Official journal of the Slovak Society of Cardiology,
Slovak Society of Hypertension and Slovak Association for Cardiac Arrhythmias

Cardiology Letters 2016, 25(5):376-383

Anti-fibrillating and defibrillating capability of atorvastatin, melatonin and omega-3 fatty acids demonstrated in acute conditions on isolated heart model

Egan Beňová T1, Knezl V2, Viczenczová C1, Szeiffová Bačová B1, Radošinská J1, 3, Tribulová N1
1 Ústav pre výskum srdca, Slovenská Akadémia Vied, Bratislava
2 Ústav experimentálnej farmakológie a toxikológie, Slovenská Akadémia Vied, Bratislava
3 Fyziologický ústav Lekárská fakulta UK v Bratislave, Slovenská republika

Objectives: Cardioprotective compounds, atorvastatin, melatonin, eicosapentaenoic (EPA) and docosahexaenoic acid (DPA) show antiarrhythmic effects in clinical as well as in experimental studies, but their acute effects are less examined. The aim of the study was to further our understanding of the effects of monitored antiarrhythmic agents and their ability to defibrillate the heart.

Methods: Experiments were performed on the isolated Langendorff perfused heart model. The effects of atorvastatin, EPA and DHA were studied in the heart of adult male and female rats with hereditary hypertriglyceridaemia (HTG) and the effects of melatonin were studied in the heart of old male and female laboratory guinea pigs. The threshold for electrically induced ventricular fibrillation was examined on the heart without treatment and following 10 min of exposure to atorvastatin (15µmol), EPA (15µmol), DHA (15μmol) and melatonin (50 μmol). Moreover, a bolus of atorvastatin (150μmol), EPA (150μmol) and DHA (150μmol) was applied to fibrillating hearts to test their defibrillating effects.

Results: Sustained ventricular fibrillation was induced in all untreated HTG rat hearts. In contrast, its incidence was reduced to 30% and 60% by atorvastatin; 70% and 75% by EPA, 60% and 60% by DHA in both male and female rat hearts respectively. Moreover, a bolus of EPA and DHA applied directly to the fibrillating heart restored sinus rhythm in 6 of 6 hearts and a bolus of atorvastatin in 4 of 6 hearts of HTG rats. The threshold to induce sustained ventricular fibrillation was 21.7 ± 3.8 mA in male and 38.3 ± 2.9 mA in female laboratory guinea pig hearts. Melatonin administration prevented the induction of persistent ventricular fibrillation regardless of the sex and even when exposed to the strongest (50mA) stimulus.

Conclusion: The results clearly indicate acute antiarrhythmic effects of atorvastatin, EPA, DHA and melatonin. These findings bring new information for clinical cardiologists and encourage experimental cardiologists to study mechanisms of their acute effects.

Keywords: ventricular fibrillation; atorvastatin; melatonin; eicosapentaenoic acid; docosahexaenoic acid

