© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia
aDepartments of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY, USA
bC&C Research Laboratories, 146-141 Annyung-ri, Taean-ub, Hwasung-gun, Kyunggi-do 445-970, South Korea
* Corresponding author. College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 West 168 Street, PH 7West-321, New York, NY 10032, USA. Tel.: +1-212-305-8754; fax: +1-212-305-8351. mrr1{at}columbia.edu
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 (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 afterdepolarization (EAD) incidence was 23% in adults, 59% in young and 8% in neonates (P<0.05). IKr but not IKs was expressed at <30 days, whereas both currents were present in adult myocardium. 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.
KEYWORDS Arrhythmia (mechanisms); Antiarrhythmic agents; Developmental biology; Membrane potential; Membrane currents; Delayed rectifier current
1 Contributed equally as first author.
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