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Biophysical and Molecular Targets

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Cardiac Arrhythmias

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Abstract

Cardiac arrhythmia is the leading cause of death in the Western world despite significant therapeutic improvements by surgical, interventional, and pharmacological approaches in the last decade. This chapter reviews the latest research in identifying drugs and targets with the aim of preventing the arrhythmia. We discuss the therapeutic regulation of ion channels which are important targets that are modulated by a range of currently prescribed drugs. Next we review efficacies of upstream therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, n-3 polyunsaturated fatty acids, and calcium channel blockers in preventing specific mechanisms of arrhythmias. We conclude with the current knowledge about microRNAs in cardiovascular diseases which are emerging as interesting new drug targets. The potential advantages of pharmacological antiarrhythmic agents motivate continued efforts to identify novel therapeutic means to restore and maintain cardiac rhythm. This review provides a succinct overview of some of the current investigational or recently approved strategies for improving efficacy and safety of antiarrhythmic therapies.

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References

  1. Adam O, Neuberger HR, et al. Prevention of atrial fibrillation with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Circulation. 2008;118:1285–93.

    Article  PubMed  Google Scholar 

  2. Antzelevitch C. Genetic basis of Brugada syndrome. Heart Rhythm. 2007;4:756.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Bányász T, Szentandrássy N. Cardiac calmodulin kinase: a potential target for drug design. Curr Med Chem. 2011;18:3707–13.

    Article  PubMed  Google Scholar 

  4. Barrington PL, Martin RL, Zhang K. Slowly inactivating sodium currents are reduced by exposure to oxidative stress. J Mol Cell Cardiol. 1997;29:3251–65.

    Article  CAS  PubMed  Google Scholar 

  5. Belevych AE, Sansom SE, et al. MicroRNA-1 and −133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLoS One. 2011;6:e28324.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Bostjancic E, Zidar N, et al. MicroRNAs miR-1, miR-133a, miR-133b and miR-208 are dysregulated in human myocardial infarction. Cardiology. 2010;115:163–9.

    Article  CAS  PubMed  Google Scholar 

  7. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802–9.

    Article  CAS  PubMed  Google Scholar 

  8. Callis TE, Pandya K, et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009;119:2772–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Carnes CA, Chung MK, et al. Ascorbate attenuates atrial pacinginduced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res. 2001;89:E32–8.

    Article  CAS  PubMed  Google Scholar 

  10. Chelu MG, Wehrens XH. Sarcoplasmic reticulum calcium leak and cardiac arrhythmias. J Mol Cell Cardiol. 2011;50:214–22.

    Article  Google Scholar 

  11. da Costa Martins PA, Bourajjaj M, et al. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation. 2008;118:1567–76.

    Article  PubMed  Google Scholar 

  12. De Jong AM, Maass AH, et al. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res. 2011;89:754–65.

    Article  PubMed  Google Scholar 

  13. Dernellis J, Panaretou M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J. 2004;25:1100–7.

    Article  CAS  PubMed  Google Scholar 

  14. Disertori M, Barlera S, et al. Systematic review and meta-analysis: renin-Angiotensin system inhibitors in the prevention of atrial fibrillation recurrences. An unfulfilled hope. Cardiovasc Drugs Ther. 2012;26:47–54.

    Article  CAS  PubMed  Google Scholar 

  15. Dobrev D. Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target. Naunyn Schmiedebergs Arch Pharmacol. 2010;381:195–206.

    Article  CAS  PubMed  Google Scholar 

  16. Dulhunty AF, Casarotto MG, Beard NA. The ryanodine receptor: a pivotal Ca2+ regulatory protein and potential therapeutic drug target. Curr Drug Targets. 2011;12:709–23.

    Article  CAS  PubMed  Google Scholar 

  17. Fang WT, Li HJ, et al. The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Br J Clin Pharmacol. 2012. doi:10.1111/j.1365-2125.2012.04258.x.

    PubMed Central  PubMed  Google Scholar 

  18. Federman J, Whitford JA, et al. Incidence of ventricular arrhythmias in first year after myocardial infarction. Br Heart J. 1998;40:1243–50.

    Article  Google Scholar 

  19. George CH, Lai FA. Developing new anti-arrhythmics: clues from the molecular basis of cardiac ryanodine receptor (RyR2) Ca + −release channel dysfunction. Biochem Soc Trans. 2007;35:952–6.

    Article  Google Scholar 

  20. Girmatsion Z, Biliczki P, et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm. 2009;6:1802–9.

    Article  PubMed  Google Scholar 

  21. Harling L, Rasoli S, et al. Do antioxidant vitamins have an anti-arrhythmic effect following cardiac surgery? A meta-analysis of randomised controlled trials. Heart. 2011;97:1636–42.

