Temporal patterns of electrical remodeling in canine ventricular hypertrophy: focus on IKs downregulation and blunted beta-adrenergic activation.

Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including beta-adrenergic (beta-A)-sensitive I-Ks. Temporal patterns of ion-channel downregulation are poorly resolved. In dogs with complete atrioventricular block (AVB), we examined (1) the time course of molecular alterations underlying I-Ks downregulation from acute to chronic hypertrophy; and (2) concomitant changing responses of repolarization to beta-adrenergic receptor (beta-AR) stimulation. Methods and Results: Serial left-ventricular (LV) biopsies were collected from anesthetized dogs during sinus rhythm (SR; control) and at 3, 7 and 30 days of AVB. KCNQ1 mRNA and protein decreased within 3 days (protein expression 58 +/- 10% of control), remaining low thereafter. beta 1-AR mRNA and protein decreased more gradually to 53 +/- 8% at 7 days. In chronic-AVB LV myocytes, I-Ks-tail density was reduced: 1.4 +/- 0.3 pA/pF versus 2.6 +/- 0.4 pA/pF in controls. beta-A enhancement of I-Ks was reduced. Isoproterenol shortened action-potential duration in control cells, while causing heterogeneous repolarization responses in chronic AVB. beta-A early afterdepolarizations were induced in 4 of 13 chronic-AVB cells, but not in controls. In intact conscious dogs, isoproterenol shortened QT(c) at SR (by -8 +/- 3% from 295 ms), left it unaltered at 3 days AVB (+1 +/- 3% from 325 ms) and prolonged QT(c) at 30 days (+6 +/- 3% from 365 ms). Conclusions: Profound decrease of KCNQ1 occurs within days after AVB induction and is followed by a more gradual decrease of beta 1-AR expression. Downregulation and blunted beta-A activation of I-Ks contribute to the loss of beta-A-induced shortening of ventricular repolarization, favoring proarrhythmia. Provocation testing with isoproterenol identifies repolarization instability based on acquired channelopathy. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.