Mechanisms of Altered Ca2+ Handling in Heart Failure

Ca2+ plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca2+ homeostatic and structural proteins, ion channels, and enzymes. This review focuses on the molecular mechanisms of defective Ca2+ cycling in heart failure and considers how fundamental understanding of these pathways may translate into novel and innovative therapies.

[1]  Ca2+ waves during triggered propagated contractions in intact trabeculae. , 1998, American journal of physiology. Heart and circulatory physiology.

[2]  Ulrike Mende,et al.  Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban , 2003, Science.

[3]  M. Yano,et al.  Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca(2+) release in heart failure. , 2000, Cardiovascular research.

[4]  Stefan Wagner,et al.  Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. , 2006, The Journal of clinical investigation.

[5]  Mark E. Anderson,et al.  Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension , 2012, Hypertension.

[6]  Lars S. Maier,et al.  Rate Dependence of [Na+]i and Contractility in Nonfailing and Failing Human Myocardium , 2002, Circulation.

[7]  M. Yacoub,et al.  Changes in sarcolemmal Ca entry and sarcoplasmic reticulum Ca content in ventricular myocytes from patients with end-stage heart failure following myocardial recovery after combined pharmacological and ventricular assist device therapy. , 2003, European heart journal.

[8]  X. Wehrens,et al.  CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome. , 2012, Heart rhythm.

[9]  T. Gudermann,et al.  Receptors and G proteins as primary components of transmembrane signal transduction , 1995, Journal of Molecular Medicine.

[10]  A. Friedl,et al.  Altered expression of titin and contractile proteins in failing human myocardium. , 1994, Journal of molecular and cellular cardiology.

[11]  B. Pitt,et al.  Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction , 2003 .

[12]  P. Karczewski,et al.  Expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in rats with hypertensive cardiac hypertrophy , 2001, Molecular and Cellular Biochemistry.

[13]  G. Rozanski.  Physiological remodelling of potassium channels in the heart. , 2012, Cardiovascular research.

[14]  G. Dorn,et al.  Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKCepsilon translocation. , 2000, Circulation research.

[15]  Mark E. Anderson,et al.  L-type Ca2+ channel facilitation mediated by phosphorylation of the beta subunit by CaMKII. , 2006, Molecular cell.

[16]  Yiming Wu,et al.  Cardiac Hypertrophy and Reduced Contractility in Hearts Deficient in the Titin Kinase Region , 2007, Circulation.

[17]  C. Heizmann,et al.  S100A1 deficiency results in prolonged ventricular repolarization in response to sympathetic activation. , 2008, General physiology and biophysics.

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

[19]  B. Kemp,et al.  Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice , 2002, Molecular and Cellular Biology.

[20]  Mark E. Anderson,et al.  Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels , 2000, Nature Cell Biology.

[21]  B. O’Rourke,et al.  Decreased Sarcoplasmic Reticulum Calcium Content Is Responsible for Defective Excitation-Contraction Coupling in Canine Heart Failure , 2001, Circulation.

[22]  W. Koch,et al.  G protein-coupled receptor kinases in normal and failing myocardium. , 2011, Frontiers in bioscience.

[23]  M. Crow,et al.  Sustained beta1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. , 2004, Circulation research.

[24]  D. Mochly‐Rosen,et al.  Identification of intracellular receptor proteins for activated protein kinase C. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  W. Linke,et al.  The Giant Protein Titin: Emerging Roles in Physiology and Pathophysiology , 1997 .

[26]  A. Terzic,et al.  Restoration of CA2+-inhibited oxidative phosphorylation in cardiac mitochondria by mitochondrial Ca2+ unloading , 2001, Molecular and Cellular Biochemistry.

[27]  S. Sheu,et al.  Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart , 2007, Pflügers Archiv - European Journal of Physiology.

[28]  S. Reiken,et al.  Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice. , 2010, The Journal of clinical investigation.

[29]  G. Dorn,et al.  Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. , 2003, The Journal of clinical investigation.

[30]  M. Böhm,et al.  Quantification of β-Adrenoceptors and β-Adrenoceptor Kinase on Protein and mRNA Levels in Heart Failure , 1994 .

[31]  O. Ritter,et al.  Calcineurin in Human Heart Hypertrophy , 2002, Circulation.

[32]  David J Weber,et al.  Three-dimensional solution structure of the calcium-signaling protein apo-S100A1 as determined by NMR. , 2002, Biochemistry.

[33]  J. Molkentin,et al.  Inducible and myocyte-specific inhibition of PKCalpha enhances cardiac contractility and protects against infarction-induced heart failure. , 2007, American journal of physiology. Heart and circulatory physiology.

[34]  X. Wehrens,et al.  Inhibition of CaMKII phosphorylation of RyR2 prevents inducible ventricular arrhythmias in mice with Duchenne muscular dystrophy. , 2013, Heart rhythm.

[35]  Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. , 1993, Journal of the American College of Cardiology.

[36]  Mark E. Anderson,et al.  CaM kinase augments cardiac L-type Ca2+ current: a cellular mechanism for long Q-T arrhythmias. , 1999, American journal of physiology. Heart and circulatory physiology.

[37]  Donald M Bers,et al.  CaMKII in myocardial hypertrophy and heart failure. , 2011, Journal of molecular and cellular cardiology.

[38]  M. Eren,et al.  Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo. , 2006, American journal of physiology. Heart and circulatory physiology.

[39]  Jay T. Groves,et al.  A Mechanism for Tunable Autoinhibition in the Structure of a Human Ca2+/Calmodulin- Dependent Kinase II Holoenzyme , 2011, Cell.

