This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pham, T. V. Articles by Rosen, M. R. Search for Related Content PubMed PubMed Citation Articles by Pham, T. V. Articles by Rosen, M. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ESTRADIOL Related Collections Animal models of human disease Arrythmias-basic studies

(Circulation. 2001;103:2207.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Impact of Sex and Gonadal Steroids on Prolongation of Ventricular Repolarization and Arrhythmias Induced by I_K-Blocking Drugs

Thai V. Pham, PhD; Eugene A. Sosunov, PhD; Ravil Z. Gainullin, PhD; Peter Danilo, Jr, PhD; Michael R. Rosen, MD

From the Departments of Pharmacology (T.V.P., E.A.S., R.Z.G., P.D., M.R.R.) and Pediatrics (M.R.R.) and Center for Molecular Therapeutics (M.R.R.), The Partnership for Women’s Health (M.R.R.), College of Physicians and Surgeons of Columbia University, New York, NY.

Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, Director, Center for Molecular Therapeutics, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH7West-321, New York, NY 10032. mrr1@columbia.edu

Background—Mechanisms for longer rate-corrected QT intervals and higher incidences of drug-induced torsade de pointes in women than in men are incompletely defined, although gonadal steroids are assumed to be important determinants of these differences.

Methods and Results—We used microelectrode techniques to study isolated rabbit right ventricular endocardium from control male and female and castrated male (ORCH) and female (OVX) rabbits. Action potential duration to 30% repolarization (APD₃₀) was significantly shorter in male than female and in ORCH than OVX at a cycle length of 500 ms. The I_Ks blocker chromanol 293B had no effect on APD in males or females. The I_Kr blocker dofetilide prolonged APD in female and ORCH more than in male and OVX. At 10^-6 mol/L dofetilide (cycle length=1 second), the incidence of early afterdepolarizations was: female, 67%; ORCH, 56%; male, 40%; and OVX, 28%. Serum 17ß-estradiol levels were unrelated to the effects of dofetilide, but as testosterone levels increased, the dofetilide effect to increase APD diminished, as did early afterdepolarization incidence.

Conclusions—Sex-related differences in basal right ventricular endocardial AP configuration persist in castrated rabbits, suggesting that extragonadal factors contribute to the differences in ventricular repolarization. In this model, drugs that block I_Kr but not I_Ks prolong repolarization in a way that suggests that protection from excess prolongation in males is attributable to testosterone, whereas the risk of excess prolongation of repolarization in females is related to sex-determined factors in addition to estrogen.

Key Words: sex • steroids • arrhythmias • ion channels • drugs

This article has been cited by other articles:

				J. Kurokawa, M. Tamagawa, N. Harada, S.-i. Honda, C.-X. Bai, H. Nakaya, and T. Furukawa Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization J. Physiol., June 15, 2008; 586(12): 2961 - 2973. [Abstract] [Full Text] [PDF]

				L. Xiao, L. Zhang, W. Han, Z. Wang, and S. Nattel Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H570 - H580. [Abstract] [Full Text] [PDF]

				C.-X. Bai, J. Kurokawa, M. Tamagawa, H. Nakaya, and T. Furukawa Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone Circulation, September 20, 2005; 112(12): 1701 - 1710. [Abstract] [Full Text] [PDF]

				T. Korte, M. Fuchs, A. Arkudas, S. Geertz, R. Meyer, A. Gardiwal, G. Klein, M. Niehaus, A. Krust, P. Chambon, et al. Female Mice Lacking Estrogen Receptor {beta} Display Prolonged Ventricular Repolarization and Reduced Ventricular Automaticity After Myocardial Infarction Circulation, May 10, 2005; 111(18): 2282 - 2290. [Abstract] [Full Text] [PDF]

				S. Brunet, F. Aimond, H. Li, W. Guo, J. Eldstrom, D. Fedida, K. A. Yamada, and J. M. Nerbonne Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult mouse ventricles J. Physiol., August 15, 2004; 559(1): 103 - 120. [Abstract] [Full Text] [PDF]

				D. M. Roden Drug-Induced Prolongation of the QT Interval N. Engl. J. Med., March 4, 2004; 350(10): 1013 - 1022. [Full Text] [PDF]

