Sympathetic nerve stimulation produces spatial heterogeneities of action potential restitution

BackgroundRestitution kinetics (RK) of action potential duration (APD) are classically studied by applying an extra impulse at varying diastolic intervals (DI) and might differ from RK elicited by sympathetic nerve stimulation (SNRK).ObjectiveTo measure 'Physiological' RK during gradual increases in heart rate caused by sympathetic nerve stimulation (SNS) and its possible spatial heterogeneities caused by non-uniform innervation of the myocardium.MethodsThe SNRK was measured from rabbit hearts with intact sympathetic innervation using optical mapping. APD versus DI were plotted from left ventricles during SNS, then with pacing using identical activation interval (AI) sequences.ResultsAI decreased (444 ± 18 ms to 284 ± 9 ms) in 25 s and recovered to baseline on SNS suspension (n = 10). APD versus DI plots were identical for SNS and pacing except that when maximum heart rate was reached, SNS elicited a further APD shortening compared with pacing. During SNS, APDs decreased from 216 ± 9 ms to 154 ± 7 ms (29% ± 2%) at the base and from 206 ± 12 ms to 158 ± 7 ms (20% ± 2%) at the apex. During pacing, APDs at the base decreased from 216 ± 9 ms to 170 ± 7 ms (21% ± 1%, SNS versus pacing: P < .05). In contrast, RK were similar at the apex for SNS and pacing. During SNS, the extra APD shortening at the base was associated with longer segments of RK curves with negative slopes and extra DI prolongation. Perfusion with the IKs inhibitor HMR 1556 (0.5 μM; n = 5) abolished differences in RK between SNS and pacing. Levels of KCNQ1 and tyrosine hydroxylase proteins were greater at the base than apex (n = 4), implying that apex–base distributions for IKs and sympathetic innervation are congruent with SNRK heterogeneities.ConclusionThe findings shed further insights on heterogeneities of sympathetic nerves, RK, and the role of IKs in cardiac repolarization.