[40]  Mark E. Anderson,et al.  Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II* , 2012, The Journal of Biological Chemistry.

[41]  B. Reichart,et al.  Effect of Inotropic Stimulation on the Negative Force‐Frequency Relationship in the Failing Human Heart , 1993, Circulation.

[42]  G. Dorn,et al.  The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. , 1996, Journal of molecular and cellular cardiology.

[43]  N. Dhalla,et al.  Defects in Sarcolemmal Ca2+ Transport in Hearts Due to Induction of Calcium Paradox , 1988, Circulation research.

[44]  A. Leenhardt,et al.  Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human , 2012, Human molecular genetics.

[45]  P. Oliveira,et al.  Carvedilol inhibits the mitochondrial permeability transition by an antioxidant mechanism , 2007, Cardiovascular Toxicology.

[46]  J. Hell,et al.  Calmodulin Kinase II Inhibition Shortens Action Potential Duration by Upregulation of K+ Currents , 2006, Circulation research.

[47]  A. Kabakov.  Activation of KATP channels by Na/K pump in isolated cardiac myocytes and giant membrane patches. , 1998, Biophysical journal.

[48]  K. Boheler,et al.  Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. , 1990, The Journal of clinical investigation.

[49]  X. Wehrens,et al.  Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation , 2011, Circulation.

[50]  György Hajnóczky,et al.  Decoding of cytosolic calcium oscillations in the mitochondria , 1995, Cell.

[51]  W. Linke,et al.  Crucial Role for Ca2+/Calmodulin-Dependent Protein Kinase-II in Regulating Diastolic Stress of Normal and Failing Hearts via Titin Phosphorylation , 2013, Circulation research.

[52]  T. Wieland,et al.  Role of RyR2 Phosphorylation at S2814 During Heart Failure Progression , 2012, Circulation research.

[53]  E. J. Brown,et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. , 1992, The New England journal of medicine.

[54]  E. Marbán,et al.  Beta-adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[55]  D. Bers,et al.  Epac enhances excitation-transcription coupling in cardiac myocytes. , 2012, Journal of molecular and cellular cardiology.

[56]  Harvard Medical School,et al.  Targeting Phospholamban by Gene Transfer in Human Heart Failure , 2002, Circulation.

[57]  Thomas J Hund,et al.  A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. , 2010, The Journal of clinical investigation.

[58]  Andrew N. Carr,et al.  Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure. , 2006, Circulation.

[59]  D. Fortin,et al.  Local energetic regulation of sarcoplasmic and myosin ATPase is differently impaired in rats with heart failure , 2008, The Journal of physiology.

[60]  Peter J. Mohler,et al.  The Ankyrin-B C-terminal Domain Determines Activity of Ankyrin-B/G Chimeras in Rescue of Abnormal Inositol 1,4,5-Trisphosphate and Ryanodine Receptor Distribution in Ankyrin-B (−/−) Neonatal Cardiomyocytes* , 2002, The Journal of Biological Chemistry.

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

[62]  K. Saku,et al.  OJ-347 Noninducibility of Atrial Fibrillation as an End Point of Pulmonary Vein Antrum Isolation for Paroxysmal Atrial Fibrillation(Arrhythmia, therapy-5 (A) OJ58,Oral Presentation (Japanese),The 70th Anniversary Annual Scientific Meeting of the Japanese Circulation Society) , 2006 .

[63]  A. Terzic,et al.  Cardiac system bioenergetics: metabolic basis of the Frank‐Starling law , 2006, The Journal of physiology.

[64]  Hendrick E D J ter Keurs,et al.  The interaction of Ca2+ with sarcomeric proteins: role in function and dysfunction of the heart. , 2012, American journal of physiology. Heart and circulatory physiology.

[65]  K. Ohlendieck,et al.  Drastic reduction in the luminal Ca2+ -binding proteins calsequestrin and sarcalumenin in dystrophin-deficient cardiac muscle. , 2004, Biochimica et biophysica acta.

[66]  Yuji Imaizumi,et al.  Regulation of Kv4.3 currents by Ca2+/calmodulin-dependent protein kinase II. , 2005, American journal of physiology. Cell physiology.

[67]  H. T. ter Keurs,et al.  Stretch and quick release of rat cardiac trabeculae accelerates Ca2+ waves and triggered propagated contractions. , 2001, American journal of physiology. Heart and circulatory physiology.

[68]  Peter Hess,et al.  Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists , 1984, Nature.

[69]  E. Olson,et al.  Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure , 2009, Circulation. Heart failure.

[70]  H. T. ter Keurs,et al.  Role of Sarcomere Mechanics and Ca2+ Overload in Ca2+ Waves and Arrhythmias in Rat Cardiac Muscle , 2006, Annals of the New York Academy of Sciences.

[71]  S. Houser,et al.  Hyperphosphorylation of the Cardiac Ryanodine Receptor at Serine 2808 Is Not Involved in Cardiac Dysfunction After Myocardial Infarction , 2012, Circulation research.

[72]  Y. Takeshima,et al.  Decreased mAKAP, ryanodine receptor, and SERCA2a gene expression in mdx hearts. , 2003, Biochemical and biophysical research communications.

[73]  U. Hoppe,et al.  Regulation of the Human Cardiac Mitochondrial Ca2+ Uptake by 2 Different Voltage-Gated Ca2+ Channels , 2009, Circulation.

[74]  P. De Koninck,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. , 1998, Science.

