Sex and Gender Aspects in Antiarrhythmic Therapy

Abstract

Although cardiac arrhythmia had long been considered a predominantly male syndrome, it is now clear that arrhythmia is also a primary cause of mortality in women. Notably, the manifestation of specific arrhythmia syndromes appears to be gender specific. In particular, female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes which occur as adverse effects of existing drugs. Males, on the other hand, are more likely to develop Brugada syndrome. Recent clinical and experimental studies suggest that these differences may stem from intrinsic sex differences in cardiac tissue. These include fundamental electrical differences resulting from variable ion channel expression and diverse sex hormonal regulation via long-term genomic and acute nongenomic pathways, and sex differences in drug responses and metabolisms. Undoubtedly, determining the effect of gender on cardiac function will be difficult and require sophisticated methodologies. However, gender differences underlying predilection to distinct arrhythmia syndromes must be revealed so that new therapeutic strategies that take gender into account can be applied to at-risk patients.

Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters

“…This is often attributed to longer QT C intervals in women than in men. The sex difference is thought to be caused by shortening of the action potential by endogenous testosterone and progesterone, which is supported by many clinical and basic studies (Kurokawa et al, 2012Zhang et al, 2011;Charbit et al, 2009;Pecori Giraldi et al, 2010). Instead, estrogen has both antiarrhythmic and arrhythmic effects.…”

“…Clinical evidence implies that sex hormones appear to play important roles in sex differences in baseline QT intervals and pro-arrhythmias (Kurokawa et al, 2012). We found that physiological serum levels of 17β-estradiol (E2) and estrone 3-sulfate acutely prolonged action potential durations and suppressed guinea pig I Kr channel currents (I Kr ) and hERG currents (Kurokawa et al, 2008;Kakusaka et al, 2009).…”

Kcne4 deletion sex‐ and age‐specifically impairs cardiac repolarization in mice

“…Uncovering sex‐dependent differences in arrhythmia susceptibility and the molecular mechanisms underlying them is therefore an early step to ward therapeutic strategies tailored toward the individual ( i.e. , precision medicine) (11).…”

“…Reduced repolarization reserve and lower I Kr density are more commonly observed in women than in men and predispose to drug-induced cardiac arrhythmia (9). Uncovering sex-dependent differences in arrhythmia susceptibility and the molecular mechanisms underlying them is therefore an early step toward therapeutic strategies tailored toward the individual (i.e., precision medicine) (11).…”

The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

“…Thus, the hERG channel has become a primary anti-target in drug development. However, drug-induced QT C prolongation is a complicated phenomenon that is related not just to unintended hERG blockade, but also to multi-channel blockade, drug–drug interactions, and a variety of patient factors, including sex [ 4 , 5 , 6 , 7 ].…”