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(Circulation Research. 2001;89:378.)
© 2001 American Heart Association, Inc.

Editorial

Taking the Gender Gap to Heart

Barry London

From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa.

Correspondence to Barry London, MD, PhD, Cardiovascular Institute, University of Pittsburgh, BST 1744, 200 Lothrop St, Pittsburgh, PA 15213. E-mail londonb{at}msx.upmc.edu

Key Words: K⁺ channel • gender • mouse • heart • transgenic models

For centuries, poets, philosophers, and writers have described differences between the male and female heart.¹ During the last several decades, many traditional male/female stereotypes have been questioned in the light of our expanding scientific knowledge.² Although progress has been made toward a more gender-neutral society, the "gender gap" still exists. At the heart of the complex issues involved, an unanswered fundamental question remains: To what extent are perceived gender differences real, and what are their implications?

Male/female differences in cardiovascular physiology and pathophysiology have long been appreciated. Premenopausal women have a lower incidence of atherosclerotic coronary artery disease, due at least in part to the protective effects of estrogen.³ Male and female hearts also differ electrophysiologically. Women have a higher incidence of atrioventricular nodal reentrant tachycardias, whereas men account for most symptomatic cases of Brugada syndrome, an autosomal dominant form of idiopathic ventricular fibrillation.^4,5 Women have longer QT intervals than men and are at greater risks for torsade de pointes from congenital and acquired long-QT syndrome.^6–8 Surprisingly, women may have a lower overall incidence of sudden cardiac death, even correcting for the difference in coronary artery disease.⁹ The molecular basis of these gender differences is largely unknown.

In this issue of Circulation Research, Dr Fiset and colleagues report for the first time on gender differences in the repolarizing K⁺ currents of mouse ventricular myocytes.¹⁰ Female hearts have decreased expression of Kv1.5 at both the RNA and protein levels compared with males. As a result, myocytes isolated from female hearts have lower densities of the rapidly activating, slowly inactivating 4-aminopyridine (4-AP)–sensitive current termed I_Kur (or I_K,slow) and longer action potentials. As expected, blocking I_Kur with 4-AP eliminates the gender differences. At one level, the importance of these findings is clear. An ever-increasing number of electrophysiological studies are being performed on transgenic and gene-targeted mice. When examining differences in repolarization, investigators will need to control for the sex of the mice. Otherwise, a study with a different percentage of females in the transgenic versus control groups could mistakenly lead to the conclusion that the transgene affects repolarization.

The results also suggest interesting possibilities that extend beyond the mouse. Kv1.5 encodes an I_Kur current in the human atrium but not in the human ventricle.¹¹ Are there differences in Kv1.5 expression and I_Kur density in the atria of men versus women? Do these differences lead to alterations in atrial electrophysiology and susceptibility to supraventricular arrhythmias? Additional investigations appear warranted.

Little is known about ion channel regulation in the heart. Recent transgenic and gene-targeting experiments on K⁺ channels in mice have demonstrated electrophysiological remodeling. Loss of Kv1.5 in the mouse heart leads to upregulation of Kv2.1, a channel that also encodes a rapidly activating, slowly inactivating current.¹² Similarly, loss of Kv4.2 and Kv4.3, the channels that encode I_to,f, results in broader expression of Kv1.4, the channel that encodes I_to,s.¹³ The mechanisms underlying these changes are unknown. In the present study, Trépanier-Boulay et al¹⁰ report higher levels of Kv1.5 expression in the hearts of male mice. Estrogens and androgens affect ion channel expression in rabbit hearts.^14,15 It remains to be seen whether the differences in mice are mediated by the sex hormones.

The electrophysiology of the mouse heart differs markedly from that of larger mammals. Mice have high heart rates (>600 bpm), short action potentials without a significant plateau, and abbreviated QT intervals on their electrocardiograms.¹² At the cellular level, the transient outward currents (I_to,f and I_to,s) and the delayed rectifier currents (I_Kur and I_K,slow) play a major role in repolarization of the mouse myocyte, whereas I_Kr and I_Ks have only minor roles. Thus, it seems unlikely that the mechanisms that underlie the gender-based transcriptional changes of Kv1.5 in the mouse ventricle will be directly applicable to the regulation of the K⁺ channels important for ventricular repolarization in rabbits or humans.

Female mice, rabbits, and humans have longer action potentials than their male counterparts. This similarity is intriguing, given the marked differences between the species. Is the 8-millisecond "gender gap" in repolarization a side effect caused by the action of gender-specific sex hormones on ion channel regulation in the heart? Does delayed repolarization provide some advantage to the female of the species? The answers to these questions are unknown. It is clear that the male and female hearts differ. For cardiovascular electrophysiology at least, the importance of this sexual diversity remains to be determined.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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