Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: ion channel remodeling in the failing ventricle

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 196–207 (2008)Cite this article

Abstract

In an attempt to compensate for compromised hemodynamics in heart failure, neurohumoral mechanisms are activated that trigger fundamental changes in gene expression and in protein processing, trafficking and post-translational regulation, resulting in myocyte hypertrophy. Unfortunately, over time these changes become maladaptive, predisposing to myocyte loss, chamber dilatation, interstitial hyperplasia and intercellular uncoupling. Intrinsic and peripheral responses to mechanical dysfunction alter the expression and function of key ion channels and calcium-handling proteins, thereby remodeling the cellular action potential and the intracellular calcium transient. This electrophysiological remodeling renders the heart more vulnerable to ventricular arrhythmias that underlie sudden cardiac death. In this Review, we consider key ventricular ionic changes that are associated with heart failure, with the intention of identifying molecular targets for antiarrhythmic therapy.

Key Points

  • Ion channel dysfunction is a hallmark of heart failure, underlying much of the electrical remodeling that occurs at the cellular level in the failing heart and predisposing individuals to ventricular arrhythmias

  • Alterations in sodium, potassium and calcium channels and transporters result in overall prolongation of the cellular action potential, an increase in the spatiotemporal gradients of repolarization, a slowing of conduction velocity, an enhanced propensity for arrhythmic triggers and conduction block—all of which combine to form a hostile environment ripe for the generation of malignant arrhythmias

  • Abnormalities in intracellular calcium cycling form an important mechanistic link between electrical and contractile dysfunction

  • Elucidation of arrhythmia mechanisms at the basic ionic level will help improve traditional pharmacological therapies and facilitate the design of novel approaches, including cell-transfer and gene-transfer strategies designed to target ion channels and transporters

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The ventricular action potential.
Figure 2: Schematic of the cardiac cell displaying surface ion channels and intracellular calcium-cycling proteins.

Similar content being viewed by others

References

  1. Schocken DD et al. (1992) Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol 20: 301–306

    Article  CAS  PubMed  Google Scholar 

  2. Tomaselli GF et al. (1994) Sudden cardiac death in heart failure: the role of abnormal repolarization. Circulation 90: 2534–2539

    Article  CAS  PubMed  Google Scholar 

  3. Estes NAM 3rd et al. (2003) Use of antiarrhythmics and implantable cardioverter-defibrillators in congestive heart failure. Am J Cardiol 91 (Suppl 1): S45–S52

    Article  CAS  Google Scholar 

  4. Echt DS et al. (1991) Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med 324: 781–788

    Article  CAS  PubMed  Google Scholar 

  5. Schram G et al. (2002) Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res 90: 939–950

    Article  CAS  PubMed  Google Scholar 

  6. Akar FG and Rosenbaum DS (2003) Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure. Circ Res 93: 638–645

    Article  CAS  PubMed  Google Scholar 

  7. Berger RD et al. (1997) Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 96: 1557–1565

    Article  CAS  PubMed  Google Scholar 

  8. Nattel S et al. (2005) Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol 20: 21–25

    PubMed  Google Scholar 

  9. Nattel S and Li D (2000) Ionic remodeling in the heart: pathophysiological significance and new therapeutic opportunities for atrial fibrillation. Circ Res 87: 440–447

    Article  CAS  PubMed  Google Scholar 

  10. Tomaselli GF and Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Circ Res 42: 270–283

    CAS  Google Scholar 

  11. Akar FG et al. (2004) Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy. Circ Res 95: 717–725

    Article  CAS  PubMed  Google Scholar 

  12. Pajouh M et al. (2005) IKs blockade reduces dispersion of repolarization in heart failure. Heart Rhythm 2: 731–738

    Article  PubMed  Google Scholar 

  13. Greenstein JL et al. (2000) Role of the calcium-independent transient outward current I(to1) in shaping action potential morphology and duration. Circ Res 87: 1026–1033

    Article  CAS  PubMed  Google Scholar 

  14. Carmeliet E (1993) K+ channels and control of ventricular repolarization in the heart. Fundam Clin Pharmacol 7: 19–28

