Abstract
Alcohol consumption may result in electrocardiographic changes and arrhythmias, at least partly due to effects of ethanol on cardiac ionic currents. Contractility and intracellular Ca2+ dynamics seem to be altered as well. In this study, we integrated the available (mostly animal) experimental data into previously published models of the rat and human ventricular myocytes to assess the share of ionic current components in ethanol-induced changes in AP configuration and cytosolic Ca2+ transient in ventricular cardiomyocytes. The rat model reproduced well the experimentally observed changes in AP duration (APD) under ethanol (slight prolongation at 0.8 mM and shortening at ≥8 mM). These changes were almost exclusively caused by the ethanol-induced alterations of I K1. The cytosolic Ca2+ transient decreased gradually with the increasing ethanol concentration as a result of the ethanol-induced inhibition of I Ca. In the human model, ethanol produced a dose-dependent APD lengthening, dominated by ethanol effect on I Kr, the key repolarising current in human ventricles. This effect might contribute to the clinically observed proarrhythmic effects of ethanol in predisposed individuals.






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References
Aasebø W, Erikssen J, Jonsbu J, Stavem K (2007) ECG changes in patients with acute ethanol intoxication. Scand Cardiovasc J 41:79–84. doi:10.1080/14017430601091698
Bébarová M, Matejovič P, Pásek M, Ohlídalová D, Jansová D, Šimurdová M, Šimurda J (2010) Effect of ethanol on action potential and ionic membrane currents in rat ventricular myocytes. Acta Physiol (Oxf) 200:301–314. doi:10.1111/j.1748-1716.2010.02162.x
Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J (2014) Dual effect of ethanol on inward rectifier potassium current IK1 in rat ventricular myocytes. J Physiol Pharmacol 65:497–509
Brown RA, Robinson E, Dunbar JC (1993) Inotropic effects of ethanol on the isolated papillary muscle of the diabetic rat. Alcohol 10:231–235. doi:10.1016/0741-8329(93)90041-L
Cameli M, Ballo P, Garzia A, Lisi M, Palmerini E, Spinelli T, Bocelli A, Mondillo S (2009) Acute effects of low doses of red wine on cardiac conduction and repolarization in young healthy subjects. Alcohol Clin Exp Res 33:2141–2146. doi:10.1111/j.1530-0277.2009.01054.x
Carryl OR, Gallardo-Carpentier A, Carpentier RG (1992) Effects of nicotine and ethanol on rat atrial membrane potentials. Alcohol 9:87–92. doi:10.1016/0741-8329(92)90016-4
Chiuve SE, Rimm EB, Mukamal KJ, Rexrode KM, Stampfer MJ, Manson JE, Albert CM (2010) Light-to-moderate alcohol consumption and risk of sudden cardiac death in women. Heart Rhythm 7:1374–1380. doi:10.1016/j.hrthm.2010.05.035
Čorovič N, Durakovič Z, Mišigoj-Durakovič M (2006) Dispersion of the corrected QT and JT interval in the electrocardiogram of alcoholic patients. Alcohol Alcohol Clin Exp Res 30:150–154. doi:10.1111/j.1530-0277.2006.00018.x
Danziger RS, Sakai M, Capogrossi MC, Spurgeon HA, Hansford RG, Lakatta EG (1991) Ethanol acutely and reversibly suppresses excitation–contraction coupling in cardiac myocytes. Circ Res 68:1660–1668. doi:10.1161/01.RES.68.6.1660
Delbridge LMD, Connell PJ, Harris PJ, Morgan TO (2000) Ethanol effects on cardiomyocyte contractility. Clin Sci 98:401–407. doi:10.1042/CS19990230
Delgado CE, Gortuin NJ, Ross RS (1975) Acute effects of low doses of alcohol on left ventricular function by echocardiography. Circulation 51:535–540. doi:10.1161/01.CIR.51.3.535
Eisenhofer G, Lambie DG, Johnson RH (1984) Effects of ethanol ingestion on α-adrenoceptor-mediated circulatory responses in man. Br J Clin Pharmac 18:581–586. doi:10.1111/j.1365-2125.1984.tb02507.x
Fink M, Noble D, Virag L, Varro A, Giles WR (2008) Contributions of HERG K+ current to repolarization of the human ventricular action potential. Prog Biophys Mol Biol 96:357–376. doi:10.1016/j.pbiomolbio.2007.07.011
