Cellular mechanisms of arrhythmogenic cardiac alternans.

Despite the strong association between mechanical dysfunction of the heart and sudden death due to arrhythmias, the causal relationship is not well understood. Cardiac alternans has been linked to arrhythmogenesis and can be mediated by intracellular calcium handling. Given the integral role intracellular calcium plays in contractile function, calcium-mediated alternans may represent an important mechanistic link between mechanical dysfunction and electrical instability. This relationship, however, is not well understood due to complex feedback between membrane currents, intracellular calcium, and contraction. This manuscript describes the cellular mechanisms of cardiac alternans. Through several pathways, calcium transient alternans is coupled to repolarization alternans that can form a substrate for reentrant excitation. Abnormal intracellular calcium cycling, either impaired release or impaired reuptake of sarcoplasmic reticulum calcium, is a cellular mechanism of calcium transient alternans. Thus, cardiac alternans is an important mechanistic link between mechanical dysfunction and sudden cardiac death.

[1]  R. Winslow,et al.  Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. , 1999, Circulation research.

[2]  A. Garfinkel,et al.  Preventing ventricular fibrillation by flattening cardiac restitution. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C H Davies,et al.  Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. , 1995, Circulation.

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

[5]  O. Hauswirth,et al.  Fosinoprilate prolongs the action potential: reduction of iK and enhancement of the L-type calcium current in guinea pig ventricular myocytes. , 1994, Cardiovascular research.

[6]  C Antzelevitch,et al.  I(NaCa) contributes to electrical heterogeneity within the canine ventricle. , 2000, American journal of physiology. Heart and circulatory physiology.

[7]  L. Blatter,et al.  Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes , 2002, The Journal of physiology.

[8]  A. Moss,et al.  T wave alternans in idiopathic long QT syndrome. , 1994, Journal of the American College of Cardiology.

[9]  Y. Kihara,et al.  Abnormal Cai2+ handling is the primary cause of mechanical alternans: study in ferret ventricular muscles. , 1991, The American journal of physiology.

[10]  Shien-Fong Lin,et al.  Spatial heterogeneity of action potential alternans during global ischemia in the rabbit heart. , 2003, American journal of physiology. Heart and circulatory physiology.

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

[12]  Robert F Gilmour,et al.  Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes. , 2004, American journal of physiology. Heart and circulatory physiology.

[13]  S. Marx,et al.  Coupled Gating Between Cardiac Calcium Release Channels (Ryanodine Receptors) , 2001, Circulation research.

[14]  C. Brooks,et al.  Comparative studies of electrical and mechanical alternation in heart cells. , 1968, Journal of electrocardiology.

[15]  R. Haworth,et al.  Abnormal Ca2+ Release, but Normal Ryanodine Receptors, in Canine and Human Heart Failure , 2002, Circulation research.

[16]  Charles Antzelevitch,et al.  Cellular and subcellular alternans in the canine left ventricle. , 2007, American journal of physiology. Heart and circulatory physiology.

[17]  D. Rosenbaum,et al.  Cellular Alternans , 2006, Annals of the New York Academy of Sciences.

[18]  M. Böhm,et al.  Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. , 1995, Circulation.

[19]  G. Tomaselli,et al.  Electrophysiological remodeling in hypertrophy and heart failure. , 1999, Cardiovascular research.

[20]  R Mohabir,et al.  Effects of ischemia and hypercarbic acidosis on myocyte calcium transients, contraction, and pHi in perfused rabbit hearts. , 1991, Circulation research.

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

[22]  H. Drexler,et al.  Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. , 1994, Circulation research.

[23]  A Garfinkel,et al.  Intracellular Ca(2+) dynamics and the stability of ventricular tachycardia. , 1999, Biophysical journal.

[24]  Willem Flameng,et al.  Reduced synchrony of Ca2+ release with loss of T-tubules-a comparison to Ca2+ release in human failing cardiomyocytes. , 2004, Cardiovascular research.