				P. Smetana, V. N. Batchvarov, K. Hnatkova, A. J. Camm, and M. Malik Ventricular gradient and nondipolar repolarization components increase at higher heart rate Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H131 - H136. [Abstract] [Full Text] [PDF]

				P. Smetana, V. Batchvarov, K. Hnatkova, A John Camm, and M. Malik Sex differences in the rate dependence of the T wave descending limb Cardiovasc Res, June 1, 2003; 58(3): 549 - 554. [Abstract] [Full Text] [PDF]

				T. V Pham Gender differences in cardiac development: are hormones at the heart of the matter? Cardiovasc Res, March 1, 2003; 57(3): 591 - 593. [Full Text] [PDF]

				E. R Valverde, M. O Biagetti, G. R Bertran, P. D Arini, H. Bidoggia, and R. A Quinteiro Developmental changes of cardiac repolarization in rabbits: Implications for the role of sex hormones Cardiovasc Res, March 1, 2003; 57(3): 625 - 631. [Abstract] [Full Text] [PDF]

				J. Brouillette, V. Trepanier-Boulay, and C. Fiset Effect of androgen deficiency on mouse ventricular repolarization J. Physiol., January 15, 2003; 546(2): 403 - 413. [Abstract] [Full Text] [PDF]

				A. F. James and J. C. Hancox Sex, drugs and arrhythmia: are gender differences in risk of torsades de pointes simply a matter of testosterone? Cardiovasc Res, January 1, 2003; 57(1): 1 - 4. [Full Text] [PDF]

				X.-K. Liu, A. Katchman, B. H Whitfield, G. Wan, E. M Janowski, R. L Woosley, and S. N Ebert In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits Cardiovasc Res, January 1, 2003; 57(1): 28 - 36. [Abstract] [Full Text] [PDF]

				X. H.T. Wehrens, M. A. Vos, P. A. Doevendans, and H. J.J. Wellens Novel Insights in the Congenital Long QT Syndrome Ann Intern Med, December 17, 2002; 137(12): 981 - 992. [Abstract] [Full Text] [PDF]

				B. Surawicz and S. R. Parikh Prevalence of male and female patterns of early ventricular repolarization in the normal ECG of males and females from childhood to old age J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1870 - 1876. [Abstract] [Full Text] [PDF]

				T. V. Pham, E. A. Sosunov, E. P. Anyukhovsky, P. Danilo Jr, and M. R. Rosen Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits Circulation, October 15, 2002; 106(16): 2132 - 2136. [Abstract] [Full Text] [PDF]

				M.-D. Drici, L. Baker, P. Plan, J. Barhanin, G. Romey, and G. Salama Mice Display Sex Differences in Halothane-Induced Polymorphic Ventricular Tachycardia Circulation, July 23, 2002; 106(4): 497 - 503. [Abstract] [Full Text] [PDF]

				T. V. Pham and M. R. Rosen Sex, hormones, and repolarization Cardiovasc Res, February 15, 2002; 53(3): 740 - 751. [Abstract] [Full Text] [PDF]

				T. V Pham, R. B Robinson, P. Danilo Jr, and M. R Rosen Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current Cardiovasc Res, February 15, 2002; 53(3): 752 - 762. [Abstract] [Full Text] [PDF]

				C. E Conrath, A. A.M Wilde, R. J.E Jongbloed, M. Alders, I. M van Langen, J Peter van Tintelen, P. A Doevendans, and T. Opthof Gender differences in the long QT syndrome: effects of {beta}-adrenoceptor blockade Cardiovasc Res, February 15, 2002; 53(3): 770 - 776. [Abstract] [Full Text] [PDF]

				B. London Taking the Gender Gap to Heart Circ. Res., August 31, 2001; 89(5): 378 - 379. [Full Text] [PDF]

				P. Smetana, V. N. Batchvarov, K. Hnatkova, A. J. Camm, and M. Malik Sex differences in repolarization homogeneity and its circadian pattern Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1889 - H1897. [Abstract] [Full Text] [PDF]

				V. Trepanier-Boulay, C. St-Michel, A. Tremblay, and C. Fiset Gender-Based Differences in Cardiac Repolarization in Mouse Ventricle Circ. Res., August 31, 2001; 89(5): 437 - 444. [Abstract] [Full Text] [PDF]