Fisher VJ, Kavaler F (1975) The action of ethanol upon the action potential and contraction of ventricular muscle. Recent Adv Stud Cardiac Struct Metab 5:415–422
Fuenmayor AJ, Fuenmayor AM (1997) Cardiac arrest following holiday heart syndrome. Int J Cardiol 59:101–103. doi:10.1016/S0167-5273(96)02903-8
Gilmour RF, Riccio ML, Locati EH, Maison-Blanche P, Coumel P, Schwartz PJ (1997) Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation. J Am Coll Cardiol 30:209–217. doi:10.1016/S0735-1097(97)00105-8
Gimeno AL, Gimeno MF, Webb JL (1962) Effects of ethanol on cellular membrane potentials and contractility of isolated rat atrium. Am J Physiol 203:194–196
Guarnieri T, Lakatta EG (1990) Mechanism of myocardial contractile depression by clinical concentrations of ethanol. A study in Ferret Papillary Muscles. J Clin Invest 85:1462–1467. doi:10.1172/JCI114592
Habuchi Y, Furukawa T, Tanaka H, Lu L, Morikawa J, Yoshimura M (1995) Ethanol inhibition of Ca2+ and Na+ currents in the guinea-pig heart. Eur J Pharmacol 292:143–149. doi:10.1016/0926-6917(95)90006-3
Haissaguerre M, Fleury B, Le Metayer P, Gabinski C, Conri C, Couzigou P, Warin JF, Blanchot P (1984) Arrhythmia in relation to acute alcoholic intoxication in the absence of obvious cardiopathy. Presse Med 13:1723–1726
Himmel HM (2007) Suitability of commonly used excipients for electrophysiological in vitro safety pharmacology assessment of effects on hERG potassium current and on rabbit Purkinje fiber action potential. J Pharmacol Toxicol Methods 56:145–158. doi:10.1016/j.vascn.2007.04.004
Horton JW, White MS (1996) Cardiac contractile and sarcoplasmic reticulum function after acute ethanol consumption. J Surg Res 64:132–138. doi:10.1006/jsre.1996.0319
Jost N, Virág L, Comtois P, Ördög B, Szuts V, Seprényi G, Bitay M, Kohajda Z, Koncz I, Nagy N, Szél T, Magyar J, Kovács M, Puskás LG, Lengyel C, Wettwer E, Ravens U, Nánási PP, Papp JG, Varró A, Nattel S (2013) Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs. J Physiol 591:4189–4206. doi:10.1113/jphysiol.2013.261198
Kelbaek H, Gjørup T, Brynjolf I, Christensen NJ, Godtfredsen J (1985) Acute effects of alcohol on left ventricular function in healthy subjects at rest and during upright exercise. Am J Cardiol 55:164–167. doi:10.1016/0002-9149(85)90320-0
Kelly LF, Goldberg SJ, Donnerstein RL, Cardy MA, Palombo GM (1996) Hemodynamic effects of acute ethanol in young adults. Am J Cardiol 78:851–854. doi:10.1016/S0002-9149(96)00439-0
Klein G, Gardiwal A, Schaefer A, Panning B, Breitmeier D (2007) Effect of ethanol on cardiac single sodium channel gating. Forensic Sci Int 171:131–135. doi:10.1016/j.forsciint.2006.10.012
Laszlo R, Eick C, Schwiebert M, Schreiner B, Weig HJ, Weretka S, Bosch RF, Schreieck J (2009) Alcohol-induced electrical remodeling: effects of sustained short-term ethanol infusion on ion currents in rabbit atrium. Alcohol Clin Exp Res 33:1697–1703. doi:10.1111/j.1530-0277.2009.01006.x
Li GR, Feng J, Yue L, Carrier M, Nattel S (1996) Evidence of two components of delayed rectifier K+ current in human ventricular myocytes. Circ Res 78:689–696. doi:10.1161/01.RES.78.4.689
Locati EH, Maison-Blanche P, Dejode P, Cauchemez B, Coumel P (1995) Spontaneous sequences of onset of torsade de pointes in patients with acquired prolonged repolarization: quantitative analysis of holter recordings. J Am Coll Cardiol 25:1564–1575. doi:10.1016/0735-1097(95)00100-I
Lorsheyd A, de Lange DW, Hijmering ML, Cramer MJ, van de Wiel A (2005) PR and QTc interval prolongation on the electrocardiogram after binge drinking in healthy individuals. Neth J Med 63:59–63
Mahida S, Hogarth AJ, Cowan C, Tayebjee MH, Graham LN, Pepper CB (2013) Genetics of congenital and drug-induced long QT syndromes: current evidence and future research perspectives. J Interv Card Electrophysiol 37:9–19. doi:10.1007/s10840-013-9779-5
