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Canine left ventricular hypertrophy predisposes to ventricular tachycardia induction by phase 2 early afterdepolarizations after administration of BAY K 8644 FREE

Joseph Ben-David, MD; Douglas P. Zipes, MD, FACC; Gregory M. Ayers, PhD, MD; Harald P. Pride, BS
[+] Author Information

This study was supported in part by the Herman C. Krannert Fund, Indianapolis; Grants HL-42370 and HL-07182 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, and the American Heart Association, Indiana Affiliate, Indianapolis.Address for correspondence: Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 West Tenth Street, Indianapolis, Indiana 46202.

J Am Coll Cardiol. 1992;20(7):1576-1584. doi:10.1016/0735-1097(92)90453-T
Published online

  Objectives. The purpose of this study was to test the hypothesis that the longer duration of ventricular action potentials in hypertrophied hearts predisposes to the development of early after-depolarizations and triggered ventricular tachyarrhythmias.Background. For unknown reasons, the incidence of sudden death is greater in patients with myocardial hypertrophy.Methods. We measured left ventricular monophasic action potentials in normal dogs and dogs with left ventricular hypertrophy before and after administration of the calcium agonist BAY K 8644 and the potassium channel blocker cesium.Results. We demonstraieo longer action potential durations in dogs with than in those without left ventricular hypertrophy. Also, BAY K 8644 produced phase 2 early afterdepolarizations and ventricular tachyarrhythmias more frequently in the dogs with than in those without left ventricular hypertrophy. Phenylephrine, an alpha agonist, further increased the action potential duration in hypertrophied hearts and the propensity to develop early afterdepolarizations and ventricular tachyarrhythmia after administration of BAY K 8644. Control and hypertrophied hearts developed early afterdepolarizations and ventricular tachyarrhythmia equally when exposed to cesium.Conclusions. Although in vitro studies have shown that fibers of hypertrophied ventricular myocardium can develop triggered activity as a result of both early and late afterdepolarizations, the present study is the first to show in vivo that the hypertrophied ventricular myocardium compared with the normal ventricle is predisposed to develop phase 2 early afterdepolarizations that appear to trigger ventricular tachyarrhythmia. It is possible that such a mechanism contributes to the development of ventricular tachyarrhythmia and sudden cardiac death in patients with left ventricular hypertrophy. If this is shown to be true, specific pharmacologic interventions can be suggested.

