Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome

Arrhythmia Center/Sinai Hospital, Detroit, Michigan 48235, USA.

OBJECTIVES: We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND: Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS: QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS: The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS: In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

This article has been cited by other articles:

				Z.-Y. Wu, K. Chen, B. Haendler, T. V. McDonald, and J.-S. Bian Stimulation of N-Terminal Truncated Isoform of Androgen Receptor Stabilizes Human Ether-a-go-go-Related Gene-Encoded Potassium Channel Protein via Activation of Extracellular Signal Regulated Kinase 1/2 Endocrinology, October 1, 2008; 149(10): 5061 - 5069. [Abstract] [Full Text] [PDF]

				M. Imboden, H. Swan, I. Denjoy, I. M. Van Langen, P. J. Latinen-Forsblom, C. Napolitano, V. Fressart, G. Breithardt, M. Berthet, S. Priori, et al. Female Predominance and Transmission Distortion in the Long-QT Syndrome N. Engl. J. Med., December 28, 2006; 355(26): 2744 - 2751. [Abstract] [Full Text] [PDF]

				E. Saarel Sudden Death and Long-QT Syndrome AAP Grand Rounds, December 1, 2006; 16(6): 62 - 63. [Full Text] [PDF]

				E. Schulze-Bahr Arrhythmia Predisposition: Between Rare Disease Paradigms and Common Ion Channel Gene Variants J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A67 - A78. [Abstract] [Full Text] [PDF]

				J. B. Hobbs, D. R. Peterson, A. J. Moss, S. McNitt, W. Zareba, I. Goldenberg, M. Qi, J. L. Robinson, A. J. Sauer, M. J. Ackerman, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA, September 13, 2006; 296(10): 1249 - 1254. [Abstract] [Full Text] [PDF]

				Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]

				Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]

				A. N. Katchman, J. Koerner, T. Tosaka, R. L. Woosley, and S. N. Ebert Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1098 - 1106. [Abstract] [Full Text] [PDF]

				C. R. Kerr and K. Humphries Gender-Related Differences in Atrial Fibrillation J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1307 - 1308. [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]

				S. Kaab and E. Schulze-Bahr Susceptibility genes and modifiers for cardiac arrhythmias Cardiovasc Res, August 15, 2005; 67(3): 397 - 413. [Abstract] [Full Text] [PDF]

				J. Brouillette, K. Rivard, E. Lizotte, and C. Fiset Sex and strain differences in adult mouse cardiac repolarization: importance of androgens Cardiovasc Res, January 1, 2005; 65(1): 148 - 157. [Abstract] [Full Text] [PDF]

				L Sugeng, L Weinert, and R M Lang Left ventricular assessment using real time three dimensional echocardiography Heart, November 1, 2003; 89(90003): iii29 - 36. [Full Text] [PDF]

				W. Zareba, A. J. Moss, E. H. Locati, M. H. Lehmann, D. R. Peterson, W. J. Hall, P. J. Schwartz, G. M. Vincent, S. G. Priori, J. Benhorin, et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype J. Am. Coll. Cardiol., July 2, 2003; 42(1): 103 - 109. [Abstract] [Full Text] [PDF]

				C. R. Bezzina, A. O. Verkerk, A. Busjahn, A. Jeron, J. Erdmann, T. T. Koopmann, Z. A. Bhuiyan, R. Wilders, M. M.A.M. Mannens, H. L. Tan, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization Cardiovasc Res, July 1, 2003; 59(1): 27 - 36. [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]

				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]

				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]

				E. Pietila, H. Fodstad, E. Niskasaari, P.a. J. Laitinen, H. Swan, M. Savolainen, Y. A. Kesaniemi, K. Kontula, and H. V. Huikuri association between HERG K897T polymorphism and QT interval in middle-aged finnish women J. Am. Coll. Cardiol., August 7, 2002; 40(3): 511 - 514. [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]

				Y. Wu and M. E Anderson Reduced repolarization reserve in ventricular myocytes from female mice Cardiovasc Res, February 15, 2002; 53(3): 763 - 769. [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]