[25]  D. Bers,et al.  Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation. , 2000, American journal of physiology. Heart and circulatory physiology.

[26]  M. Yano,et al.  Altered Stoichiometry of FKBP12.6 Versus Ryanodine Receptor as a Cause of Abnormal Ca2 Leak Through Ryanodine Receptor in Heart Failure , 2000, Circulation.

[27]  B. Xiao,et al.  Protein Kinase A Phosphorylation at Serine-2808 of the Cardiac Ca2+-Release Channel (Ryanodine Receptor) Does Not Dissociate 12.6-kDa FK506-Binding Protein (FKBP12.6) , 2004, Circulation research.

[28]  Alan Garny,et al.  Effects of mechanosensitive ion channels on ventricular electrophysiology: experimental and theoretical models , 2006, Experimental physiology.

[29]  J. Ruskin,et al.  Electrical alternans and vulnerability to ventricular arrhythmias. , 1994, The New England journal of medicine.

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

[31]  E. Lakatta,et al.  &bgr;-Adrenergic Stimulation Synchronizes Intracellular Ca2+ Release During Excitation-Contraction Coupling in Cardiac Myocytes , 2001, Circulation research.

[32]  D. Rosenbaum,et al.  Hysteresis Effect Implicates Calcium Cycling as a Mechanism of Repolarization Alternans , 2003, Circulation.

[33]  R. Walsh,et al.  Influence of transgenic overexpression of phospholamban on postextrasystolic potentiation. , 1999, Journal of molecular and cellular cardiology.

[34]  A. Fabiato,et al.  Time and calcium dependence of activation and inactivation of calcium- induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell , 1985, The Journal of general physiology.

[35]  B. Pieske,et al.  Alternans goes subcellular: a "disease" of the ryanodine receptor? , 2002, Circulation research.

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

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

[38]  Brian O'Rourke,et al.  Enhanced Ca2+-Activated Na+-Ca2+ Exchange Activity in Canine Pacing-Induced Heart Failure , 2000 .

[39]  Kenneth R. Laurita,et al.  Transmural Heterogeneity of Calcium Handling in Canine , 2003, Circulation research.

[40]  G Arnold,et al.  Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium. , 1996, Circulation.

[41]  Sandor Györke,et al.  Termination of Ca2+ release during Ca2+ sparks in rat ventricular myocytes , 1998, The Journal of physiology.

[42]  M. Lab,et al.  Electrical alternans and the onset of rate-induced pulsus alternans during acute regional ischaemia in the anaesthetised pig heart. , 1996, Cardiovascular research.

[43]  David S. Rosenbaum,et al.  Role of Calcium Cycling Versus Restitution in the Mechanism of Repolarization Alternans , 2004, Circulation research.

[44]  J. R. Blinks,et al.  Active shortening retards the decline of the intracellular calcium transient in mammalian heart muscle. , 1983, Science.

[45]  Thomas Lewis,et al.  NOTES UPON ALTERNATION OF THE HEART , 1911 .

[46]  S. M. Collins,et al.  Sectional and segmental variability of left ventricular function: experimental and clinical studies using ultrafast computed tomography. , 1988, Journal of the American College of Cardiology.

[47]  Alain Karma,et al.  Coupled dynamics of voltage and calcium in paced cardiac cells. , 2005, Physical review. E, Statistical, nonlinear, and soft matter physics.

[48]  D. Dobrev,et al.  Regulation of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban in the failing and nonfailing heart. , 2000, Cardiovascular research.

[49]  D. Rosenbaum,et al.  Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure , 2003, Circulation research.

[50]  E Erdmann,et al.  Ca(2+)-currents and intracellular [Ca2+]i-transients in single ventricular myocytes isolated from terminally failing human myocardium. , 1992, Basic research in cardiology.

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

[52]  H. Hellerstein,et al.  Electrical alternation in experimental coronary artery occlusion. , 1950, The American journal of physiology.