References

Kannel  WB, Sorlie  P; Left ventricular hypertrophy in hypertension: prognostic and pathogenetic implications. The Framingham Study.Strauer  R; The Heart in Hypertension. 1981 Springer-Verlag Berlin:223-242.
McLenachan  JM, Henderson  E, Morris  KI, Dargie  HJ; Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med. 317 1987:787-792.
CrossRef | PubMed
McLenachan  JM, Dargie  HJ; Left ventricular hypertrophy as a factor in arrhythmias and sudden death. Am J Hypertens. 2 1989:128-131.
PubMed
Koren  MJ, Dcvcrcux  RB, Casale  PN, Savage  DD, Laragh  JH; Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 114 1991:345-352.
PubMed
Aronson  RS; Mechanisms of arrhythmias in ventricular hypertrophy. J Cardiovasc Electrophysiol. 2 1991:249-261.
CrossRef
Cameron  JS, Myerburg  RJ, Wong  SS; Electrophysiologic consequences of chronic experimentally induced left ventricular pressure overload. J Am Coll Cardiol. 2 1983:481-487.
CrossRef | PubMed
Schechter  JA, O'Connor  KM, Friehling  TD, Mark  R, Uboh  C, Kowey  PR; Electrophysiologic effects of left ventricular hypertrophy in the intact cat. Am J Hypertens. 2 1989:81-85.
PubMed
Cooper  G; Cardiocyte adaptation to chronically altered load. Ann Rev Physiol. 49 1987:501-518.
CrossRef
Nakanishi  H, Makino  N, Hata  T, Matsui  H, Yano  K, Yamaga  T; Sarcolemal Ca2+ transport activities in cardiac hypertrophy caused by pressure overload. Am J Physiol. 257 1989:H349-H356.
PubMed
Andrawis  NS, Kuo  TH, Giacomelli  F, Wiener  J; Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension. J Mol Cell Cardiol. 20 1988:625-634.
CrossRef | PubMed
Brachmann  J, Scherlag  BJ, Rosenshtraukh  LV, Lazzara  R; Bradycardia-dependent triggered activity: relevance of drug-induced multiform ventricular tachycardia. Circulation. 68 1983:846-856.
CrossRef | PubMed
Isenberg  G; Cardiac Purkinje fibers: cesium as a tool to block inward rectifying potassium currents. Pflugers Arch. 365 1976:99-106.
CrossRef | PubMed
Schramm  M, Thomas  G, Towart  R, Franckowiak  G; Novel dihydropyridines with positive inotropic action through activation of Ca+- channels. Nature. 303 1983:535-537.
CrossRef | PubMed
Kuss  RS; Voltage-dependent modulation of cardiac calcium channel current by optical isomers of Bay K 8644: implications for channel gating. Circ Res. 61 (suppl I) 1987:I-1-I-5.
Thomas  G, Chung  M, Cohen  CJ; A dihydropyridine (Bay K 8644) that enhances calcium currents in guinea pig and calf myocardial cells. Circ Res. 56 1985:87-96.
CrossRef | PubMed
January  CT, Riddle  JM, Salata  JJ; A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644. Circ Res. 62 1988:563-571.
CrossRef | PubMed
January  CT, Riddle  JM; Early afterdepolarizations: newer insights into cellular mechanisms. J Cardiovasc Electrophysiol. 1 1990:161-169.
CrossRef
Koyanagi  S, Easthamn  C, Marcus  ML; Effects of chronic hypertension and left ventricular hypertrophy on the incidence of sudden cardiac death after coronary artery occlusion in conscious dogs. Circulation. 65 1982:1192-1198.
CrossRef | PubMed
Martins  JB, Kim  W, Marcus  ML; Chronic hypertension and left ventricular hypertrophy facilitale induction of sustained ventricular tachycardia in dogs 3 hours after left circumflex coronary artery occlusion. J Am Coll Cardiol. 14 1989:1365-1373.
CrossRef | PubMed
Folkow  B; Impulse frequency in sympathetic vasomotor libers: correlation to the release and elimination of transmitter. Acta Physiol Scand. 25 1942:47-52.
Martins  JB, Zipes  DP; Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res. 46 1980:100-110.
CrossRef | PubMed
Franz  MR, Flaherty  JT, Platia  EV, Bulkley  BH, Weisfeldt  ML; Localization of regional myocardial ischemia by recording of monophasic action potentials. Circulation. 69 1984:593-604.
CrossRef | PubMed
Ben-David  J, Zipes  DP; Differential response to the right and left ansae subclaviac stimulation of early afterdepolarizations and ventricular tachycardia induced by cesium in dogs. Circulation. 78 1988:1241-1250.
CrossRef | PubMed
Cranefield  PF, Aronson  RS; Cardiac arrhythmias: the role of triggered activity and other mechanisms. 1988 Futura Mt. Kisco, NY:199-265.
Bailie DS, Inoue H, Kaseda S, Ben-David I, Zipes DP. Magnesium suppression of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium in dogs. Circulation 19,9:77:1395-402.
Ben-David  J, Zipes  DP; Alpha adrenoceptor stimulation and blockade modulates cesium-induced early afterdepolarizations and ventricular tachyarrhythmias in dogs. Circulation. 82 1990:225-233.
CrossRef | PubMed
Rosen  MR, Bilezikian  JP, Cohen  IS, Robinson  RB; Alpha adrenergic modulation of cardiac rhythm.Zipes  DP, Jalife  J; Cardiac Electrophysiology. From Cell to Bedside. 1990 WB Saunders Philadelphia:300-304.
Corr  PB, Yamada  KA, Witkowski  FX; Mechanisms controlling cardiac autonomic function and their relation to arrhythmogeresis.Fozzard  H; The Heart and Cardiovascular System. 1986 Raven New York:1343-1403.
Fedida  D, Shimoni  Y, Giles  VR; A novel effect of norepincphrine on cardiac cells is mediated by alpha-adrenoceptors. Am J Physiol(Heart Circ Physiol 25). 256 1989:H1500-H1504.
Corr  PB, Heathers  GP, Yamada  KA; Mechanism contributing to the arrhythmogenic influences of adrenergic stimulation in the ischemic heart. Am J Med. 87 (suppl 2A) 1989:19S-25S.
CrossRef | PubMed
Bentivegha  LA, Ransil  BJ, Grossman  W, Gwathney  JK, Morgan  JP; Cardiac hypertrophy and abnormal calcium handling in human myocardium (abstr). Circulation. 80 (Suppl II) 1989:II-617.
Damiano  BP, Rosen  MR; Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation. 69 1984:1013-1025.
CrossRef | PubMed
Kowey  PR, Frichling  TD, Sewter  J; Electrophysiological effects of left ventricular hypertrophy: effect of calcium and potassium channel blockade. Circulation. 83 1991:2067-2075.
CrossRef | PubMed
Kohya  T, Kimura  S, Myerburg  RJ, Basselt  AL; Susceptibility of hypertrophied rat hearts to ventricular fibrillation during acute ischemia. J Mol Cell Cardiol. 20 1988:159-168.
CrossRef | PubMed
Cupples  LA, Gagnon  DR, Kannel  WB; Long- and short-term risk of sudden cardiac death: population at risk. Circulation. 85 (suppl I) 1992:I-11-I-18.
Fish  FA, Prakash  C, Roden  DM; Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators. Circulation. 82 1990:1362-1369.
CrossRef | PubMed
Gocthals  MA, Sy  SU, Stroobandt  R, Andries  E, Paulus  WJ; Delayed afterpotentials elicit diastolic aftercontractions in the hypertrophied left ventricle of human aortic stenosis (abstr). Circulation. 82 (suppl III) 1990:III-581.

