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Mechanisms of Disease: new mechanisms of antiarrhythmic actions

Nature Clinical Practice Cardiovascular Medicine volume 1, pages 37–41 (2004)Cite this article

Abstract

Cardiac arrhythmias are a leading cause of morbidity and mortality in many developed countries. Despite intensive investigation, the cellular mechanisms for most cardiac arrhythmias have not been clearly established. As a consequence, drug therapy for most forms of atrial and ventricular arrhythmias remains largely empirical and ineffective, leading to the increased use of nonpharmacologic treatments. Clearly, new approaches to the prevention of cardiac arrhythmias are needed. Here we review the current experimental basis for several promising antiarrhythmic strategies, with a focus on those targeted against atrial and ventricular fibrillation. Although none of these strategies is yet ready for clinical application, they provide a basis for cautious optimism that effective pharmacologic therapy for fatal cardiac rhythm disturbances could be forthcoming.

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References

  1. Zipes DP et al. (1998) Sudden cardiac death. Circulation 98: 2334–2351

    Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. Waldo AL et al.; SWORD Investigators (1996) Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 348: 7–12

    Article  CAS  Google Scholar 

  4. Winfree AT (1998) Evolving perspectives during 12 years of electrical turbulence. Chaos 8: 1–20

    Article  Google Scholar 

  5. Jais P et al. (1997) A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 95: 572–576

    Article  CAS  Google Scholar 

  6. Antzelevitch C (2000) Electrical heterogeneity, cardiac arrhythmias, and the sodium channel. Circ Res 87: 964–965

    Article  CAS  Google Scholar 

  7. Janse J and Wit AL (1989) Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 69: 1049–1169

    Article  CAS  Google Scholar 

  8. Karma A (1994) Electrical alternans and spiral wave breakup in cardiac tissue. Chaos 4: 461–472

    Article  Google Scholar 

  9. Fox JJ et al. (2002) Spatiotemporal transition to conduction block in canine ventricle. Circ Res 90: 289–296

    Article  CAS  Google Scholar 

  10. Weiss JN et al. (2002) Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol 13: 292–295

    Article  Google Scholar 

  11. Pastore JM et al. (1999) Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. Circ Res 99: 1385–1394

    Article  CAS  Google Scholar 

  12. Riccio ML et al. (1999) Electrical restitution and spatiotemporal organization during ventricular fibrillation. Circ Res 84: 955–963

    Article  CAS  Google Scholar 

  13. Garfinkel A et al. (2000) Preventing ventricular fibrillation by flattening cardiac restitution. Proc Natl Acad Sci USA 97: 6061–6066

    Article  CAS  Google Scholar 

  14. Chen PS et al. (2003) A tale of two fibrillations. Circulation 108: 2298–2303

    Article  Google Scholar 

  15. Fox JJ et al. (2002) Ionic mechanism of cardiac alternans. Am J Physiol Heart Circ Physiol 282: H516–H530

    Article  CAS  Google Scholar 

  16. Salata JJ et al. (1998) A novel benzodiazepine that activates cardiac slow delayed rectifier K+ channels. Mol Pharmacol 53: 220–230

    Article  Google Scholar 

  17. Heath BM and Terrar DA (2000) Protein kinase C enhances the rapidly activated delayed rectifier potassium current, IKr, through a reduction in C-type inactivation in guinea pig ventricular myocytes. J Physiol 522: 391–402

    Article  CAS  Google Scholar 

  18. Marx SO et al. (2002) Requirement of a macromolecular signaling complex for β adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295: 496–499

    Article  CAS  Google Scholar 

  19. Hua F et al. (2004) Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes. Am J Physiol Heart Circ Physiol 286: H2342–H2351

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Ennis IL et al. (2002) Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility. J Clin Invest 109: 393–400

    Article  CAS  Google Scholar 

  22. Samie FH et al. (2001) Rectification of the background potassium current: a determinant of rotor dynamics in ventricular fibrillation. Circ Res 89: 1216–1223

    Article  CAS  Google Scholar 

  23. Nishikawa M and Huang L (2001) Nonviral vectors in the new millennium: delivery barriers in gene transfer. Hum Gene Ther 12: 861–870

    Article  CAS  Google Scholar 

  24. Sarmast F et al. (2003) Cholinergic atrial fibrillation: IK,ACh gradients determine unequal left/right atrial frequencies and rotor dynamics. Cardiovasc Res 59: 863–873

    Article  CAS  Google Scholar 

  25. Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415: 219–226

    Article  CAS  Google Scholar 

  26. Goldhaber JI et al. (2002) Cellular basis of action potential duration alternans: role of the L-type calcium current and intracellular calcium cycling. Circulation 106: 228–228

    Google Scholar 

  27. Wehrens XHT et al. (2004) Protection from cardiac arrhythmias through ryanodine receptor-stabilizing protein calstabin2. Science 304: 292–296