[75]  Hugo A. Katus,et al.  The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload , 2009, Proceedings of the National Academy of Sciences.

[76]  Yuejin Wu,et al.  Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy , 2006, Circulation.

[77]  G A Rutter,et al.  Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate connection. , 2000, Trends in biochemical sciences.

[78]  A. Terzic,et al.  Cardiac KATP channels in health and disease. , 2005, Journal of molecular and cellular cardiology.

[79]  Yinhan Liu,et al.  Intermolecular Failure of L-type Ca2+ Channel and Ryanodine Receptor Signaling in Hypertrophy , 2007, PLoS biology.

[80]  S. Sollott,et al.  Regulation and pharmacology of the mitochondrial permeability transition pore. , 2009, Cardiovascular research.

[81]  V. Mootha,et al.  Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter , 2011, Nature.

[82]  H. Tsutsui,et al.  Oxidative stress and mitochondrial DNA damage in heart failure. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[83]  M. Böhm,et al.  Molecular aspects of adrenergic signal transduction in cardiac failure , 1998, Journal of Molecular Medicine.

[84]  R. Schwinger,et al.  Reduced sodium pump alpha1, alpha3, and beta1-isoform protein levels and Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levels in human heart failure. , 1999, Circulation.

[85]  Mark E. Anderson,et al.  CaMKII in the cardiovascular system: sensing redox states. , 2011, Physiological reviews.

[86]  William Craelius,et al.  Stretch activated ion channels in ventricular myocytes , 1988, Bioscience reports.

[87]  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.

[88]  A. Rokita,et al.  New Therapeutic Targets in Cardiology: Arrhythmias and Ca2+/Calmodulin-Dependent Kinase II (CaMKII) , 2012, Circulation.

[89]  K. Mikoshiba,et al.  Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. , 1995, Circulation.

[90]  S. Vatner,et al.  Progressive loss of creatine maintains a near normal DeltaG approximately (ATP) in transgenic mouse hearts with cardiomyopathy caused by overexpressing Gsalpha. , 2010, Journal of molecular and cellular cardiology.

[91]  N. Dalton,et al.  Phospholamban Ablation Rescues Sarcoplasmic Reticulum Ca2+ Handling but Exacerbates Cardiac Dysfunction in CaMKII&dgr;C Transgenic Mice , 2010, Circulation research.

[92]  M. Matsuzaki,et al.  Carvedilol inhibits mitochondrial oxygen consumption and superoxide production during calcium overload in isolated heart mitochondria. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[93]  R. Hajjar,et al.  Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart Failure , 2001, Circulation.

[94]  Jie Zhang,et al.  Contactin-2 Expression in the Cardiac Purkinje Fiber Network , 2010, Circulation. Arrhythmia and electrophysiology.

[95]  T. Klitzner,et al.  Ca2+ channel kinetics in acutely isolated fetal, neonatal, and adult rabbit cardiac myocytes. , 1993, Circulation research.

[96]  A. Mattiazzi,et al.  Phospholamban phosphorylation by CaMKII under pathophysiological conditions. , 2008, Frontiers in bioscience : a journal and virtual library.

[97]  J. Gummert,et al.  Inhibition of Elevated Ca2+/Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium , 2010, Circulation research.

[98]  M. Bristow,et al.  Ca2+ uptake by cardiac sarcoplasmic reticulum from patients with idiopathic dilated cardiomyopathy. , 1989, Circulation research.

[99]  A. Means,et al.  Pressure overload selectively up-regulates Ca2+/calmodulin-dependent protein kinase II in vivo. , 2003, Molecular endocrinology.

[100]  Mark E. Anderson,et al.  A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation , 2008, Cell.

[101]  V. Mootha,et al.  MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake , 2010, Nature.

[102]  D. Burkhoff,et al.  &bgr;-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure , 2003, Circulation.

[103]  F. Lezoualc’h,et al.  cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy , 2005, Circulation research.

[104]  B. Pitt,et al.  Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting: The RED-CABG Randomized Controlled Trial , 2013 .

[105]  S. Matecki,et al.  Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy , 2010, Proceedings of the National Academy of Sciences.

[106]  Xiu-Jie Wang,et al.  In Vivo Suppression of MicroRNA-24 Prevents the Transition Toward Decompensated Hypertrophy in Aortic-Constricted Mice , 2013, Circulation research.

[107]  O. Sejersted,et al.  Reduced myocardial Na+, K(+)-pump capacity in congestive heart failure following myocardial infarction in rats. , 1998, Journal of molecular and cellular cardiology.

[108]  Mark E. Anderson,et al.  CaMKII determines mitochondrial stress responses in heart , 2012, Nature.

[109]  MasafumiYano,et al.  Altered Stoichiometry of FKBP12.6 Versus Ryanodine Receptor as a Cause of Abnormal Ca2+ Leak Through Ryanodine Receptor in Heart Failure , 2000 .

[110]  Bertram Pitt,et al.  Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction , 1996, The Lancet.

[111]  T. Prolla,et al.  Mitochondrial Oxidative Stress Mediates Angiotensin II–Induced Cardiac Hypertrophy and G&agr;q Overexpression–Induced Heart Failure , 2011, Circulation research.

[112]  Eric I. Rossman,et al.  Altered myocardial Ca2+ cycling after left ventricular assist device support in the failing human heart. , 2004, Journal of the American College of Cardiology.

[113]  S. Reiken,et al.  Role of CaMKIIδ phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure , 2010, Proceedings of the National Academy of Sciences.