[53]  G. Hasenfuss,et al.  Alterations of calcium-regulatory proteins in heart failure. , 1998, Cardiovascular research.

[54]  Alan Garfinkel,et al.  Spatially Discordant Alternans in Cardiac Tissue: Role of Calcium Cycling , 2006 .

[55]  David C. Warltier,et al.  Characterization of a Novel PKA Phosphorylation Site, Serine-2030, Reveals No PKA Hyperphosphorylation of the Cardiac Ryanodine Receptor in Canine Heart Failure , 2005, Circulation research.

[56]  D. Rosenbaum,et al.  Molecular correlates of repolarization alternans in cardiac myocytes. , 2005, Journal of molecular and cellular cardiology.

[57]  R. Gilmour,et al.  Electrical restitution and spatiotemporal organization during ventricular fibrillation. , 1999, Circulation research.

[58]  K. Laurita.  Role of Action Potential Duration Restitution in Arrhythmogenesis , 2004, Journal of cardiovascular electrophysiology.

[59]  M R Franz,et al.  Effect of ischemia on calcium-dependent fluorescence transients in rabbit hearts containing indo 1. Correlation with monophasic action potentials and contraction. , 1988, Circulation.

[60]  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.

[61]  J P Miller,et al.  The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. , 1984, Circulation.

[62]  H. T. ter Keurs,et al.  Arrhythmogenic Ca(2+) release from cardiac myofilaments. , 2006, Progress in biophysics and molecular biology.

[63]  M. Josephson,et al.  Prognostic factors in nonsustained ventricular tachycardia. , 1984, The American journal of cardiology.

[64]  H M Hastings,et al.  Mechanisms for Discordant Alternans , 2001, Journal of cardiovascular electrophysiology.

[65]  David S. Rosenbaum,et al.  Optical mapping of cardiac excitation and arrhythmias , 2001 .

[66]  J. Windle.  THE INCIDENCE AND PROGNOSTIC VALUE OF THE PULSUS ALTERNANS IN MYOCARDIAL AND ARTERIAL DISEASE , 1913 .

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

[68]  M J Lab,et al.  Regional electromechanical alternans in anesthetized pig hearts: modulation by mechanoelectric feedback. , 1994, The American journal of physiology.

[69]  P. Kohl,et al.  Mechanoelectric feedback in cardiac cells , 2001, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[70]  Richard A Gray,et al.  Effect of Action Potential Duration and Conduction Velocity Restitution and Their Spatial Dispersion on Alternans and the Stability of Arrhythmias , 2002, Journal of cardiovascular electrophysiology.

[71]  S. Priori,et al.  Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia: Insights From a RyR2 R4496C Knock-In Mouse Model , 2006 .

[72]  J. Bogaert,et al.  Regional nonuniformity of normal adult human left ventricle. , 2001, American journal of physiology. Heart and circulatory physiology.

[73]  D. Bers,et al.  Ca2+/Calmodulin-Dependent Protein Kinase II Phosphorylation of Ryanodine Receptor Does Affect Calcium Sparks in Mouse Ventricular Myocytes , 2006, Circulation research.

[74]  Roy C. P. Kerckhoffs,et al.  Cardiac resynchronization: insight from experimental and computational models. , 2008, Progress in biophysics and molecular biology.

[75]  Z. Kubalová,et al.  Enhanced ryanodine receptor-mediated calcium leak determines reduced sarcoplasmic reticulum calcium content in chronic canine heart failure. , 2007, Biophysical journal.

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

[77]  G. Hasenfuss,et al.  Heterogeneous transmural gene expression of calcium-handling proteins and natriuretic peptides in the failing human heart. , 1999, Cardiovascular research.

[78]  D. Rosenbaum,et al.  Occult T Wave Alternans in Long QT Syndrome , 1996, Journal of cardiovascular electrophysiology.

