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Cardiovascular Research 2003 57(3):591-593; doi:10.1016/S0008-6363(03)00221-9
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Gender differences in cardiac development: are hormones at the heart of the matter?

Thai V Pham*

Department of Molecular & Cellular Pharmacology, University of Miami School of Medicine, 1600 NW 10th Ave., RMSB 6068, Miami, FL 33136, USA

* Tel.: +1-305-243-5922; fax: +1-305-243-4555. tpham{at}med.miami.edu

See article by Valverde et al. [10] (pgaes 625–631) in this issue.

Male/female differences in cardiac electrophysiology have long been noted, but only in recent years has there been an increased awareness and appreciation of the influence of a patient's sex on presentation of various cardiac arrhythmias [1]. One of the most dramatic and important differences between men and women regarding sex and arrhythmia is the greater risk in women of torsades de pointes induced by drugs that prolong repolarization [2]. Additionally, female gender is an independent risk factor for syncope and sudden death in the congenital long QT syndrome [3]. Although the molecular mechanisms for these sex-related differences are largely unknown, fundamental differences in the electrophysiology of the male and female hearts are postulated to be responsible. Women have faster resting heart rates and longer rate-corrected QTc intervals than men [4]. However, young boys and girls have similar heart rates and QT intervals [5,6]. From puberty through adult years, the duration of the QTc in men abbreviates and then gradually increases until the age of 50 when QTc approaches that of women [5]. These gender- and age-dependent changes in ventricular repolarization are also present in congenital LTQS patients [7,8]. Further, there is an age-dependent distribution of initial arrhythmic events [9]. The probability of a first ventricular tachyarrhythmia is higher in boys than girls. In males, this risk decreases after puberty while the opposite is seen in females [9]. In addition, mortality from the first arrhythmic event is higher in males than females. The role of gender in the development of cardiac electrophysiology has not been clearly defined. On the other hand, because age-dependent changes in QT interval coincide with the onset of puberty, could changes in sex hormone levels be the key to unlock these gender differences?

In this issue, Valverde et al. [10] report age-associated changes in rabbit QT duration and ventricular repolarization that are similar to those previously found in humans [5,7,8]. There is no gender-related difference in QT interval or ventricular action potential duration (APD) in neonatal (pre-pubertal) rabbits. In adult male rabbits the QT intervals and APDs shorten, while in adult females the ventricular repolarization duration remains equal to those of neonates. These investigators showed that gonadectomized male and female rabbits do not exhibit differences in repolarization duration, such that QT intervals and APDs recorded from orchiectomized male rabbits equal those from oophorectomized females but are longer than those of normal adult males. Further, there is an association between the age-dependent change in QT durations observed in male rabbits with serum testosterone levels, such that pre-pubertal males and orchiectomized males have lower dihydrotestosterone (DHT) levels than normal adult male rabbits.

Experimental studies, largely in rabbits, have begun to address the cellular and ionic basis of sex hormones on gender-related differences in cardiac electrophysiology and drug-induced arrhythmias (for an extensive review see Ref. [11]). In male rabbits, more recent experimental studies have provided direct evidence for the protective role of testosterone against drug-induced arrhythmia [12–14]. In vivo DHT treatment of orchiectomized males resulted in shortening of the QT interval [14] and APD90 [12] compared to placebo-treated animals. In addition, the effect of quinidine- and dofetilide-induced QT [14] and APD [12] prolongation was minimized. Further, DHT treatment decreases the incidence of EAD induced by dofetilide [12]. A similar effect of chronic DHT treatment on drug response was seen in DHT-treated normal female rabbits [13]. DHT-treatment resulted in shortening of baseline APD and diminished the APD prolongation and incidence of early afterdepolarizations (EAD) induced by dofetilide compared to normal females [13]. Further, in orchiectomized male rabbits DHT treatment increases IKr and outward IK1 densities [14]. The increase in these K+ currents could explain in part the effects of DHT on ventricular repolarization and developmental changes in QT interval in males. The above data demonstrate clearly a protective role of testosterone against proarrhythmic risk of long QT (i.e. congenital or acquired (drug-induced) LQTS), in males. Together with data presented in this issue by Valverde et al. [10] these findings suggest a pivotal role of testosterone in defining gender-related differences in the development of cardiac electrophysiology. Nevertheless, an interesting point remains; although the baseline repolarization duration is normalized by removal of the ovarian (in female rabbits) and testicular (in male rabbits) hormonal axes [10,12], the risk of proarrhythmic effects of drugs are not normalized but rather it is reversed in gonadectomized rabbits compared to normal male and female rabbits [12]. These data imply that even though the electrophysiologic phenotype appears to be similar (i.e. baseline repolarization duration is equal) there are distinct repolarization mechanisms in male and female hearts that are not influenced by sex hormones.

In females the role of sex hormones in ventricular repolarization and risk of drug-induced proarrhythmia has not been completely characterized. In female patients, there is evidence that estrogen or progesterone may be key factors in susceptibility to ventricular arrhythmias. Women taking oral contraceptives are at greater risk of ventricular ectopy than those who are not taking oral contraceptives [15]. This suggests that either estrogen or progesterone may increase proarrhythmic risk. A more recent study [16] examining the effects of ibutilide on QTc in women at different phases of the menstrual cycle suggest that it may be the ratio of progesterone to estrogen that may contribute to proarrhythmic effects of ibutilide. It was determined that progesterone and progesterone to estrogen ratio are inversely correlated with ibutilide QTc prolongation. In rabbits, it has been demonstrated that estrogen at high levels can increase proarrhythmic risk yet it is not a unique determinant for gender differences in the baseline ventricular repolarization [11]. Because the progesterone serum levels have not been measured in any of the experimental studies to date, no inferences can be made with regards to the role of progesterone in modulation of baseline repolarization or susceptibility to drug-induced proarrhythmia.

It is clear from available data that sex hormones (testosterone and estrogen) are important modulators of ventricular repolarization, in part through their regulation of ionic currents (i.e. ICa,L, IK1 and IKr) that control repolarization [11]. Although progress has been made toward defining the role of sex hormones in gender-based difference in ventricular repolarization, little is known about the underlying factors or mechanisms for gender-associated developmental changes in cardiac electrophysiology.

At the heart of this complex matter are unanswered questions that will ultimately aid us in devising novel gender-specific therapeutic approaches. Are there male and female hearts and are they developmentally distinct? Are there gender-related differences in risk of drug-induced arrhythmia in neonatal rabbits? If so, what are the non-sex hormone factors that underlie gender-specific susceptibility to drug-induced proarrhythmia. These are some of the few questions that we can begin to address using the rabbit model presented by Valverde et al. [10].


   References
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  13. Pham T.V., Sosunov E.A., Anyukhovsky E.P., Danilo P. Jr., Rosen M.R. Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits. Circulation (2002) 106:2132–2136.[Abstract/Free Full Text]
  14. Liu X.K., Katchman A., Whitfield B.H., et al. 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 (2003) 57:28–36.[Abstract/Free Full Text]
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