Key result
Dofetilide-induced proarrhythmia occurred in 86% of young dogs, 40% of adults, and 0% of neonates (P<0.05), indicating that APD prolongation requires transmural dispersion to cause proarrhythmia.
Absolute Event Rate: 86% vs 40%
p-value: p=<0.05
Age-dependent changes in repolarization currents (I(Kr) and I(Ks)) determine the susceptibility to dofetilide-induced proarrhythmia, which requires both transmural dispersion of repolarization and early after depolarizations.
Hypothesis-generating for greater I(Kr) blocker proarrhythmia risk in immature hearts; leaves open age-dependent I(Ks) contributions to repolarization reserve.
OBJECTIVE: Clinical and experimental studies suggest that immature hearts are as or more sensitive than adult hearts to adverse effects of I(Kr) blocking drugs. We hypothesized that age-dependent changes in I(Kr) and I(Ks) contribute to the different repolarization reserves and proarrhythmic effects of I(Kr) 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 I(Kr) blocker dofetilide; (2) dofetilide effects on action potential duration (APD) recorded with microelectrodes from left ventricular (LV) slabs; (3) I(Kr) and I(Ks) 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 (P<0.05). Isolated tissue experiments showed no transmural gradient for repolarization from neonate through 3 months of age, after which the gradient increased through adulthood. In the presence of dofetilide, the greatest APD prolongation occurred in neonates. Yet, transmural dispersion did not increase in neonates but significantly increased in young and adults. Dofetilide-induced early after depolarization (EAD) incidence was 23% in adults, 59% in young and 8% in neonates (P<0.05). I(Kr) but not I(Ks) was expressed at <30 days, whereas both currents were present in adult myocardium. CONCLUSIONS: Our data suggest that a lack of I(Ks) results in a greater dependence on I(Kr) for repolarization in neonates and is associated with exaggerated effects of I(Kr)-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 I(Kr) blocking drugs appears to be the ultimate determinant of proarrhythmia.
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Obreztchikova et al. (2003) studied Proarrhythmia. Dofetilide vs. Different age groups (neonates, young, adults) was evaluated on Dofetilide-induced proarrhythmia in situ (p=<0.05). Dofetilide-induced proarrhythmia occurred in 86% of young dogs, 40% of adults, and 0% of neonates (P<0.05), indicating that APD prolongation requires transmural dispersion to cause proarrhythmia.
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