[114]  Tullio Pozzan,et al.  Microdomains of intracellular Ca2+: molecular determinants and functional consequences. , 2006, Physiological reviews.

[115]  I. Ambudkar,et al.  Faculty Opinions recommendation of A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. , 2011 .

[116]  Donald M Bers,et al.  Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes , 2003, Circulation research.

[117]  S. Houser,et al.  Sodium/calcium exchange contributes to contraction and relaxation in failed human ventricular myocytes. , 1999, The American journal of physiology.

[118]  Godfrey L. Smith,et al.  Calcium/calmodulin‐dependent protein kinase II activity is increased in sarcoplasmic reticulum from coronary artery ligated rabbit hearts , 1999, FEBS letters.

[119]  B. Massie,et al.  Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. , 1993, Journal of the American College of Cardiology.

[120]  T. Pozzan,et al.  Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. , 1993, Science.

[121]  F. Wang,et al.  Cardiotoxic and Cardioprotective Features of Chronic &bgr;-Adrenergic Signaling , 2013, Circulation research.

[122]  E R Weibel,et al.  Scaling mitochondrial volume in heart to body mass. , 1984, Respiration physiology.

[123]  H. Keurs,et al.  The interaction of Ca2+ with sarcomeric proteins: role in function and dysfunction of the heart , 2012 .

[124]  A. Emery.  Muscular dystrophy into the new millennium , 2002, Neuromuscular Disorders.

[125]  L. Goldman,et al.  Do defects in the late sodium current in human ventricular cells cause heart failure? , 2002, Journal of molecular and cellular cardiology.

[126]  M. Boerries,et al.  Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. , 2004, The Journal of clinical investigation.

[127]  Dmitry Terentyev,et al.  Redox Modification of Ryanodine Receptors Contributes to Sarcoplasmic Reticulum Ca2+ Leak in Chronic Heart Failure , 2008, Circulation research.

[128]  H. Singer,et al.  Novel Ca2+/Calmodulin-dependent Protein Kinase II γ-Subunit Variants Expressed in Vascular Smooth Muscle, Brain, and Cardiomyocytes* , 1997, The Journal of Biological Chemistry.

[129]  S. Gupte,et al.  Ryanodine receptor: a novel therapeutic target in heart disease. , 2007, Recent patents on cardiovascular drug discovery.

[130]  Mark E. Anderson,et al.  Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. , 2009, The Journal of clinical investigation.

[131]  R. Schwinger,et al.  Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium. , 2002, Journal of molecular and cellular cardiology.

[132]  W. Lederer,et al.  Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. , 1997, Science.

[133]  Godfrey L. Smith,et al.  S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes. , 2005, Journal of molecular and cellular cardiology.

[134]  M. Kohlhaas,et al.  Interplay of defective excitation-contraction coupling, energy starvation, and oxidative stress in heart failure. , 2011, Trends in cardiovascular medicine.

[135]  M. Böhm,et al.  Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. , 1993, Circulation.

[136]  M. Boerries,et al.  Ca2+-Dependent Interaction of S100A1 with F1-ATPase Leads to an Increased ATP Content in Cardiomyocytes , 2007, Molecular and Cellular Biology.

[137]  M. Martone,et al.  Chronic Phospholamban–Sarcoplasmic Reticulum Calcium ATPase Interaction Is the Critical Calcium Cycling Defect in Dilated Cardiomyopathy , 1999, Cell.

[138]  F. Verdonck,et al.  [Na(+)] in the subsarcolemmal 'fuzzy' space and modulation of [Ca(2+)](i) and contraction in cardiac myocytes. , 2004, Cell calcium.

[139]  T. Hewett,et al.  PKC-α regulates cardiac contractility and propensity toward heart failure , 2004, Nature Medicine.

[140]  T. Doetschman,et al.  Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. , 1994, Circulation research.

[141]  Josep Roca,et al.  Modeling of spatial metabolite distributions in the cardiac sarcomere. , 2007, Biophysical journal.

[142]  Donald M. Bers,et al.  β-Adrenergic Enhancement of Sarcoplasmic Reticulum Calcium Leak in Cardiac Myocytes Is Mediated by Calcium/Calmodulin-Dependent Protein Kinase , 2007 .

[143]  G. Meissner,et al.  Characterization of Recombinant Skeletal Muscle (Ser-2843) and Cardiac Muscle (Ser-2809) Ryanodine Receptor Phosphorylation Mutants* , 2003, Journal of Biological Chemistry.

[144]  Dan M Roden,et al.  Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy , 2002, Circulation.

[145]  H. Rockman,et al.  Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. , 1997, The Journal of clinical investigation.

[146]  Shi-Xian Deng,et al.  Protection from Cardiac Arrhythmia Through Ryanodine Receptor-Stabilizing Protein Calstabin2 , 2004, Science.

[147]  J. Finsterer,et al.  The Heart in Human Dystrophinopathies , 2003, Cardiology.

[148]  Hani N Sabbah,et al.  Gating of the late Na+ channel in normal and failing human myocardium. , 2002, Journal of molecular and cellular cardiology.

[149]  D. Bers,et al.  Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Regulates Cardiac Sodium Channel NaV1.5 Gating by Multiple Phosphorylation Sites* , 2012, The Journal of Biological Chemistry.

[150]  R. Colbran,et al.  CaV1.2 β-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations , 2010, Proceedings of the National Academy of Sciences.

[151]  I. Efimov,et al.  Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. , 2013, The Journal of clinical investigation.

