Spark-Induced Sparks As a Mechanism of Intracellular Calcium Alternans in Cardiac Myocytes

Rationale: Intracellular calcium (Ca) alternans has been widely studied in cardiac myocytes and tissue, yet the underlying mechanism remains controversial. Objective: In this study, we used computational modeling and simulation to study how randomly occurring Ca sparks interact collectively to result in whole-cell Ca alternans. Methods and Results: We developed a spatially distributed intracellular Ca cycling model in which Ca release units (CRUs) are locally coupled by Ca diffusion throughout the myoplasm and sarcoplasmic reticulum (SR) network. Ca sparks occur randomly in the CRU network when periodically paced with a clamped voltage waveform, but Ca alternans develops as the pacing speeds up. Combining computational simulation with theoretical analysis, we show that Ca alternans emerges as a collective behavior of Ca sparks, determined by 3 critical properties of the CRU network from which Ca sparks arise: “randomness” (of Ca spark activation), “refractoriness” (of a CRU after a Ca spark), and “recruitment” (Ca sparks inducing Ca sparks in adjacent CRUs). We also show that the steep nonlinear relationship between fractional SR Ca release and SR Ca load arises naturally as a collective behavior of Ca sparks, and Ca alternans can occur even when SR Ca is held constant. Conclusions: We present a general theory for the mechanisms of intracellular Ca alternans, which mechanistically links Ca sparks to whole-cell Ca alternans, and is applicable to Ca alternans in both physiological and pathophysiological conditions.

[1]  Dmitry Terentyev,et al.  Redox modification of ryanodine receptors underlies calcium alternans in a canine model of sudden cardiac death. , 2009, Cardiovascular research.

[2]  Gil Bub,et al.  Dynamical Mechanism for Subcellular Alternans in Cardiac Myocytes , 2009, Circulation research.

[3]  Alan Garfinkel,et al.  Period-doubling bifurcation in an array of coupled stochastically excitable elements subjected to global periodic forcing. , 2009, Physical review letters.

[4]  M. Diaz,et al.  The effects of membrane potential, SR Ca2+ content and RyR responsiveness on systolic Ca2+ alternans in rat ventricular myocytes , 2009, The Journal of physiology.

[5]  Matthew Gittinger,et al.  Heart failure enhances susceptibility to arrhythmogenic cardiac alternans. , 2009, Heart rhythm.

[6]  D. Bers,et al.  Termination of Cardiac Ca2+ Sparks: Role of Intra-SR [Ca2+], Release Flux, and Intra-SR Ca2+ Diffusion , 2008, Circulation research.

[7]  Alan Garfinkel,et al.  Intracellular Ca alternans: coordinated regulation by sarcoplasmic reticulum release, uptake, and leak. , 2008, Biophysical journal.

[8]  Dmitry Terentyev,et al.  Modulation of SR Ca release by luminal Ca and calsequestrin in cardiac myocytes: effects of CASQ2 mutations linked to sudden cardiac death. , 2008, Biophysical journal.

[9]  Henggui Zhang,et al.  Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study. , 2008, American journal of physiology. Heart and circulatory physiology.

[10]  D. Bers.  Calcium cycling and signaling in cardiac myocytes. , 2008, Annual review of physiology.

[11]  X. Wehrens,et al.  Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure. , 2007, American journal of physiology. Heart and circulatory physiology.

[12]  Christian Soeller,et al.  Analysis of ryanodine receptor clusters in rat and human cardiac myocytes , 2007, Proceedings of the National Academy of Sciences.

[13]  Daniel T Gillespie,et al.  Stochastic simulation of chemical kinetics. , 2007, Annual review of physical chemistry.

[14]  H. T. ter Keurs,et al.  Calcium and arrhythmogenesis. , 2007, Physiological reviews.

[15]  Donald M Bers,et al.  Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations , 2006, Circulation research.

[16]  A. Kadish,et al.  Pacing-induced Heterogeneities in Intracellular Ca2+ Signaling, Cardiac Alternans, and Ventricular Arrhythmias in Intact Rat Heart , 2006, Circulation research.

[17]  Petter Laake,et al.  T‐tubule disorganization and reduced synchrony of Ca2+ release in murine cardiomyocytes following myocardial infarction , 2006, The Journal of physiology.

[18]  Christian Soeller,et al.  Three-dimensional distribution of ryanodine receptor clusters in cardiac myocytes. , 2006, Biophysical journal.

[19]  A. Garfinkel,et al.  From Pulsus to Pulseless: The Saga of Cardiac Alternans , 2006, Circulation research.

[20]  James Coromilas,et al.  Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[21]  W. Lederer,et al.  Restitution of Ca2+ Release and Vulnerability to Arrhythmias , 2006, Journal of cardiovascular electrophysiology.

[22]  Donald M Bers,et al.  Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model. , 2005, Biophysical journal.

[23]  Eric A Sobie,et al.  Local recovery of Ca2+ release in rat ventricular myocytes , 2005, The Journal of physiology.

[24]  Clara Franzini-Armstrong,et al.  Ca2+ blinks: rapid nanoscopic store calcium signaling. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Tanskanen,et al.  A simplified local control model of calcium-induced calcium release in cardiac ventricular myocytes. , 2004, Biophysical journal.

