Biophysical and Molecular Targets

  • Mark Slevin
  • Michael Carroll
  • Chris Murgatroyd
  • Garry McDowell
Chapter

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.

Keywords

Cardiac arrhythmia microRNA Ion channels n-3 Polyunsaturated fatty acids ACE inhibitors Statins CaMKII 

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 2.
    Antzelevitch C. Genetic basis of Brugada syndrome. Heart Rhythm. 2007;4:756.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Bányász T, Szentandrássy N. Cardiac calmodulin kinase: a potential target for drug design. Curr Med Chem. 2011;18:3707–13.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802–9.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Chelu MG, Wehrens XH. Sarcoplasmic reticulum calcium leak and cardiac arrhythmias. J Mol Cell Cardiol. 2011;50:214–22.CrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Dobrev D. Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target. Naunyn Schmiedebergs Arch Pharmacol. 2010;381:195–206.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Federman J, Whitford JA, et al. Incidence of ventricular arrhythmias in first year after myocardial infarction. Br Heart J. 1998;40:1243–50.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 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.PubMedCentralPubMedGoogle Scholar
  24. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Huang CX, Liu Y, et al. Oxidative stress: a possible pathogenesis of atrial fibrillation. Med Hypotheses. 2009;72:466–7.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Laurita KR, Rosenbaum DS. Cellular mechanisms of arrhythmogenic cardiac alternans. Prog Biophys Mol Biol. 2008;97:332–47.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Lu Y, Zhang Y, et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010;122:2378–87.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Mihm MJ, Yu F, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001;104:174–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Mohammed KS, Kowey PR, Musco S. Adjuvant therapy for atrial fibrillation. Future Cardiol. 2010;6:67–81.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 42.
    Nattel S, Shiroshita-Takeshita A, et al. Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol. 2005;20:21–5.PubMedGoogle Scholar
  43. 43.
    Ono K, Kuwabara Y, Han J. MicroRNAs and cardiovascular diseases. FEBS J. 2011;278:1619–33.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res. 2011;108:871–83.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 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. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 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.PubMedCentralPubMedGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Schumaker SM, Martens JR. Ion channel trafficking: a new therapeutic horizon for atrial fibrillation. Heart Rhythm. 2010;7:1309–15.CrossRefGoogle Scholar
  55. 55.
    Stauffer BL, Sobus RD, Sucharov CC. Sex differences in cardiomyocyte connexin43 expression. J Cardiovasc Pharmacol. 2011;58:32–9.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Thireau J, Pasquie JL, et al. New drugs vs. old concepts: a fresh look at antiarrhythmics. Pharmacol Ther. 2011;132:125–45.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 59.
    Vaughan Williams EM. Subgroups of class 1 antiarrhythmic drugs. Eur Heart J. 1984;5:96–8.PubMedGoogle Scholar
  60. 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.CrossRefGoogle Scholar
  61. 61.
    Wang R, Li N, et al. Circulating MicroRNAs are promising novel biomarkers of acute myocardial infarction. Intern Med. 2011;50:1789–95.PubMedCrossRefGoogle Scholar
  62. 62.
    Wehrens XH, Lehnart SE, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science. 2004;304:292–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Wilson LD, Rosenbaum DS, et al. Targeting ryanodine receptors for anti-arrhythmic therapy. Acta Pharmacol Sin. 2011;32:749–57.CrossRefGoogle Scholar
  64. 64.
    Xiao J, Liang D, et al. MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics. 2011;43:655–64.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 67.
    Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363–72.Google Scholar
  68. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Mark Slevin
    • 1
    • 2
  • Michael Carroll
    • 2
  • Chris Murgatroyd
    • 2
  • Garry McDowell
    • 3
  1. 1.SBCHSManchester Metropolitan UniversityManchesterUK
  2. 2.School of Healthcare ScienceManchester Metropolitan UniversityManchesterUK
  3. 3.Health and Biomedical ScienceUniversity of EdgehillOrmskirk, LiverpoolUK

Personalised recommendations