[152]  H. E. Keurs,et al.  Reverse Excitation‐Contraction Coupling: Ca2+ Ions as Initiators of Arrhythmias , 2001, Journal of cardiovascular electrophysiology.

[153]  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.

[154]  H. Erickson,et al.  Structural and functional characterization of the purified cardiac ryanodine receptor-Ca2+ release channel complex. , 1989, The Journal of biological chemistry.

[155]  C. Granger,et al.  Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction , 2008, Circulation.

[156]  Brian O'Rourke,et al.  Elevated Cytosolic Na+ Decreases Mitochondrial Ca2+ Uptake During Excitation–Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes , 2006, Circulation research.

[157]  E. Marbán,et al.  Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. , 1999, The Journal of clinical investigation.

[158]  C. Ward,et al.  Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. , 2008, The Journal of clinical investigation.

[159]  W. Rogers,et al.  Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. , 1989, The New England journal of medicine.

[160]  S. Nattel,et al.  Ca2+-Related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm , 2011, Circulation.

[161]  G. Kroemer,et al.  The mitochondrion in apoptosis: how Pandora's box opens , 2001, Nature Reviews Molecular Cell Biology.

[162]  M. Crow,et al.  Sustained &bgr;1-Adrenergic Stimulation Modulates Cardiac Contractility by Ca2+/Calmodulin Kinase Signaling Pathway , 2004 .

[163]  D. Bers.  Ryanodine receptor S2808 phosphorylation in heart failure: smoking gun or red herring. , 2012, Circulation research.

[164]  T. Carrel,et al.  S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes. , 2011, Journal of the American College of Cardiology.

[165]  Olha Koval,et al.  Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease , 2008, Proceedings of the National Academy of Sciences.

[166]  B. Stambler,et al.  Persistent activation of a swelling-activated cation current in ventricular myocytes from dogs with tachycardia-induced congestive heart failure. , 1998, Circulation research.

[167]  H N Sabbah,et al.  Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. , 1998, Circulation.

[168]  D. Kang,et al.  Mitochondrial DNA Damage and Dysfunction Associated With Oxidative Stress in Failing Hearts After Myocardial Infarction , 2001, Circulation research.

[169]  R Hetzer,et al.  Identification and expression of delta-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. , 1999, Circulation research.

[170]  David E. Clapham,et al.  The mitochondrial calcium uniporter is a highly selective ion channel , 2004, Nature.

[171]  A. Zahradníková,et al.  Frequency and release flux of calcium sparks in rat cardiac myocytes: a relation to RYR gating , 2010, The Journal of general physiology.

[172]  B. Pitt,et al.  Eplerenone , a Selective Aldosterone Blocker , in Patients with Left Ventricular Dysfunction after Myocardial Infarction , 2003 .

[173]  Fach,et al.  Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF) , 1999, The Lancet.

[174]  Stefan Neubauer,et al.  The failing heart--an engine out of fuel. , 2007, The New England journal of medicine.

[175]  W. Stevenson,et al.  Sudden Death Prevention in Patients With Advanced Ventricular Dysfunction , 1993, Circulation.

[176]  M. Anderson,et al.  Dual role of KATP channel C-terminal motif in membrane targeting and metabolic regulation , 2009, Proceedings of the National Academy of Sciences.

[177]  J. Benitah,et al.  L-type Ca(2+) current in ventricular cardiomyocytes. , 2010, Journal of molecular and cellular cardiology.

[178]  T. Hewett,et al.  Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. , 2007, The Journal of clinical investigation.

[179]  T. Gudermann,et al.  Receptors and G proteins as primary components of transmembrane signal transduction , 1995, Journal of Molecular Medicine.

[180]  S. Verma,et al.  Lack of S100A1 in mice confers a gender-dependent hypertensive phenotype and increased mortality after myocardial infarction. , 2009, American journal of physiology. Heart and circulatory physiology.

[181]  G. Dorn,et al.  Histidine-rich Ca binding protein: a regulator of sarcoplasmic reticulum calcium sequestration and cardiac function. , 2006, Journal of molecular and cellular cardiology.

[182]  J. Black,et al.  Preliminary CommunicationsA NEW ADRENERGIC: BETA-RECEPTOR ANTAGONIST , 1964 .

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

[184]  A. Takeshita,et al.  Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. , 1999, Circulation research.

[185]  T. Soderling,et al.  Characterization of a calmodulin kinase II inhibitor protein in brain. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[186]  B. Pitt,et al.  EPLERENONE POST-ACUTE MYOCARDIAL INFARCTION HEART FAILURE EFFICACY AND SURVIVAL STUDY INVESTIGATORS. EPLERENONE, A SELECTIVE ALDOSTERONE BLOCKER, IN PATIENTS WITH LEFT VENTRICULAR DYSFUNCTION AFTER MYOCARDIAL INFARCTION , 2003 .

[187]  L. Blatter,et al.  Mitochondrial Ca2+ and the heart. , 2008, Cell calcium.

[188]  P. Doevendans,et al.  Requirement of Nuclear Factor of Activated T-cells in Calcineurin-mediated Cardiomyocyte Hypertrophy* , 2002, The Journal of Biological Chemistry.

[189]  S. Houser,et al.  [Na+]i handling in the failing human heart. , 2003, Cardiovascular research.

[190]  M. Weir,et al.  The Cardiac Arrhythmia Suppression Trial Investigators: Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression After Myocardial Infarction. , 1990 .

[191]  T. Hewett,et al.  PKC-alpha regulates cardiac contractility and propensity toward heart failure. , 2004, Nature medicine.

[192]  G. Isenberg,et al.  Microheterogeneity of subsarcolemmal sodium gradients. Electron probe microanalysis in guinea‐pig ventricular myocytes. , 1993, The Journal of physiology.

[193]  Rosario Rizzuto,et al.  Mitochondria as sensors and regulators of calcium signalling , 2012, Nature Reviews Molecular Cell Biology.

[194]  M. Mongillo,et al.  Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. , 2010, The Journal of clinical investigation.

[195]  J. Gwathmey,et al.  Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. , 1990, Circulation.

[196]  P. Powers,et al.  Intact &bgr;-Adrenergic Response and Unmodified Progression Toward Heart Failure in Mice With Genetic Ablation of a Major Protein Kinase A Phosphorylation Site in the Cardiac Ryanodine Receptor , 2007, Circulation research.

[197]  D. Allen,et al.  Effects of stretch‐activated channel blockers on [Ca2+]i and muscle damage in the mdx mouse , 2005, The Journal of physiology.

[198]  M. Böhm,et al.  Quantification of beta-adrenoceptors and beta-adrenoceptor kinase on protein and mRNA levels in heart failure. , 1994, European heart journal.

[199]  T. Hisada,et al.  Mitochondrial colocalization with Ca2+ release sites is crucial to cardiac metabolism. , 2013, Biophysical journal.

[200]  J. Ervasti,et al.  Membrane organization of the dystrophin-glycoprotein complex , 1991, Cell.

[201]  G. Dorn,et al.  The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy , 2008, European heart journal.

[202]  Sheng Wei,et al.  T-Tubule Remodeling During Transition From Hypertrophy to Heart Failure , 2010, Circulation research.

[203]  R. Balaban.  Cardiac energy metabolism homeostasis: role of cytosolic calcium. , 2002, Journal of molecular and cellular cardiology.

[204]  R. Xiao,et al.  β-Adrenergic receptor subtype signaling in heart: From bench to bedside , 2012, Acta Pharmacologica Sinica.

[205]  J. Colyer,et al.  Stoichiometric phosphorylation of cardiac ryanodine receptor on serine 2809 by calmodulin-dependent kinase II and protein kinase A. , 2003, The Journal of biological chemistry.

[206]  Minoru Hongo,et al.  MLP-Deficient Mice Exhibit a Disruption of Cardiac Cytoarchitectural Organization, Dilated Cardiomyopathy, and Heart Failure , 1997, Cell.

[207]  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.

[208]  A. Wysłouch-Cieszyńska,et al.  Redox modifications of the C-terminal cysteine residue cause structural changes in S100A1 and S100B proteins. , 2004, Biochimica et biophysica acta.

[209]  M. Mattson,et al.  Superoxide Flashes in Single Mitochondria , 2008, Cell.

[210]  D. Bers,et al.  Ca2+/Calmodulin–Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure , 2005, Circulation research.

[211]  Donald M Bers,et al.  Intracellular Na+ Concentration Is Elevated in Heart Failure But Na/K Pump Function Is Unchanged , 2002, Circulation.

[212]  S. Marx,et al.  Ser1928 Is a Common Site for Cav1.2 Phosphorylation by Protein Kinase C Isoforms* , 2005, Journal of Biological Chemistry.

[213]  F. Sam,et al.  Aldosterone Stimulates Matrix Metalloproteinases and Reactive Oxygen Species in Adult Rat Ventricular Cardiomyocytes , 2005, Hypertension.

[214]  D. Sanoudou,et al.  Histidine-rich Ca-binding protein interacts with sarcoplasmic reticulum Ca-ATPase. , 2007, American journal of physiology. Heart and circulatory physiology.

[215]  D. Mancini,et al.  Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. , 2009, Journal of cardiac failure.

[216]  J. Molkentin,et al.  Impaired cardiac hypertrophic response in Calcineurin Aβ-deficient mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[217]  S. Viatchenko‐Karpinski,et al.  Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. , 2011, American journal of physiology. Cell physiology.

[218]  Godfrey L. Smith,et al.  S100A1: A regulator of myocardial contractility , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[219]  M. Cutler,et al.  Targeted Sarcoplasmic Reticulum Ca2+ ATPase 2a Gene Delivery to Restore Electrical Stability in the Failing Heart , 2012, Circulation.

[220]  H. Drexler,et al.  Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. , 1994, Circulation research.

[221]  Kevin M Flanigan,et al.  The Muscular Dystrophies , 1999, Seminars in Neurology.

[222]  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.

[223]  Niels Voigt,et al.  Oxidized CaMKII causes cardiac sinus node dysfunction in mice. , 2011, The Journal of clinical investigation.

[224]  Mark E. Anderson,et al.  β‐Adrenergic receptor antagonists ameliorate myocyte T‐tubule remodeling following myocardial infarction , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[225]  H. T. ter Keurs,et al.  Spontaneous diastolic contractions and phosphorylation of the cardiac ryanodine receptor at serine-2808 in congestive heart failure in rat. , 2006, Cardiovascular research.

[226]  R. Levi,et al.  Properties of cardiac cells from dystrophic mouse. , 1995, Journal of molecular and cellular cardiology.

[227]  R. Schwinger,et al.  Reduced Ca2+-Sensitivity of SERCA 2a in Failing Human Myocardium due to Reduced Serin-16 Phospholamban Phoshorylation , 1999 .

[228]  Mark E. Anderson,et al.  Ankyrin-B Protein in Heart Failure , 2012, The Journal of Biological Chemistry.