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References

Kannel  WB, Sorlie  P; Left ventricular hypertrophy in hypertension: prognostic and pathogenetic implications. The Framingham Study.Strauer  R; The Heart in Hypertension. 1981 Springer-Verlag Berlin:223-242.
McLenachan  JM, Henderson  E, Morris  KI, Dargie  HJ; Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med. 317 1987:787-792.
CrossRef | PubMed
McLenachan  JM, Dargie  HJ; Left ventricular hypertrophy as a factor in arrhythmias and sudden death. Am J Hypertens. 2 1989:128-131.
PubMed
Koren  MJ, Dcvcrcux  RB, Casale  PN, Savage  DD, Laragh  JH; Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 114 1991:345-352.
PubMed
Aronson  RS; Mechanisms of arrhythmias in ventricular hypertrophy. J Cardiovasc Electrophysiol. 2 1991:249-261.
CrossRef
Cameron  JS, Myerburg  RJ, Wong  SS; Electrophysiologic consequences of chronic experimentally induced left ventricular pressure overload. J Am Coll Cardiol. 2 1983:481-487.
CrossRef | PubMed
Schechter  JA, O'Connor  KM, Friehling  TD, Mark  R, Uboh  C, Kowey  PR; Electrophysiologic effects of left ventricular hypertrophy in the intact cat. Am J Hypertens. 2 1989:81-85.
PubMed
Cooper  G; Cardiocyte adaptation to chronically altered load. Ann Rev Physiol. 49 1987:501-518.
CrossRef
Nakanishi  H, Makino  N, Hata  T, Matsui  H, Yano  K, Yamaga  T; Sarcolemal Ca2+ transport activities in cardiac hypertrophy caused by pressure overload. Am J Physiol. 257 1989:H349-H356.
PubMed
Andrawis  NS, Kuo  TH, Giacomelli  F, Wiener  J; Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension. J Mol Cell Cardiol. 20 1988:625-634.
CrossRef | PubMed
Brachmann  J, Scherlag  BJ, Rosenshtraukh  LV, Lazzara  R; Bradycardia-dependent triggered activity: relevance of drug-induced multiform ventricular tachycardia. Circulation. 68 1983:846-856.
CrossRef | PubMed
Isenberg  G; Cardiac Purkinje fibers: cesium as a tool to block inward rectifying potassium currents. Pflugers Arch. 365 1976:99-106.
CrossRef | PubMed
Schramm  M, Thomas  G, Towart  R, Franckowiak  G; Novel dihydropyridines with positive inotropic action through activation of Ca+- channels. Nature. 303 1983:535-537.
CrossRef | PubMed
Kuss  RS; Voltage-dependent modulation of cardiac calcium channel current by optical isomers of Bay K 8644: implications for channel gating. Circ Res. 61 (suppl I) 1987:I-1-I-5.
Thomas  G, Chung  M, Cohen  CJ; A dihydropyridine (Bay K 8644) that enhances calcium currents in guinea pig and calf myocardial cells. Circ Res. 56 1985:87-96.
CrossRef | PubMed
January  CT, Riddle  JM, Salata  JJ; A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644. Circ Res. 62 1988:563-571.
CrossRef | PubMed
January  CT, Riddle  JM; Early afterdepolarizations: newer insights into cellular mechanisms. J Cardiovasc Electrophysiol. 1 1990:161-169.
CrossRef
Koyanagi  S, Easthamn  C, Marcus  ML; Effects of chronic hypertension and left ventricular hypertrophy on the incidence of sudden cardiac death after coronary artery occlusion in conscious dogs. Circulation. 65 1982:1192-1198.
CrossRef | PubMed
Martins  JB, Kim  W, Marcus  ML; Chronic hypertension and left ventricular hypertrophy facilitale induction of sustained ventricular tachycardia in dogs 3 hours after left circumflex coronary artery occlusion. J Am Coll Cardiol. 14 1989:1365-1373.
CrossRef | PubMed
Folkow  B; Impulse frequency in sympathetic vasomotor libers: correlation to the release and elimination of transmitter. Acta Physiol Scand. 25 1942:47-52.
Martins  JB, Zipes  DP; Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res. 46 1980:100-110.
CrossRef | PubMed
Franz  MR, Flaherty  JT, Platia  EV, Bulkley  BH, Weisfeldt  ML; Localization of regional myocardial ischemia by recording of monophasic action potentials. Circulation. 69 1984:593-604.
CrossRef | PubMed
Ben-David  J, Zipes  DP; Differential response to the right and left ansae subclaviac stimulation of early afterdepolarizations and ventricular tachycardia induced by cesium in dogs. Circulation. 78 1988:1241-1250.
CrossRef | PubMed
Cranefield  PF, Aronson  RS; Cardiac arrhythmias: the role of triggered activity and other mechanisms. 1988 Futura Mt. Kisco, NY:199-265.
Bailie DS, Inoue H, Kaseda S, Ben-David I, Zipes DP. Magnesium suppression of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium in dogs. Circulation 19,9:77:1395-402.
Ben-David  J, Zipes  DP; Alpha adrenoceptor stimulation and blockade modulates cesium-induced early afterdepolarizations and ventricular tachyarrhythmias in dogs. Circulation. 82 1990:225-233.
CrossRef | PubMed
Rosen  MR, Bilezikian  JP, Cohen  IS, Robinson  RB; Alpha adrenergic modulation of cardiac rhythm.Zipes  DP, Jalife  J; Cardiac Electrophysiology. From Cell to Bedside. 1990 WB Saunders Philadelphia:300-304.
Corr  PB, Yamada  KA, Witkowski  FX; Mechanisms controlling cardiac autonomic function and their relation to arrhythmogeresis.Fozzard  H; The Heart and Cardiovascular System. 1986 Raven New York:1343-1403.
Fedida  D, Shimoni  Y, Giles  VR; A novel effect of norepincphrine on cardiac cells is mediated by alpha-adrenoceptors. Am J Physiol(Heart Circ Physiol 25). 256 1989:H1500-H1504.
Corr  PB, Heathers  GP, Yamada  KA; Mechanism contributing to the arrhythmogenic influences of adrenergic stimulation in the ischemic heart. Am J Med. 87 (suppl 2A) 1989:19S-25S.
CrossRef | PubMed
Bentivegha  LA, Ransil  BJ, Grossman  W, Gwathney  JK, Morgan  JP; Cardiac hypertrophy and abnormal calcium handling in human myocardium (abstr). Circulation. 80 (Suppl II) 1989:II-617.
Damiano  BP, Rosen  MR; Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation. 69 1984:1013-1025.
CrossRef | PubMed
Kowey  PR, Frichling  TD, Sewter  J; Electrophysiological effects of left ventricular hypertrophy: effect of calcium and potassium channel blockade. Circulation. 83 1991:2067-2075.
CrossRef | PubMed
Kohya  T, Kimura  S, Myerburg  RJ, Basselt  AL; Susceptibility of hypertrophied rat hearts to ventricular fibrillation during acute ischemia. J Mol Cell Cardiol. 20 1988:159-168.
CrossRef | PubMed
Cupples  LA, Gagnon  DR, Kannel  WB; Long- and short-term risk of sudden cardiac death: population at risk. Circulation. 85 (suppl I) 1992:I-11-I-18.
Fish  FA, Prakash  C, Roden  DM; Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators. Circulation. 82 1990:1362-1369.
CrossRef | PubMed
Gocthals  MA, Sy  SU, Stroobandt  R, Andries  E, Paulus  WJ; Delayed afterpotentials elicit diastolic aftercontractions in the hypertrophied left ventricle of human aortic stenosis (abstr). Circulation. 82 (suppl III) 1990:III-581.

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