Published: May 1, 2016  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Beňová ET, Knezl V, Viczenczová C, Bačová SB, Radošinská J, Tribulová N. Anti-fibrillating and defibrillating capability of atorvastatin, melatonin and omega-3 fatty acids demonstrated in acute conditions on isolated heart model. Cardiology Letters. 2016;25(5):376-383.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Severs NJ. Pathophysiology of gap junctions in heart disease. J Cardiovasc Electrophysiol 1994;5:462-475. Go to original source...
    2. Severs NJ. Gap junction remodeling and cardiac arrhythmogenesis: cause or coincidence? J Cell Mol Med 2001;5:355-366. Go to original source...
    3. Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 2004;84:431-488. Go to original source...
    4. Tribulova N, Manoach M, Varon D, Okruhlicova L, Zinman T, Shainberg A. Dispersion of cell-to-cell uncoupling precedes low K+-induced ventricular fibrillation. Physiol Res 2001;50:247259. Go to original source...
    5. Tribulova N, Seki S, Radosinska J, et al. Myocardial Ca2+ handling and cell-to-cell coupling, key factors in prevention of sudden cardiac death. Can J Physiol Pharmacol 2009;87:1120-1129. Go to original source...
    6. Lopshire JC, Zipes DP. Sudden cardiac death: better understanding of risks, mechanisms, and treatment. Circulation 2006;114:1134-1136. Go to original source...
    7. Albert CM, Stevenson WG. The future of arrhythmias and electro­ physiology. Circulation 2016;133:2687-2696. Go to original source...
    8. Singh BN. Augmenting maintenance of sinus rhythm in the control of atrial fibrillation by antiarrhythmic drug combinations. J Cardiovasc Pharmacol Ther 2010;15:31-35. Go to original source...
    9. Anderson KP. Lipid-lowering therapy for prevention of ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42:88-92. Go to original source...
    10. Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003;107:2646-2652. Go to original source...
    11. Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom AP, AVID Investigators. Are lipid lowering drugs also antiarrhythmic drugs? An analysis of the antiarrhythmics versus implantable defibrillators (AVID) trial. J Am Coll Cardiol 2003;42:81-87. Go to original source...
    12. London B, Albert C, Anderson ME, et al. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop. Circulation 2007;116:e320-e335. Go to original source...
    13. Al-Gubory KH. Mitochondria: omega-3 in the route of mitochondrial reactive oxygen species. Int J Biochem Cell Biol 2012;44:1569-1573. Go to original source...
    14. Chang CL, Deckelbaum RJ. Omega-3 fatty acids: mechanisms underlying "protective effects" in atherosclerosis. Curr Opin Lipidol 2013;24:345-350. Go to original source...
    15. Tribulova N, Egan Benova T, Szeiffova Bacova B, Viczenczova C, Barancik M. New aspects of pathogenesis of atrial fibrill­ ation: remodelling of intercalated discs. J Physiol Pharmcol 2015;66:625-634.
    16. Bacova B, Radosinska J, Knezl V, et al. Omega-3 fatty acids and atorvastatin suppress ventricular fibrillation inducibility in hypertriglyceridemic rat hearts: implication of intracellular coupling protein, connexin-43. J Physiol Pharmacol 2010;61:717-723.
    17. Radosinska J, Bacova B, Knezl V, et al. Dietary omega-3 fatty acids attenuate myocardial arrhythmogenic factors and propensity of the heart to lethal arrhythmias in a rodent model of human essential hypertension. J Hypertens 2013;31:1876-1885. Go to original source...
    18. Benova T, Viczenczova C, Radosinska J, et al. Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythm­ ias. Can J Physiol Pharmacol 2013;91:633-639. Go to original source...
    19. Simko F, Paulis L. Antifibrotic effect of melatonin - perspective protection in hypertensive heart disease. Int J Cardiol 2013;168:2876-2877. Go to original source...
    20. Simko F, Paulis L. Melatonin as a potential antihypertensive treatment. J Pineal Res 2007;42:319-322. Go to original source...
    21. Benova T, Knezl V, Viczenczova C, Bacova BS, Radosinska J, Tribulova N. Acute anti-fibrillating and defibrillating potential of atorvastatin, melatonin, eicosapentaenoic acid and docosahexaenoic acid demonstrated in isolated heart model. J Physiol Pharmacol 2015;66:83-89.
    22. Dhein S, Michaelis B, Mohr FW. Antiarrhythmic and electrophysio­ logical effects of long-chain omega-3 polyunsaturated fatty acids. Naunyn Schmiedebergs Arch Pharmacol 2005; 371:202211. Go to original source...
    23. Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation 1999;99:2452-2457. Go to original source...
    24. Schrepf R, Limmert T, Claus Weber P, Theisen K, Sellmayer A. Immediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet 2004;363(9419):1441-1442. Go to original source...
    25. Den Ruijter HM, Berecki G, Opthof T, Verkerk AO, Zock PL, Coronel R. Pro- and antiarrhythmic properties of a diet rich in fish oil. Cardiovasc Res 2007;73:316-325. Go to original source...
    26. Diez ER, Prados LV, Carrion A, Ponce AZ, Miatello RM. A novel electrophysiologic effect of melatonin on ishcemia/reperfusioninduced arrhythmias in isolated rat hearts. J Pineal Res 2009;46:155-160. Go to original source...
    27. Strosberg AD, Nahmias C. G-protein-coupled receptor signalling through protein networks. Biochem Soc Trans 2007;35:23-27. Go to original source...
    28. Martinez AD, Saez JC. Regulation of astrocyte gap junctions by hypoxia-reoxygenation. Brain Res Brain Res Rev 2000;32:250258. Go to original source...
    29. Drobnik J, Tosik D, Piera L, et al. Melatonin-induced glyco­ saminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol 2013;64:737-744.
    30. Szarszoi O, Maly J, Osadal P, et al. Effect of acute and chronic simvastatin treatment on post-ischemic contractile dysfunction in isolated rat heart. Physiol Res 2008;57:793-796. Go to original source...
    31. Ozturk N, Yaras N, Ozmen A, Ozdemir S. Long-term administration of rosuvastatin prevents contractile and electrical remodelling of diabetic rat heart. J Bioenerg Biomembr 2013;45:343-352. Go to original source...
    32. Qiu Z, Zhang W, Fan F, et al. Rosuvastatin-attenuated heart failure in aged spontaneously hypertensive rats via PKCa/b2 signal pathway. J Cell Mol Med 2012;16:3052-3061. Go to original source...
    33. Korybalska K, Kawka E, Breborowicz A, Witowski J. Atorvastatin does not impair endothelial cell wound healing in an in vitro model of vascular injury. J Physiol Pharmacol 2012;63:389395.
    34. Herve JC. The communicating junctions, composition, structure and characteristics. Biochim Biophys Acta 2012;1818:18031806. Go to original source...
    35. Meyer R, Schreckenberg R, Kraus D, Kretschmer F, Schulz R, Schlüter KD. Cardiac effects of osteostatin in mice. J Physiol Pharmacol 2012;63:17-22.
    36. Chen VC, Gouw JW, Naus CC, Foster LJ. Connexin multisite phosphorylation: Mass spectrometry-based proteomics fills the gap. Biochim Biophys Acta 2013;1828:23-24. Go to original source...
    37. Dhein S, Hagen A, Jozwiak J, et al. Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the act­ ion of antiarrhythmic peptides. Naunyn Schmiedebergs Arch Pharmacol 2010;381:221-234. Go to original source...
    38. Rohr S, Kucera JP, Fast VG, Kleber AG. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science 1997;275:841-844. Go to original source...
    39. Radosinska J, Knezl V, Benova T, Urban L, Tribulova N, Slezak J. Alterations of the intercellular coupling protein, connexin-43, during ventricular fibrillation and sinus rhythm restoration demonstrated in male and female rat hearts. A pilot study. Exp Clin Cardiol 2011;16:116-120.
    40. Sovari AA, Bonini MG, Dudley SC. Effective antioxidant therapy for the management of arrhythmia. Expert Rev Cardiovasc Ther 2011;9:797-800. Go to original source...
    41. Sakr HF. Modulation of metabolic and cardiac dysfunctions by swimming in overweight rats on a high cholesterol and fructose diet: possible role of adiponectin. J Physiol Pharmacol 2013;64:231-240.
    42. Tribulova N, Dupont E, Soukup T, Okruhlicova L, Severs NJ. Sex differences in connexin-43 expression in left ventricles of aging rats. Physiol Res 2005;54:705-708. Go to original source...
    43. Mitasikova M, Smidova S, Macsaliova A, et al. Aged male and female spontaneously hypertensive rats benefit from n-3 polyunsaturated fatty acids supplementation. Physiol Res 2008;57:39-48. Go to original source...

    Return to the content