    Article  CAS  PubMed  Google Scholar 

  15. Rozanski GJ et al. (1998) Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction. Am J Physiol 274: H259–H265

    CAS  PubMed  Google Scholar 

  16. Kaab S et al. (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98: 1383–1393

    Article  CAS  PubMed  Google Scholar 

  17. Guo W et al. (1999) Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes. J Physiol 521: 587–599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Akar FG et al. (2004) Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito. Am J Physiol Heart Circ Physiol 286: H602–H609

    Article  CAS  PubMed  Google Scholar 

  19. Akar FG et al. (2005) Molecular mechanisms underlying potassium current down-regulation in heart failure. Am J Physiol Heart Circ Physiol 288: H2887–H2896

    Article  CAS  PubMed  Google Scholar 

  20. Lebeche D et al. (2004) In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis. Circulation 110: 3435–3443

    Article  CAS  PubMed  Google Scholar 

  21. Pourrier M et al. (2003) Properties, expression and potential roles of cardiac K+ channel accessory subunits: MinK, MiRPs, KChIP, and KChAP. J Membr Biol 194: 141–152

    Article  CAS  PubMed  Google Scholar 

  22. Jerng HH et al. (2004) Molecular physiology and modulation of somatodendritic A-type potassium channels. Mol Cell Neurosci 27: 343–369

    Article  CAS  PubMed  Google Scholar 

  23. An WF et al. (2000) Modulation of A-type potassium channels by a family of calcium sensors. Nature 403: 553–556

    Article  CAS  PubMed  Google Scholar 

  24. Rosati B et al. (2001) Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol 533: 119–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McCrossan ZA and Abbott GW (2004) The MinK-related peptides. Neuropharmacology 47: 787–821

    Article  CAS  PubMed  Google Scholar 

  26. Wang Z et al. (1998) Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. Circulation 98: 2422–2428

    Article  CAS  PubMed  Google Scholar 

  27. Nuss HB et al. (1999) Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am J Physiol 277: H80–H91

    CAS  PubMed  Google Scholar 

  28. Miake J et al. (2002) Biological pacemaker created by gene transfer. Nature 419: 132–133

    Article  CAS  PubMed  Google Scholar 

  29. Warren M et al. (2003) Blockade of the inward rectifying potassium current terminates ventricular fibrillation in the guinea pig heart. J Cardiovasc Electrophysiol 14: 621–631

    Article  PubMed  Google Scholar 

  30. Noujaim SF et al. (2007) Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors. J Physiol 578: 315–326

    Article  CAS  PubMed  Google Scholar 

  31. Nattel S (2000) Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders. Cardiovasc Res 48: 188–190

    Article  CAS  PubMed  Google Scholar 

  32. Li GR et al. (2002) Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283: H1031–H1041

    Article  CAS  PubMed  Google Scholar 

  33. Tsuji Y et al. (2006) Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes. Circulation 113: 345–355

    Article  CAS  PubMed  Google Scholar 

  34. Han W et al. (2001) Ionic remodeling of cardiac Purkinje cells by congestive heart failure. Circulation 104: 2095–2100

    Article  CAS  PubMed  Google Scholar 

  35. Akar FG et al. (2002) Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome. Circulation 105: 1247–1253

    Article  PubMed  Google Scholar 

  36. Choy A-M et al. (1996) Regional expression of HERG and KvLQT1 in heart failure. Circulation 94: 164

    Google Scholar 

  37. Ehrlich JR et al. (2004) KvLQT1 modulates the distribution and biophysical properties of HERG: a novel α-subunit interaction between delayed rectifier currents. J Biol Chem 279: 1233–1241

    Article  CAS  PubMed  Google Scholar 

  38. Nuss HB et al. (1999) Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. J Clin Invest 103: 889–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mazhari R et al. (2002) Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval. J Clin Invest 109: 1083–1090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kimura S et al. (1991) Differences in the effect of metabolic inhibition on action potentials and calcium currents in endocardial and epicardial cells. Circulation 84: 768–777

