Regulation of cardiac ion channels via non-genomic action of sex steroid hormones: Implication for the gender difference in cardiac arrhythmias

Long QT syndrome (LQTS) is a disorder associated with prolonged electrocardiographic QT intervals and the development of ventricular arrhythmias. LQTS occurs as a congenital form in an autosomal-dominant or an autosomal-recessive manner, and as an acquired form occurred in various cardiac disorders and induced by drug side actions. Accumulating clinical information indicates the presence of gender difference in LQTS. Rate-corrected QT interval (QTc interval) is longer in females than in males, and female gender itself is an independent risk factor for development of arrhythmias in both congenital and acquired forms of LQTS. Gender differences in QTc interval and arrhythmic event in LQTS are not observed before puberty, while they become suddenly notable upon the onset of puberty. In females, QTc interval and risk of arrhythmic events in LQTS patients fluctuates during the menstrual cycle, and is affected by hormone replacement therapy. These clinical data suggest a critical role of sex steroid hormones on QTc interval and gender difference in LQTS risk. Sex steroid hormones have been traditionally considered as transactivation factors regulating the expression of target genes. However, accumulating evidences indicate the presence of novel non-transcriptional mechanisms of signal transduction through steroid hormone receptors. Sex steroid hormones rapidly regulate cardiac ion channel activity without transcription processes, which involves nitric oxides produced via the PI3-kinase/Akt/eNOS signaling cascade. In addition to transcriptional regulation, non-transcriptional regulation of cardiac ion channels is in part responsible for the gender difference in LQTS risk and its fluctuation during the menstrual cycle in females.