Mason DT, Spann JF Jr, Miller RR, Lee G, Arbogast R, Segel LD (1978) Effects of acute ethanol on the contractile state of normal and failing cat papillary muscles. Eur J Cardiol 7:311–316
Modell SM, Lehmann MH (2006) The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med 8:143–155. doi:10.1097/01.gim.0000204468.85308.86
Moss AJ (1999) The QT interval and torsade de pointes. Drug Saf 21:5–10. doi:10.2165/00002018-199921001-00002
Nattel S, Maguy A, Le Bouter S, Yeh YH (2007) Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87:425–456. doi:10.1152/physrev.00014.2006
O’Leary ME (2002) Inhibition of HERG potassium channels by cocaethylene: a metabolite of cocaine and ethanol. Cardiovasc Res 53:59–67. doi:10.1016/S0008-6363(01)00458-8
Pásek M, Šimurda J, Orchard CH (2012) Role of t-tubules in the control of trans-sarcolemmal ion flux and intracellular Ca2+ in a model of the rat cardiac ventricular myocyte. Eur Biophys J 41:491–503. doi:10.1007/s00249-012-0804-x
Rosenqvist M (1998) Alcohol and cardiac arrhythmias. Alcohol Clin Exp Res 22:318S–322S. doi:10.1111/j.1530-0277.1998.tb04385.x
Rossinen J, Sinisalo J, Partanen J, Nieminen MS, Viitasalo M (1999) Effects of acute alcohol infusion on duration and dispersion of QT interval in male patients with coronary artery disease and in healthy controls. Clin Cardiol 22:591–594. doi:10.1002/clc.4960220910
Rudy Y, Ackerman MJ, Bers DM, Clancy CE, Houser SR, London B, McCulloch AD, Przywara DA, Rasmusson RL, Solaro RJ, Trayanova NA, Van Wagoner DR, Varró A, Weiss JN, Lathrop DA (2008) System approach to understanding electromechanical activity in the human heart: a national heart, lung, and blood institute workshop summary. Circulation 118:1202–1211. doi:10.1161/CIRCULATIONAHA.108.772715
Thomas AP, Sass EJ, Tun-Kirchmann TT, Rubin E (1989) Ethanol inhibits electrically-induced calcium transients in isolated rat cardiac myocytes. J Mol Cell Cardiol 21:555–565. doi:10.1016/0022-2828(89)90821-3
Thomas AP, Rozanski DJ, Renard DC, Rubin E (1994) Effects of ethanol on the contractile function of the heart: a review. Alcohol Clin Exp Res 18:121–131. doi:10.1111/j.1530-0277.1994.tb00891.x
Tristani-Firouzi M, Etheridge SP (2010) Kir2.1 channelopathies: the Andersen–Tawil syndrome. Pflügers Arch 460:289–294. doi:10.1007/s00424-010-0820-6
Tsai CS, Loh SH, Jin JS, Hong GJ, Lin HT, Chiung CS, Chang CY (2005) Effects of alcohol on intracellular pH regulators and electromechanical parameters in human myocardium. Alcohol Clin Exp Res 29:1787–1795. doi:10.1097/01.alc.0000183512.31705.74
Tseng GN, Robinson RB, Hoffman BF (1987) Passive properties and membrane currents of canine ventricular myocytes. J Gen Physiol 90:671–701. doi:10.1085/jgp.90.5.671
Veldkamp MW, van Ginneken ACG, Opthof T, Bouman LN (1995) Delayed rectifier channels in human ventricular myocytes. Circulation 92:3497–3504. doi:10.1161/01.CIR.92.12.3497
Williams ES, Mirro MJ, Bailey JC (1980) Electrophysiological effects of ethanol, acetaldehyde, and acetate on cardiac tissues from dog and guinea pig. Circ Res 47:473–478. doi:10.1161/01.RES.47.3.473
Yap YG, Camm AJ (2003) Drug induced QT prolongation and torsades de pointes. Heart 89:1363–1372. doi:10.1136/heart.89.11.1363
Acknowledgments
This study was realised with the institutional support RVO: 61388998 and with the support of the Grant Project NT14301-3/2013 from the Ministry of Health of the Czech Republic. Georges Christé’s work was supported by Université Lyon 1 research allowances to the EA4612 Neurocardiology Unit.
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Pásek, M., Bébarová, M., Christé, G. et al. Acute effects of ethanol on action potential and intracellular Ca2+ transient in cardiac ventricular cells: a simulation study. Med Biol Eng Comput 54, 753–762 (2016). https://doi.org/10.1007/s11517-015-1366-8
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DOI: https://doi.org/10.1007/s11517-015-1366-8