    Article  CAS  PubMed  Google Scholar 

  41. O'Rourke B (2000) Myocardial K(ATP) channels in preconditioning. Circ Res 87: 845–855

    Article  CAS  PubMed  Google Scholar 

  42. Akar FG et al. (2005) The mitochondrial origin of postischemic arrhythmias. J Clin Invest 115: 3527–3535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Aon MA et al. (2006) Mitochondrial criticality: a new concept at the turning point of life or death. Biochim Biophys Acta 1762: 232–240

    Article  CAS  PubMed  Google Scholar 

  44. Baruscotti M and Difrancesco D (2004) Pacemaker channels. Ann NY Acad Sci 1015: 111–121

    Article  PubMed  Google Scholar 

  45. Cerbai E et al. (1997) Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart. Circulation 95: 568–571

    Article  CAS  PubMed  Google Scholar 

  46. Hoppe UC et al. (1998) Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation 97: 55–65

    Article  CAS  PubMed  Google Scholar 

  47. Cerbai E et al. (1996) Occurrence and properties of the hyperpolarization-activated current If in ventricular myocytes from normotensive and hypertensive rats during aging. Circulation 94: 1674–1681

    Article  CAS  PubMed  Google Scholar 

  48. Ludwig A et al. (1998) A family of hyperpolarization-activated mammalian cation channels. Nature 393: 587–591

    Article  CAS  PubMed  Google Scholar 

  49. Santoro B et al. (1998) Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93: 717–729

    Article  CAS  PubMed  Google Scholar 

  50. Zicha S et al. (2005) Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc Res 66: 472–481

    Article  CAS  PubMed  Google Scholar 

  51. Tse HF et al. (2006) Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model. Circulation 114: 1000–1011

    Article  CAS  PubMed  Google Scholar 

  52. Mulder P and Thuillez C (2006) Heart rate slowing for myocardial dysfunction/heart failure. Adv Cardiol 43: 97–105

    Article  PubMed  Google Scholar 

  53. Brooksby P et al. (1993) The electrophysiological characteristics of hypertrophied ventricular myocytes from the spontaneously hypertensive rat. J Hypertens 11: 611–622

    Article  CAS  PubMed  Google Scholar 

  54. Cerbai E et al. (1994) Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc Res 28: 1180–1187

    Article  CAS  PubMed  Google Scholar 

  55. Richard S et al. (1998) Ca2+ currents in compensated hypertrophy and heart failure. Cardiovasc Res 37: 300–311

    Article  CAS  PubMed  Google Scholar 

  56. Hill JA (2003) Electrical remodeling in cardiac hypertrophy. Trends Cardiovasc Med 13: 316–322

    Article  CAS  PubMed  Google Scholar 

  57. Ouadid H et al. (1995) Calcium currents in diseased human cardiac cells. J Cardiovasc Pharmacol 25: 282–291

    Article  CAS  PubMed  Google Scholar 

  58. Ryder KO et al. (1993) Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aortic coarctation. Cardiovasc Res 27: 1278–1287

    Article  CAS  PubMed  Google Scholar 

  59. Schroder F et al. (1998) Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle. Circulation 98: 969–976

    Article  CAS  PubMed  Google Scholar 

  60. Sipido KR et al. (1998) A critical role for L-type Ca2+ current in the regulation of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from dilated cardiomyopathy. Ann NY Acad Sci 853: 353–356

    Article  CAS  PubMed  Google Scholar 

  61. Cingolani E et al. (2007) Gene therapy to inhibit the calcium channel β subunit: physiological consequences and pathophysiological effects in models of cardiac hypertrophy. Circ Res 101: 166–175

    Article  CAS  PubMed  Google Scholar 

  62. Samie FH et al. (2000) A mechanism of transition from ventricular fibrillation to tachycardia: effect of calcium channel blockade on the dynamics of rotating waves. Circ Res 86: 684–691

    Article  CAS  PubMed  Google Scholar 

  63. Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16: 521–555

    Article  CAS  PubMed  Google Scholar 

  64. Clozel JP et al. (1999) Voltage-gated T-type Ca2+ channels and heart failure. Proc Assoc Am Physicians 111: 429–437

    Article  CAS  PubMed  Google Scholar 

  65. Nuss HB and Houser SR (1993) T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res 73: 777–782

    Article  CAS  PubMed  Google Scholar 

  66. Wang HS and Cohen IS (2003) Calcium channel heterogeneity in canine left ventricular myocytes. J Physiol 547: 825–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Winslow RL et al. (1999) Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. Circ Res 84: 571–586

    Article  CAS  PubMed  Google Scholar 

  68. O'Rourke B et al. (1999) Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies. Circ Res 84: 562–570

    Article  CAS  PubMed  Google Scholar 

  69. Levine BA et al. (1999) Sites on the cytoplasmic region of phospholamban involved in interaction with the calcium-activated ATPase of the sarcoplasmic reticulum. Eur J Biochem 264: 905–913

    Article  CAS  PubMed  Google Scholar 

  70. McKenna E et al. (1996) Dissociation of phospholamban regulation of cardiac sarcoplasmic reticulum Ca2+ATPase by quercetin. J Biol Chem 271: 24517–24525

    Article  CAS  PubMed  Google Scholar 

  71. Ohizumi Y et al. (1996) Stimulation of sarcoplasmic reticulum Ca(2+)-ATPase by gingerol analogues. Biol Pharm Bull 19: 1377–1379

    Article  CAS  PubMed  Google Scholar 

  72. del Monte F et al. (2001) Overwhelming evidence of the beneficial effects of SERCA gene transfer in heart failure. Circ Res 88: E66–E67

    Article  CAS  PubMed  Google Scholar 

  73. Sakata S et al. (2007) Targeted gene transfer increases contractility and decreases oxygen cost of contractility in normal rat hearts. Am J Physiol Heart Circ Physiol 292: H2356–H2363

    Article  CAS  PubMed  Google Scholar 

  74. Sakata S et al. (2007) Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol 42: 852–861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hasenfuss G et al. (1997) Calcium handling proteins in the failing human heart. Basic Res Cardiol 92 (Suppl 1): S87–S93

    Article  Google Scholar 

  76. del Monte F et al. (2002) Targeting phospholamban by gene transfer in human heart failure. Circulation 105: 904–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Janczewski AM et al. (2004) Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model. Cardiovasc Res 62: 468–480

    Article  CAS  PubMed  Google Scholar 

  78. Bers DM et al. (2002) Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure. Basic Res Cardiol 97 (Suppl 1): I36–I42

    PubMed  Google Scholar 

  79. Mattiello JA et al. (1998) Contribution of reverse-mode sodium-calcium exchange to contractions in failing human left ventricular myocytes. Cardiovasc Res 37: 424–431

    Article  CAS  PubMed  Google Scholar 

  80. Houser SR et al. (2000) Functional properties of failing human ventricular myocytes. Trends Cardiovasc Med 10: 101–107

    Article  CAS  PubMed  Google Scholar 

  81. Sipido KR et al. (2002) Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy. Cardiovasc Res 53: 782–805

    Article  CAS  PubMed  Google Scholar 

  82. Arai M et al. (1993) Alterations in sarcoplasmic reticulum gene expression in human heart failure: a possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res 72: 463–469

    Article  CAS  PubMed  Google Scholar 

  83. Hobai IA et al. (2004) Partial inhibition of sodium/calcium exchange restores cellular calcium handling in canine heart failure. Circ Res 95: 292–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Meyer M et al. (1995) Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92: 778–784

    Article  CAS  PubMed  Google Scholar 

  85. Heerdt PM et al. (2000) Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation 102: 2713–2719

    Article  CAS  PubMed  Google Scholar 

  86. Marx SO et al. (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101: 365–376

    Article  CAS  PubMed  Google Scholar 

  87. Curran J et al. (2007) Beta-adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase. Circ Res 100: 391–398

    Article  CAS  PubMed  Google Scholar 

  88. Marks AR (2006) Novel therapy for heart failure and exercise-induced ventricular tachycardia based on 'fixing' the leak in ryanodine receptors. Novartis Found Symp 274: 132–147

