Sex-specific cardiac electrophysiological remodeling influences the susceptibility to arrhythmias in elderly rats

Advanced age is a well-known risk factor for cardiovascular disease (CVD), with sex differences contributing significantly to age-dependent clinical heterogeneity. The incidence of CVD increases with age in both sexes, although men and women are predisposed toward different CVDs. However, the sex-specific arrhythmogenic alterations in aged individuals are still not described in depth. The present work aimed to analyze gross anatomical and relevant cardiac electrophysiological parameters in vivo in aged female and male rats, emphasizing sex-related disparities and their relationship with enhanced arrhythmia vulnerability. Studies were performed on healthy wild-type Groningen rats: 13 adult males (8.2 ± 1.2 mo), 13 aged males (25.6 ± 0.7 mo), 13 adult females (9.8 ± 3.2 mo), and 13 aged females (23.0 ± 1.4 mo). The adult female heart was hypertrophic compared with adult males, but aging was associated with cardiac hypertrophy only in male rats. Adult female rats had longer effective refractory period and QTc than males, but only male rats showed a significant increase in these parameters with age. Conversely, aged animals showed longer ventricular activation time than adults in both sexes. Although conduction velocity remained consistent across groups, phase map study during programmed electrical stimulation revealed prolonged activation time in the aged female compared with all other groups. Notably, although aged rats were more prone to spontaneous supraventricular extrasystoles, only aged males were more susceptible to spontaneous ventricular arrhythmias. In conclusion, sex strongly influences the cardiac electrical remodeling, with male who could experience more significant adaptations. Accordingly, when the heart is exposed to proarrhythmic stimuli, the susceptibility to arrhythmias differs between elderly males and females.<b>NEW & NOTEWORTHY</b> Aged heart is more prone to develop cardiovascular diseases including arrhythmias. The age-related electrical remodeling of the heart results in specific electrophysiological alterations in male and female rats. Males could experience more challenging adaptations as they age. They show prolongations of atrial and ventricular activation, ventricular repolarization, and refractoriness. Aged females display alterations in ventricular activation. Arrhythmias are more likely to occur in aged animals with males being more susceptible to spontaneous and induced arrhythmias.