[229]  D. Bers,et al.  Ankyrin-B reduction enhances Ca spark-mediated SR Ca release promoting cardiac myocyte arrhythmic activity. , 2012, Journal of molecular and cellular cardiology.

[230]  D M Bers,et al.  Calcium fluxes involved in control of cardiac myocyte contraction. , 2000, Circulation research.

[231]  S. Sedej,et al.  JTV519 (K201) reduces sarcoplasmic reticulum Ca2+ leak and improves diastolic function in vitro in murine and human non‐failing myocardium , 2012, British journal of pharmacology.

[232]  M. Völkers,et al.  Cardiac S100A1 Protein Levels Determine Contractile Performance and Propensity Toward Heart Failure After Myocardial Infarction , 2006, Circulation.

[233]  Mark A Sussman,et al.  Prevention of cardiac hypertrophy in mice by calcineurin inhibition. , 1998, Science.

[234]  S. Houser,et al.  Contribution of reverse-mode sodium-calcium exchange to contractions in failing human left ventricular myocytes. , 1998, Cardiovascular research.

[235]  F. Lezoualc’h,et al.  Epac Mediates &bgr;-Adrenergic Receptor–Induced Cardiomyocyte Hypertrophy , 2008, Circulation research.

[236]  David J Weber,et al.  S100A1: Structure, Function, and Therapeutic Potential. , 2009, Current chemical biology.

[237]  M. Tymianski,et al.  Calcium, ischemia and excitotoxicity. , 2010, Cell calcium.

[238]  G. Dorn,et al.  Protein kinase cascades in the regulation of cardiac hypertrophy. , 2005, The Journal of clinical investigation.

[239]  N. Silverman,et al.  Abnormal mitochondrial respiration in failed human myocardium. , 2000, Journal of molecular and cellular cardiology.

[240]  U. Schotten,et al.  Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. , 2009, The Journal of clinical investigation.

[241]  Konrad Frank,et al.  Reduced Sodium Pump α1, α3, and β1-Isoform Protein Levels and Na+,K+-ATPase Activity but Unchanged Na+-Ca2+ Exchanger Protein Levels in Human Heart Failure , 1999 .

[242]  M. Birnbaum,et al.  MICU1 Is an Essential Gatekeeper for MCU-Mediated Mitochondrial Ca2+ Uptake that Regulates Cell Survival , 2012, Cell.

[243]  M. Caron,et al.  Removal of phosphorylation sites from the β2-adrenergic receptor delays onset of agonist-promoted desensitization , 1988, Nature.

[244]  J. Molkentin,et al.  Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy. , 2000, Circulation.

[245]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[246]  Tracy J. Pritchard,et al.  The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase. , 2012, Journal of molecular and cellular cardiology.

[247]  J. Metzger,et al.  Genetic manipulation of calcium-handling proteins in cardiac myocytes. I. Experimental studies. , 2005, American journal of physiology. Heart and circulatory physiology.

[248]  R. Schwinger,et al.  Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation. , 1999, Journal of molecular and cellular cardiology.

[249]  R. Hajjar,et al.  Modulation of Cardiac Contractility by the Phopholamban/SERCA2a Regulatome , 2012, Circulation research.

[250]  S. Day,et al.  Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function , 2007, Journal of Molecular Medicine.

[251]  Mark E. Anderson,et al.  Ryanodine Receptor Phosphorylation by Calcium/Calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice With Heart Failure , 2010, Circulation.

[252]  A. Mattiazzi,et al.  Angiotensin II–Induced Oxidative Stress Resets the Ca2+ Dependence of Ca2+–Calmodulin Protein Kinase II and Promotes a Death Pathway Conserved Across Different Species , 2009, Circulation research.

[253]  T. Levine,et al.  Calcium uptake by cardiac sarcoplasmic reticulum in human dilated cardiomyopathy. , 1987, Cardiovascular research.

[254]  C. Zazueta,et al.  Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post‐ischaemic functional recovery in rats in vivo , 2006, British journal of pharmacology.

[255]  S. Houser,et al.  Protein Kinase Cα, but Not PKCβ or PKCγ, Regulates Contractility and Heart Failure Susceptibility: Implications for Ruboxistaurin as a Novel Therapeutic Approach , 2009, Circulation research.

[256]  A. Mansur,et al.  Mutations in the human phospholamban gene in patients with heart failure. , 2011, American heart journal.

[257]  Tong Zhang,et al.  Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. , 2009, The Journal of clinical investigation.

[258]  F Sachs,et al.  Stretch‐activated single ion channel currents in tissue‐cultured embryonic chick skeletal muscle. , 1984, The Journal of physiology.

[259]  J. Molkentin,et al.  Calcineurin and human heart failure , 1999, Nature Medicine.

[260]  E. Kranias,et al.  Role of PP1 in the regulation of Ca cycling in cardiac physiology and pathophysiology. , 2009, Frontiers in bioscience.

[261]  S. Houser,et al.  Adrenergic Regulation of Cardiac Contractility Does Not Involve Phosphorylation of the Cardiac Ryanodine Receptor at Serine 2808 , 2008, Circulation research.

[262]  Donald M Bers,et al.  Beta-adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase. , 2007, Circulation research.

[263]  Michael J Ackerman,et al.  Disrupted Junctional Membrane Complexes and Hyperactive Ryanodine Receptors After Acute Junctophilin Knockdown in Mice , 2011, Circulation.

[264]  H. Kawashima,et al.  Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes. , 2009, Journal of molecular and cellular cardiology.

[265]  G. Dorn,et al.  Cardiotrophic Effects of Protein Kinase C ε Analysis by In Vivo Modulation of PKCε Translocation , 2000 .

