| First Author | Hu Z | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 8258 |
| PubMed ID | 29844497 | Mgi Jnum | J:263713 |
| Mgi Id | MGI:6162757 | Doi | 10.1038/s41598-018-26599-8 |
| Citation | Hu Z, et al. (2018) Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice. Sci Rep 8(1):8258 |
| abstractText | 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 beta-subunit, is upregulated by 5alpha-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. |