    CAS  PubMed  Google Scholar 

  89. Kirchhefer U et al. (1999) Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts. Cardiovasc Res 42: 254–261

    Article  CAS  PubMed  Google Scholar 

  90. Maier LS and Bers DM (2002) Calcium, calmodulin, and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Mol Cell Cardiol 34: 919–939

    Article  CAS  PubMed  Google Scholar 

  91. Lokuta AJ et al. (1995) Modulation of cardiac ryanodine receptors of swine and rabbit by a phosphorylation-dephosphorylation mechanism. J Physiol 487: 609–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kohlhaas M et al. (2006) Increased sarcoplasmic reticulum calcium leak but unaltered contractility by acute CaMKII overexpression in isolated rabbit cardiac myocytes. Circ Res 98: 235–244

    Article  CAS  PubMed  Google Scholar 

  93. Anderson ME et al. (2006) Disease mechanisms and emerging therapies: protein kinases and their inhibitors in myocardial disease. Nat Clin Pract Cardiovasc Med 3: 437–445

    Article  CAS  PubMed  Google Scholar 

  94. Pogwizd SM et al. (2003) Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res 57: 887–896

    Article  CAS  PubMed  Google Scholar 

  95. Shimizu W and Antzelevitch C (1997) Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade de pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation 96: 2038–2047

    Article  CAS  PubMed  Google Scholar 

  96. Pu J and Boyden PA (1997) Alterations of Na+ currents in myocytes from epicardial border zone of the infarcted heart: a possible ionic mechanism for reduced excitability and postrepolarization refractoriness. Circ Res 81: 110–119

    Article  CAS  PubMed  Google Scholar 

  97. Undrovinas AI et al. (1999) Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current. Cell Mol Life Sci 55: 494–505

    Article  CAS  PubMed  Google Scholar 

  98. Auerbach D et al. (2006) Antifibrillatory action of increased excitability in neonatal rat ventricular monolayers overexpressing hSCN5A [abstract]. Circulation 114 (Suppl): II-268–II-269

    Google Scholar 

  99. Baartscheer A et al. (2003) Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res 57: 1015–1024

    Article  CAS  PubMed  Google Scholar 

  100. Baartscheer A et al. (2003) [Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure. Cardiovasc Res 57: 986–995

    Article  CAS  PubMed  Google Scholar 

  101. Karmazyn M et al. (2001) The myocardial Na+/H+ exchanger: a potential therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and attenuation of postinfarction heart failure. Drugs 61: 375–389

    Article  CAS  PubMed  Google Scholar 

  102. Pogwizd SM (2003) Clinical potential of sodium-calcium exchanger inhibitors as antiarrhythmic agents. Drugs 63: 439–452

    Article  CAS  PubMed  Google Scholar 

  103. Erhardt LR (1999) GUARD During Ischemia Against Necrosis (GUARDIAN) trial in acute coronary syndromes. Am J Cardiol 83 (May Suppl 1): S23–S25

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. RD Nass is a Research Fellow in the Cardiovascular Research Center and FG Akar is Assistant Professor of Medicine, Pharmacology, and Systems Therapeutics at the Mount Sinai School of Medicine, New York, NY,

    Robert D Nass & Fadi G Akar

  2. T Aiba is a Postdoctoral Research Fellow in the Division of Cardiology and GF Tomaselli is the David J Carver Professor of Medicine and Chair of Cardiology at Johns Hopkins University, Baltimore, MD, USA.,

    Takeshi Aiba & Gordon F Tomaselli

Authors
  1. Robert D Nass
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Aiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gordon F Tomaselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fadi G Akar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fadi G Akar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nass, R., Aiba, T., Tomaselli, G. et al. Mechanisms of Disease: ion channel remodeling in the failing ventricle. Nat Rev Cardiol 5, 196–207 (2008). https://doi.org/10.1038/ncpcardio1130

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1130

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing