S. McCulle, W. J. Lederer, C. W. Balke, and H. Cheng Orphaned ryanodine receptors in the failing heart. PNAS, March 14, 2006; 103(11): 4305 - 4310. [Abstract] [Full Text] [PDF]

				P. N. Jordan and D. J. Christini Action Potential Morphology Influences Intracellular Calcium Handling Stability and the Occurrence of Alternans Biophys. J., January 15, 2006; 90(2): 672 - 680. [Abstract] [Full Text] [PDF]

				T. R. Shannon, F. Wang, and D. M. Bers Regulation of Cardiac Sarcoplasmic Reticulum Ca Release by Luminal [Ca] and Altered Gating Assessed with a Mathematical Model Biophys. J., December 1, 2005; 89(6): 4096 - 4110. [Abstract] [Full Text] [PDF]

				M. L. Koller, S. K.G. Maier, A. R. Gelzer, W. R. Bauer, M. Meesmann, and R. F. Gilmour Jr Altered Dynamics of Action Potential Restitution and Alternans in Humans With Structural Heart Disease Circulation, September 13, 2005; 112(11): 1542 - 1548. [Abstract] [Full Text] [PDF]

				L.-S. Song, Y. Pi, S.-J. Kim, A. Yatani, S. Guatimosim, R. K. Kudej, Q. Zhang, H. Cheng, L. Hittinger, B. Ghaleh, et al. Paradoxical Cellular Ca2+ Signaling in Severe but Compensated Canine Left Ventricular Hypertrophy Circ. Res., September 2, 2005; 97(5): 457 - 464. [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]

				J. Kockskamper, A. V. Zima, and L. A. Blatter Modulation of sarcoplasmic reticulum Ca2+ release by glycolysis in cat atrial myocytes J. Physiol., May 1, 2005; 564(3): 697 - 714. [Abstract] [Full Text] [PDF]

				H. J. Knot, I. Laher, E. A. Sobie, S. Guatimosim, L. Gomez-Viquez, H. Hartmann, L.-S. Song, W.J. Lederer, W. F. Graier, R. Malli, et al. Twenty Years of Calcium Imaging: Cell Physiology to Dye For Mol. Interv., April 1, 2005; 5(2): 112 - 127. [Abstract] [Full Text] [PDF]

				D. A. Eisner, M. E. Diaz, Y. Li, S. C. O'Neill, and A. W. Trafford Stability and instability of regulation of intracellular calcium Exp Physiol, January 1, 2005; 90(1): 3 - 12. [Abstract] [Full Text] [PDF]

				L. Mackenzie, H. L. Roderick, M. J. Berridge, S. J. Conway, and M. D. Bootman The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction J. Cell Sci., December 15, 2004; 117(26): 6327 - 6337. [Abstract] [Full Text] [PDF]

				S. C. O'Neill, L. Miller, R. Hinch, and D. A. Eisner Interplay between SERCA and sarcolemmal Ca2+ efflux pathways controls spontaneous release of Ca2+ from the sarcoplasmic reticulum in rat ventricular myocytes J. Physiol., August 15, 2004; 559(1): 121 - 128. [Abstract] [Full Text] [PDF]

				Y. Wang and J. I. Goldhaber Return of calcium: Manipulating intracellular calcium to prevent cardiac pathologies PNAS, April 20, 2004; 101(16): 5697 - 5698. [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]