[26]  Heping Cheng,et al.  RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Sandor Györke,et al.  The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. , 2004, Biophysical journal.

[28]  M. Diaz,et al.  Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans , 2004, Circulation research.

[29]  A Garfinkel,et al.  Model of intracellular calcium cycling in ventricular myocytes. , 2003, Biophysical journal.

[30]  C. Orchard,et al.  T‐Tubule Function in Mammalian Cardiac Myocytes , 2003, Circulation research.

[31]  Masashi Inoue,et al.  Ca2+ Sparks in Rabbit Ventricular Myocytes Evoked by Action Potentials: Involvement of Clusters of L-Type Ca2+ Channels , 2003, Circulation research.

[32]  G. Oreto,et al.  Verapamil‐Induced Electrical and Cycle Length Alternans During Supraventricular Tachycardia: , 2003, Journal of cardiovascular electrophysiology.

[33]  Katherine A. Sheehan,et al.  Local calcium gradients during excitation–contraction coupling and alternans in atrial myocytes , 2003, The Journal of physiology.

[34]  M. Diaz,et al.  Depressed Ryanodine Receptor Activity Increases Variability and Duration of the Systolic Ca2+ Transient in Rat Ventricular Myocytes , 2002, Circulation research.

[35]  D. Terentyev,et al.  Luminal Ca2+ Controls Termination and Refractory Behavior of Ca2+-Induced Ca2+ Release in Cardiac Myocytes , 2002, Circulation research.

[36]  I. Efimov,et al.  Mechanical alternans and restitution in failing SHHF rat left ventricles. , 2002, American journal of physiology. Heart and circulatory physiology.

[37]  Shien-Fong Lin,et al.  Spatial Heterogeneity of Calcium Transient Alternans During the Early Phase of Myocardial Ischemia in the Blood-Perfused Rabbit Heart , 2001, Circulation.

[38]  W. Lederer,et al.  Heart Failure After Myocardial Infarction: Altered Excitation-Contraction Coupling , 2001, Circulation.

[39]  E. Lakatta,et al.  Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells , 2001, Nature.

[40]  Donald M. Bers,et al.  Allosteric Regulation of Na/Ca Exchange Current by Cytosolic Ca in Intact Cardiac Myocytes , 2001, The Journal of general physiology.

[41]  M. Diaz,et al.  Integrative Analysis of Calcium Cycling in Cardiac Muscle , 2000, Circulation research.

[42]  S. Litwin,et al.  Dyssynchronous Ca2+ Sparks in Myocytes From Infarcted Hearts , 2000, Circulation research.

[43]  E. Ríos,et al.  Fast imaging in two dimensions resolves extensive sources of Ca2+ sparks in frog skeletal muscle , 2000, The Journal of physiology.

[44]  R. Walsh,et al.  Cardiac-specific overexpression of calsequestrin results in left ventricular hypertrophy, depressed force-frequency relation and pulsus alternans in vivo. , 2000, Journal of molecular and cellular cardiology.

[45]  Katherine A. Sheehan,et al.  Functional coupling between glycolysis and excitation—contraction coupling underlies alternans in cat heart cells , 2000, The Journal of physiology.

[46]  F. Protasi,et al.  Shape, size, and distribution of Ca(2+) release units and couplons in skeletal and cardiac muscles. , 1999, Biophysical journal.

[47]  A. Garfinkel,et al.  An advanced algorithm for solving partial differential equation in cardiac conduction , 1999, IEEE Transactions on Biomedical Engineering.

[48]  P R Ershler,et al.  Properties of Ca2+ sparks evoked by action potentials in mouse ventricular myocytes , 1999, The Journal of physiology.

[49]  J. Pearson,et al.  Fire-diffuse-fire model of dynamics of intracellular calcium waves. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Michael D. Stern,et al.  Local Control Models of Cardiac Excitation–Contraction Coupling , 1999, The Journal of general physiology.

[51]  J. Pearson,et al.  Saltatory propagation of Ca2+ waves by Ca2+ sparks. , 1998, Biophysical journal.

[52]  W. Wier,et al.  Ca2+ sparks involving multiple Ca2+ release sites along Z‐lines in rat heart cells. , 1996, The Journal of physiology.

[53]  J. Keizer,et al.  Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations. , 1994, Biophysical journal.

[54]  W. Lederer,et al.  Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. , 1993, Science.

[55]  M. Stern,et al.  Theory of excitation-contraction coupling in cardiac muscle. , 1992, Biophysical journal.

[56]  J. C. Bailey,et al.  Action potential duration alternans in dog Purkinje and ventricular muscle fibers. Further evidence in support of two different mechanisms. , 1989, Circulation.

[57]  W. Lederer,et al.  Calcium sparks. , 2008, Physiological reviews.

[58]  Heping Cheng,et al.  RyR 2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca 2 release ( SOICR ) , 2004 .

[59]  D. Bers,et al.  Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. , 2000, Biophysical journal.

[60]  John E. Pearson,et al.  Saltatory Propagation of Ca 2+ Waves by Ca 2+ Sparks , 1998 .

[61]  W. Lederer,et al.  Calcium sparks and [Ca2+]i waves in cardiac myocytes. , 1996, The American journal of physiology.