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Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel β-subunit, is upregulated by 5α-dihydrotestosterone (DHT). Thus, ventricular  Kcne4  expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causing a sex-independent electrical substrate at 13 months of age (22% QT prolongation in both males and females; P < 0.01),  Kcne4  deletion preferentially predisposed aged male mice to ischemia/reperfusion (IR)-provoked ventricular tachyarrhythmias. Interestingly,  Kcne4  deletion caused baseline induction of cardioprotective RISK and SAFE pathways in 13-m-old female, but not male, mice. IR-invoked RISK/SAFE induction was also deficient in male but not female  Kcne4  −/−  mice. Pharmacological inhibition of RISK/SAFE pathways in  Kcne4  −/−  females eliminated sex-specific differences in IR-invoked tachyarrhythmia predisposition. Furthermore, castration of  Kcne4  −/−  males eliminated sex-specific differences in both baseline and post-IR RISK/SAFE pathway induction, and tachyarrhythmia predisposition. Our results demonstrate for the first time that male sex can predispose in aged mice to dangerous ventricular tachyarrhythmias despite sex-independent electrical and ischemic substrates, because of testosterone-dependent impairment of RISK/SAFE pathway induction.

Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice