The apicobasal dispersion of ventricular repolarization in humans is associated with age and affects arrhythmia vulnerability

The apicobasal repolarization gradient (ABRG) plays an important role in determining the sequence of ventricular repolarization, but the effects of sex and age on ABRG are unknown. In this study, we investigate the age- and sex-related differences in ABRG and evaluate their possible role in vulnerability to arrhythmia. Electrocardiographic imaging was performed in 22 healthy subjects (16 females and 6 males) during sinus rhythm, and the average recovery time (RT) at the ventricular apex and base was determined. Fifty-six different ABRGs were simulated in a male and female model of human ventricular epicardium with sex-specific electrophysiology by simultaneously adjusting the apicobasal gradients of the slow and rapid delayed rectifier potassium currents. The models were burst paced from the ventricular apex and right ventricular outflow tract to assess the effect of ABRGs on arrhythmia vulnerability. Apicobasal differences in RT (human subjects) and repolarization time (simulation data) were calculated to quantify the ABRGs. In human subjects, ABRGs diminished and eventually inverted (longer RT at the apex than at the base) with increasing age (r = -0.7265, P = 0.0001). In both male and female models, apical pacing resulted in arrhythmia in 20/ 56 simulations, whereas right ventricular outflow tract pacing resulted in arrhythmia in 15/56 simulations. Arrhythmias were attributable to re-entry from unidirectional block and generally lasted longer in the models with shorter RT at the apex than at the base. Our findings demonstrate that the ABRG diminishes or inverts with ageing in both male and female human ventricles, which can reduce vulnerability to re-entrant ventricular arrhythmia. KEY POINTS: The apicobasal repolarization gradient (ABRG) determines the sequence of ventricular repolarization. Little is known about ABRG variability in humans and the effects of sex and age on the ABRG. Using electrocardiographic imaging data from healthy human subjects, we found that ABRG diminishes or inverts with ageing, in both males and females. Our simulations in computational models of human ventricular epicardium show that diminishing and inverting the ABRG is associated with a low vulnerability to arrhythmia. By linking together electrocardiographic imaging data and computer simulations, we demonstrate that vulnerability to ventricular arrhythmia might depend on age-related differences in ABRG.