    Article  CAS  Google Scholar 

  28. Anderson ME (2004) Calmodulin kinase and L-type calcium channels: a recipe for arrhythmias? Trends Cardiovasc Med 14: 152–161

    Article  CAS  Google Scholar 

  29. Satoh T and Zipes DP (1996) Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation. J Cardiovasc Electrophysiol 7: 833–842

    Article  CAS  Google Scholar 

  30. Janse MJ et al. (2003) Mechanical effects on arrhythmogenesis: from pipette to patient. Prog Biophys Mol Biol 82: 187–195

    Article  Google Scholar 

  31. Craelius W et al. (1988) Stretch activated ion channels in ventricular myocytes. Biosci Rep 8: 407–414

    Article  CAS  Google Scholar 

  32. Clemo HF et al. (1999) Swelling-activated chloride current is persistently activated in ventricular myocytes from dogs with tachycardia-induced heart failure. Circ Res 84: 157–165

    Article  CAS  Google Scholar 

  33. Niu W and Sachs F (2003) Dynamic properties of stretch-activated K+ channels in adult rat myocytes. Prog Biophys Mol Biol 82: 121–135

    Article  CAS  Google Scholar 

  34. Isenberg G et al. (2003) Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes. Prog Biophys Mol Biol 82: 43–56

    Article  CAS  Google Scholar 

  35. Bode F et al. (2001) Tarantula peptide inhibits atrial fibrillation. Nature 409: 35–36

    Article  CAS  Google Scholar 

  36. Chen RL et al. (2003) Stretch-induced regional mechanoelectric dispersion and arrhythmias in the right ventricle of anesthetized lambs. Am J Physiol Heart Circ Physiol 286: H1008–H1014

    Article  Google Scholar 

  37. Komoro I and Yazaki Y (1993) Control of cardiac gene expression by mechanical stress. Ann Rev Physiol 55: 55–75

    Article  Google Scholar 

  38. Allessie MA et al. (2002) Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 54: 230–246

    Article  CAS  Google Scholar 

  39. Li D et al. (2001) Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing induced congestive heart failure. Circulation 104: 2608–2614

    Article  CAS  Google Scholar 

  40. Moreno AP (2004) Biophysical properties of homomeric and heteromultimeric channels formed by cardiac connexins. Cardiovasc Res 62: 276–286

    Article  CAS  Google Scholar 

  41. Poelzing S et al. (2003) Heterogeneous connexin43 expression produces electrophysiological heterogeneities across the ventricular wall. Am J Physiol Heart Circ Physiol 286: H2001–H2009

    Article  Google Scholar 

  42. Saffitz JE et al. (1999) Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res 42: 309–317

    Article  CAS  Google Scholar 

  43. Kucera J et al. (2002) Localization of sodium channels in intercalated disks modulates cardiac conduction. Circ Res 91: 1176–1182

    Article  CAS  Google Scholar 

  44. Poelzing S et al. (online 17 June 2004) Altered connexin43 expression produces arrhythmia substrate in heart failure [http://ajpheart.physiology.org/cgi/reprint/00346.2004v1] (accessed 15 September 2004)

  45. Kostin S et al. (2004) Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc Res 62: 426–436

    Article  CAS  Google Scholar 

  46. Yao J-A et al. (2003) Remodeling of gap junction channel function in epicardial border zone of healing canine infarcts. Circ Res 92: 437–443

    Article  CAS  Google Scholar 

  47. Yamada KA et al. (2003) Up-regulation of connexin45 in heart failure. J Cardiovasc Electrophysiol 14: 1205–1212

    Article  Google Scholar 

  48. Gaudesius G et al. (2003) Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ Res 93: 421–428

    Article  CAS  Google Scholar 

  49. John SA et al. (1999) Connexin-43 hemichannels opened by metabolic inhibition. J Biol Chem 274: 236–240

    Article  CAS  Google Scholar 

  50. Eloff BC et al. (2003) Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction: evidence supporting a novel target for antiarrhythmic therapy. Circulation 108: 3157–3163

    Article  CAS  Google Scholar 

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Acknowledgements

Grants given by: NIH, National Science Foundation, American Heart Association, New York State Affiliate Inc and Krannert Charitable Trust.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA

    Robert F Gilmour Jr & Douglas P Zipes

  2. Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA

    Robert F Gilmour Jr & Douglas P Zipes

Authors
  1. Robert F Gilmour Jr
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  2. Douglas P Zipes
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Correspondence to Robert F Gilmour Jr.

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DZ is a consultant for and has received grants from Medtronic.

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Gilmour, R., Zipes, D. Mechanisms of Disease: new mechanisms of antiarrhythmic actions. Nat Rev Cardiol 1, 37–41 (2004). https://doi.org/10.1038/ncpcardio0024

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