Developmental changes in and contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia

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Abstract
Objective: Clinical and experimental studies suggest that immature hearts are as or more sensitive than adult hearts to adverse effects of IKr blocking drugs. We hypothesized that age-dependent changes in IKr and IKs contribute to the different repolarization reserves and proarrhythmic effects of IKr blockers in the young and adult heart. Methods: Dogs aged 1–150 days and adults were used to study (1) proarrhythmic effects in situ of the IKr blocker dofetilide; (2) dofetilide effects on action potential duration (APD) recorded with microelectrodes from left ventricular (LV) slabs; (3) IKr and IKs in single LV myocytes using whole-cell voltage clamp. Results: In situ, dofetilide-induced proarrhythmia occurred in 40% of adults, 86% of young (20–150 day) dogs and 0% of neonatal (1–19 day) dogs (PPIKr but not IKs was expressed at Conclusions: Our data suggest that a lack of IKs results in a greater dependence on IKr for repolarization in neonates and is associated with exaggerated effects of IKr-blockade on APD. However, APD prolongation alone is insufficient for expression of proarrhythmia, which also requires transmural dispersion of repolarization and EADs. The extent to which APD prolongation, transmural dispersion and EADs are manifested at various ages in the absence and presence of IKr blocking drugs appears to be the ultimate determinant of proarrhythmia.

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