    Article  CAS  PubMed  Google Scholar 

  22. He X, Gao X, et al. Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7. Circ Res. 2011;108:164–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Hodgkin AL, Huxley AF. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol. 1952;116:449–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Hu D, Viskin S, et al. Genetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias. J Electrocardiol. 2007;40:S26–9.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Huang CX, Liu Y, et al. Oxidative stress: a possible pathogenesis of atrial fibrillation. Med Hypotheses. 2009;72:466–7.

    Article  CAS  PubMed  Google Scholar 

  26. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol. 2007;50:2021–8.

    Article  CAS  PubMed  Google Scholar 

  27. Kim YM, Guzik TJ, et al. A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res. 2005;97:629–36.

    Article  CAS  PubMed  Google Scholar 

  28. Komatsu T, Tachibana H, et al. Long-term efficacy of upstream therapy with lipophilic or hydrophilic statins on antiarrhythmic drugs in patients with paroxysmal atrial fibrillation: comparison between atorvastatin and pravastatin. Int Heart J. 2011;52:359–65.

    Article  CAS  PubMed  Google Scholar 

  29. Korantzopoulos P, Kolettis TM, et al. The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. Int J Cardiol. 2007;115:135–43.

    Article  PubMed  Google Scholar 

  30. Kumagai K, Nakashima H, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41:2197–204.

    Article  CAS  PubMed  Google Scholar 

  31. Lampert R, McPherson CA, et al. Gender differences in ventricular arrhythmia recurrence in patients with coronary artery disease and implantable cardioverter-defibrillators. J Am Coll Cardiol. 2004;43:2293–9.

    Article  PubMed  Google Scholar 

  32. Laurita KR, Rosenbaum DS. Cellular mechanisms of arrhythmogenic cardiac alternans. Prog Biophys Mol Biol. 2008;97:332–47.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lehnart SE, Terrenoire C, et al. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. Proc Natl Acad Sci U S A. 2006;103:7906–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Liu N, Williams AH, et al. An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133. Proc Natl Acad Sci U S A. 2007;104:20844–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Lu Y, Zhang Y, et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010;122:2378–87.

    Article  CAS  PubMed  Google Scholar 

  36. Luo X, Xiao J, et al. Transcriptional activation by stimulating protein 1 and post-transcriptional repression by muscle-specific microRNAs of IKs-encoding genes and potential implications in regional heterogeneity of their expressions. J Cell Physiol. 2007;212:358–67.

    Article  CAS  PubMed  Google Scholar 

  37. Matkovich SJ, Wang W, et al. MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res. 2010;106:166–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Mihm MJ, Yu F, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001;104:174–80.

    Article  CAS  PubMed  Google Scholar 

  39. Mohammed KS, Kowey PR, Musco S. Adjuvant therapy for atrial fibrillation. Future Cardiol. 2010;6:67–81.

    Article  PubMed  Google Scholar 

  40. Moreno JD, Clancy CE. Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol. 2012;52:608–19.

    Article  CAS  PubMed  Google Scholar 

  41. Nattel S, Maguy A, et al. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87:425–56.

    Article  CAS  PubMed  Google Scholar 

  42. Nattel S, Shiroshita-Takeshita A, et al. Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol. 2005;20:21–5.

    PubMed  Google Scholar 

  43. Ono K, Kuwabara Y, Han J. MicroRNAs and cardiovascular diseases. FEBS J. 2011;278:1619–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res. 2011;108:871–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Rahimi K, Emberson J, et al. Executive effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ. 2011;16:342.

    Google Scholar 

  46. Rao PK, Toyama Y, et al. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure. Circ Res. 2009;105:585–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Rasoli S, Kakouros N, et al. Antioxidant vitamins in the prevention of atrial fibrillation: what is the evidence? Cardiol Res Pract. 2011;2011:164078.

    PubMed Central  PubMed  Google Scholar 

  48. Recanatini M, Poluzzi E, et al. QT prolongation through hERG K + channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev. 2005;25:133–66.

    Article  CAS  PubMed  Google Scholar 

  49. Rodrigo R, Vinay J, et al. Use of vitamins C and E as a prophylactic therapy to prevent postoperative atrial fibrillation. Int J Cardiol. 2010;138:221–8.