[79]  W Yuan,et al.  Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. , 1995, The American journal of physiology.

[80]  K. Laurita,et al.  Ryanodine receptor dysfunction and triggered activity in the heart. , 2007, American journal of physiology. Heart and circulatory physiology.

[81]  A. Takeshita,et al.  Endocardial versus epicardial differences of sarcoplasmic reticulum Ca2+-ATPase gene expression in the canine failing myocardium , 1999, Basic Research in Cardiology.

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

[83]  G. Ellis‐Davies,et al.  Rapid adaptation of cardiac ryanodine receptors: modulation by Mg2+ and phosphorylation. , 1995, Science.

[84]  S. Narayan,et al.  Acute volume overload elevates T-wave alternans magnitude. , 2007, Journal of applied physiology.

[85]  S. Priori,et al.  FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death , 2003, Cell.

[86]  I. Györke,et al.  Regulation of calcium release by calcium inside the sarcoplasmic reticulum in ventricular myocytes , 1996, Pflügers Archiv - European Journal of Physiology.

[87]  S. Houser,et al.  Patients With End-Stage Congestive Heart Failure Treated With &bgr;-Adrenergic Receptor Antagonists Have Improved Ventricular Myocyte Calcium Regulatory Protein Abundance , 2001, Circulation.

[88]  A. Lompré,et al.  Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. , 1990, Circulation research.

[89]  D. Rosenbaum,et al.  Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. , 1999, Circulation.

[90]  Eric A Sobie,et al.  Orphaned ryanodine receptors in the failing heart. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[91]  M R Franz,et al.  Ischaemia induced alternans of action potential duration in the intact-heart: dependence on coronary flow, preload and cycle length. , 1993, European heart journal.

[92]  E. Homsher,et al.  Regulation of contraction in striated muscle. , 2000, Physiological reviews.

[93]  D. Burkhoff,et al.  PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor) Defective Regulation in Failing Hearts , 2000, Cell.

[94]  D. Bers,et al.  Frequency-dependent acceleration of relaxation in the heart depends on CaMKII, but not phospholamban. , 2002, Journal of molecular and cellular cardiology.

[95]  M J Lab,et al.  Mechanoelectric feedback (transduction) in heart: concepts and implications. , 1996, Cardiovascular research.

[96]  G. Hasenfuss,et al.  Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy. , 1995, Circulation.

[97]  K. Sipido.  Understanding Cardiac Alternans: The Answer Lies in the Ca2+ Store , 2004, Circulation research.

[98]  Peter Taggart,et al.  Cardiac mechano-electric feedback and electrical restitution in humans. , 2008, Progress in biophysics and molecular biology.

[99]  F Sachs,et al.  Stretch-activated ion channels in the heart. , 1997, Journal of molecular and cellular cardiology.

[100]  Deborah DiSilvestre,et al.  Transmural Heterogeneity of Na+–Ca2+ Exchange: Evidence for Differential Expression in Normal and Failing Hearts , 2005, Circulation research.

[101]  M. Yano,et al.  Propranolol Prevents the Development of Heart Failure by Restoring FKBP12.6-Mediated Stabilization of Ryanodine Receptor , 2002, Circulation.

[102]  Etienne Pruvot,et al.  Intracellular calcium handling heterogeneities in intact guinea pig hearts. , 2004, American journal of physiology. Heart and circulatory physiology.

[103]  E. Caref,et al.  Mechanism of Discordant T Wave Alternans in the In Vivo Heart , 2003, Journal of cardiovascular electrophysiology.

[104]  M Restivo,et al.  The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns. , 1996, Circulation research.

[105]  D. Bers,et al.  Factors That Control Sarcoplasmic Reticulum Calcium Release in Intact Ventricular Myocytesa , 1998, Annals of the New York Academy of Sciences.

[106]  M. Rosen.  Cellular electrophysiology of digitalis toxicity. , 1985, Journal of the American College of Cardiology.