				M.-D. Drici Influence of gender on drug-acquired long QT syndrome Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K41 - K47. [Abstract] [PDF]

				P. E. Puddu, A. Criniti, and F Monti Screening for drug-induced (acquired) long QT syndrome: is it time to apply new methods? Eur. Heart J., March 1, 2001; 22(5): 363 - 369. [PDF]

				G. Lande, F. Kyndt, I. Baro, D. Chabannes, P. Boisseau, J.-C. Pony, D. Escande, and H. Le Marec Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype Eur. Heart J., March 1, 2001; 22(5): 410 - 422. [Abstract] [PDF]

				C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]

				C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]

				M.-D. Drici, B. C. Knollmann, W.-X. Wang, and R. L. Woosley Cardiac Actions of Erythromycin: Influence of Female Sex JAMA, November 25, 1998; 280(20): 1774 - 1776. [Abstract] [Full Text] [PDF]

				W. C. Allan, M. Anglim;, M. J. Ackerman, and C.-b. J. Porter Long QT Syndrome Pediatrics, November 1, 1998; 102(5): 1220 - 1221. [Full Text]

				B. J. Maron, J. H. Moller, C. E. Seidman, G. M. Vincent, H. C. Dietz, A. J. Moss, J. A. Towbin, H. M. Sondheimer, R. E. Pyeritz, G. McGee, et al. Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome : A Statement for Healthcare Professionals From the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association Circulation, October 6, 1998; 98(14): 1460 - 1471. [Full Text] [PDF]

				W. Zareba, A. J. Moss, P. J. Schwartz, G. M. Vincent, J. L. Robinson, S. G. Priori, J. Benhorin, E. H. Locati, J. A. Towbin, M. T. Keating, et al. Influence of the Genotype on the Clinical Course of the Long-QT Syndrome N. Engl. J. Med., October 1, 1998; 339(14): 960 - 965. [Abstract] [Full Text] [PDF]

				P. Babij, G. R. Askew, B. Nieuwenhuijsen, C.-M. Su, T. R. Bridal, B. Jow, T. M. Argentieri, J. Kulik, L. J. DeGennaro, W. Spinelli, et al. Inhibition of Cardiac Delayed Rectifier K+ Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic Mice Circ. Res., September 21, 1998; 83(6): 668 - 678. [Abstract] [Full Text] [PDF]

				J. D. Marsh, M. H. Lehmann, R. H. Ritchie, J. K. Gwathmey, G. E. Green, and R. J. Schiebinger Androgen Receptors Mediate Hypertrophy in Cardiac Myocytes Circulation, July 21, 1998; 98(3): 256 - 261. [Abstract] [Full Text] [PDF]

				M.-D. Drici, I. Arrighi, C. Chouabe, J. R. Mann, M. Lazdunski, G. Romey, and J. Barhanin Involvement of IsK-Associated K+ Channel in Heart Rate Control of Repolarization in a Murine Engineered Model of Jervell and Lange-Nielsen Syndrome Circ. Res., July 13, 1998; 83(1): 95 - 102. [Abstract] [Full Text] [PDF]

				E. H. Locati, W. Zareba, A. J. Moss, P. J. Schwartz, G. M. Vincent, M. H. Lehmann, J. A. Towbin, S. G. Priori, C. Napolitano, J. L. Robinson, et al. Age- and Sex-Related Differences in Clinical Manifestations in Patients With Congenital Long-QT Syndrome : Findings From the International LQTS Registry Circulation, June 9, 1998; 97(22): 2237 - 2244. [Abstract] [Full Text] [PDF]

				M. Hara, P. Danilo Jr., and M. R. Rosen Effects of Gonadal Steroids on Ventricular Repolarization and on the Response to E4031 J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1068 - 1072. [Abstract] [Full Text]

				P. Yang, H. Kanki, B. Drolet, T. Yang, J. Wei, P. C. Viswanathan, S. H. Hohnloser, W. Shimizu, P. J. Schwartz, M. Stanton, et al. Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes Circulation, April 23, 2002; 105(16): 1943 - 1948. [Abstract] [Full Text] [PDF]