    Article  PubMed  Google Scholar 

  50. Savelieva I, Kakouros N, et al. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace. 2011;13:308–28.

    Article  PubMed  Google Scholar 

  51. Savelieva I, Kakouros N, et al. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace. 2011;13:610–25.

    Article  PubMed  Google Scholar 

  52. Saxena A, Tabin CJ. MiRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A. 2010;107:87–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Schumacher SM, McEwen DP, et al. Antiarrhythmic drug-induced internalization of the atrial-specific K + channel Kv1.5. Circ Res. 2009;104:1390–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Schumaker SM, Martens JR. Ion channel trafficking: a new therapeutic horizon for atrial fibrillation. Heart Rhythm. 2010;7:1309–15.

    Article  Google Scholar 

  55. Stauffer BL, Sobus RD, Sucharov CC. Sex differences in cardiomyocyte connexin43 expression. J Cardiovasc Pharmacol. 2011;58:32–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Thireau J, Pasquie JL, et al. New drugs vs. old concepts: a fresh look at antiarrhythmics. Pharmacol Ther. 2011;132:125–45.

    Article  CAS  PubMed  Google Scholar 

  57. Thum T, Galuppo P, et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007;116:258–67.

    Article  CAS  PubMed  Google Scholar 

  58. Van Wagoner DR. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J Cardiovasc Pharmacol. 2008;52:306–13.

    Article  PubMed  Google Scholar 

  59. Vaughan Williams EM. Subgroups of class 1 antiarrhythmic drugs. Eur Heart J. 1984;5:96–8.

    CAS  PubMed  Google Scholar 

  60. Wang Y, Joyner RW, et al. Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress. Am J Physiol Heart Circ Physiol. 2009;296:1227–35.

    Article  Google Scholar 

  61. Wang R, Li N, et al. Circulating MicroRNAs are promising novel biomarkers of acute myocardial infarction. Intern Med. 2011;50:1789–95.

    Article  CAS  PubMed  Google Scholar 

  62. Wehrens XH, Lehnart SE, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science. 2004;304:292–6.

    Article  CAS  PubMed  Google Scholar 

  63. Wilson LD, Rosenbaum DS, et al. Targeting ryanodine receptors for anti-arrhythmic therapy. Acta Pharmacol Sin. 2011;32:749–57.

    Article  Google Scholar 

  64. Xiao J, Liang D, et al. MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics. 2011;43:655–64.

    Article  CAS  PubMed  Google Scholar 

  65. Xiao J, Luo X, et al. MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts. J Biol Chem. 2007;282:12363–7.

    Article  CAS  PubMed  Google Scholar 

  66. Yang B, Lin H, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007;13:486–91.

    Article  CAS  PubMed  Google Scholar 

  67. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363–72.

    Google Scholar 

  68. Zhao Y, Ransom JF, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129:303–17.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. SBCHS, Manchester Metropolitan University, Chester Street, Manchester, UK

    Mark Slevin PhD, FRCPath

  2. School of Healthcare Science, Manchester Metropolitan University, Manchester, UK

    Mark Slevin PhD, FRCPath, Michael Carroll PhD & Chris Murgatroyd PhD

  3. Health and Biomedical Science, University of Edgehill, Ormskirk, Liverpool, UK

    Garry McDowell PhD, FRCPath

Authors
  1. Mark Slevin PhD, FRCPath
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  2. Michael Carroll PhD
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  3. Chris Murgatroyd PhD
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  4. Garry McDowell PhD, FRCPath
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Corresponding author

Correspondence to Mark Slevin PhD, FRCPath .

Editor information

Editors and Affiliations

  1. Department of Cardiology, Center Hospitalier Coutances, Coutances, France

    Ambrose S. Kibos

  2. Department of Internal Medicine Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Bradley P. Knight

  3. Division of Cardiology, McGill University Health Center, Montreal, Québec, Canada

    Vidal Essebag

  4. Department of Cardiology, Miami Children's Hospital, Miami, Florida, USA

    Steven B. Fishberger

  5. School of Biology, Chemistry and Health, Manchester Metropolitan University, Manchester, United Kingdom

    Mark Slevin

  6. “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Carol Davila” University of Medicine and Pharmacy, “Titu Maiorescu” University Faculty of Medicine,, Bucharest, Romania

    Ion C. Țintoiu

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Slevin, M., Carroll, M., Murgatroyd, C., McDowell, G. (2014). Biophysical and Molecular Targets. In: Kibos, A., Knight, B., Essebag, V., Fishberger, S., Slevin, M., Țintoiu, I. (eds) Cardiac Arrhythmias. Springer, London. https://doi.org/10.1007/978-1-4471-5316-0_25

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  • DOI: https://doi.org/10.1007/978-1-4471-5316-0_25

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