[266]  Claus W Heizmann,et al.  S100 proteins: structure, functions and pathology. , 2002, Frontiers in bioscience : a journal and virtual library.

[267]  J. Kurokawa,et al.  Neurohormonal Regulation of Cardiac Ion Channels in Chronic Heart Failure , 2009, Journal of cardiovascular pharmacology.

[268]  J. Molkentin,et al.  Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[269]  S. Neubauer,et al.  Cardiac dysfunction and development of heart failure. , 1993, European heart journal.

[270]  R. Gupta,et al.  Cardiopulmonary actions of 1-isopropylamino-3-(3-tolyloxy)-2-propanol hydrochloride: a new adrenergic beta receptor antagonist. , 1970, The Indian journal of medical research.

[271]  G. Hajnóczky,et al.  Quantification of calcium signal transmission from sarco‐endoplasmic reticulum to the mitochondria , 2000, The Journal of physiology.

[272]  D. Sawyer,et al.  &bgr;-Adrenergic Receptor–Stimulated Apoptosis in Cardiac Myocytes Is Mediated by Reactive Oxygen Species/c-Jun NH2-Terminal Kinase–Dependent Activation of the Mitochondrial Pathway , 2003, Circulation research.

[273]  Mark E. Anderson,et al.  RETRACTED: L-Type Ca2+ Channel Facilitation Mediated by Phosphorylation of the β Subunit by CaMKII , 2006 .

[274]  S. Reiken,et al.  Phosphodiesterase 4D Deficiency in the Ryanodine-Receptor Complex Promotes Heart Failure and Arrhythmias , 2005, Cell.

[275]  J. Mccormack,et al.  Role of calcium ions in regulation of mammalian intramitochondrial metabolism. , 1990, Physiological reviews.

[276]  S. Houser,et al.  CaMKII Negatively Regulates Calcineurin–NFAT Signaling in Cardiac Myocytes , 2009, Circulation research.

[277]  U. Schmidt,et al.  Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. , 1999, Circulation.

[278]  H. Bundgaard,et al.  Human myocardial Na,K-ATPase concentration in heart failure , 1996, Molecular and Cellular Biochemistry.

[279]  H. T. ter Keurs,et al.  Role of the sarcolemma in triggered propagated contractions in rat cardiac trabeculae. , 1991, Circulation research.

[280]  H. Sabbah.  Biologic Rationale for the Use of Beta-Blockers in the Treatment of Heart Failure , 2004, Heart Failure Reviews.

[281]  S. Currie.  Cardiac ryanodine receptor phosphorylation by CaM Kinase II: keeping the balance right. , 2009, Frontiers in bioscience.

[282]  Brian K. Kobilka,et al.  Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsin , 1986, Nature.

[283]  Tong Zhang,et al.  The &dgr;C Isoform of CaMKII Is Activated in Cardiac Hypertrophy and Induces Dilated Cardiomyopathy and Heart Failure , 2003, Circulation research.

[284]  Timothy E. Hewett,et al.  Pharmacological- and Gene Therapy–Based Inhibition of Protein Kinase Cα/β Enhances Cardiac Contractility and Attenuates Heart Failure , 2006 .

[285]  P. Bennett.  From myofibril to membrane; the transitional junction at the intercalated disc. , 2012, Frontiers in bioscience.

[286]  Mark E. Anderson,et al.  Oxidation of CaMKII determines the cardiotoxic effects of aldosterone , 2011, Nature Medicine.

[287]  H. T. ter Keurs,et al.  Spatial Nonuniformity of Excitation–Contraction Coupling Causes Arrhythmogenic Ca2+ Waves in Rat Cardiac Muscle , 2005, Circulation research.

[288]  A. Fabiato,et al.  CALCIUM‐INDUCED RELEASE OF CALCIUM FROM THE SARCOPLASMIC RETICULUM OF SKINNED CELLS FROM ADULT HUMAN, DOG, CAT, RABBIT, RAT, AND FROG HEARTS AND FROM FETAL AND NEW‐BORN RAT VENTRICLES * , 1978, Annals of the New York Academy of Sciences.

[289]  Stephan E. Lehnart,et al.  Ca2+/Calmodulin-Dependent Protein Kinase II Phosphorylation Regulates the Cardiac Ryanodine Receptor , 2004, Circulation research.

[290]  R. Balaban,et al.  Role of mitochondrial Ca2+ in the regulation of cellular energetics. , 2012, Biochemistry.

[291]  D. Bers,et al.  Epac2 Mediates Cardiac &bgr;1-Adrenergic–Dependent Sarcoplasmic Reticulum Ca2+ Leak and Arrhythmia , 2013, Circulation.

[292]  C. Heizmann,et al.  Altered expression of the Ca(2+)-binding protein S100A1 in human cardiomyopathy. , 1996, Biochimica et biophysica acta.

[293]  Guy Salama,et al.  Calmodulin kinase II inhibition protects against structural heart disease , 2005, Nature Medicine.

[294]  G. Kaczorowski.  A molecular formula for heart failure and sudden cardiac death. Focus on "Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice". , 2011, American journal of physiology. Cell physiology.

[295]  U. Schmidt,et al.  Human heart failure: cAMP stimulation of SR Ca2+-ATPase activity and phosphorylation level of phospholamban. , 1999, American journal of physiology. Heart and circulatory physiology.

[296]  H. Ueda,et al.  Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes. , 2011, American journal of physiology. Heart and circulatory physiology.