Referenced in: none

Automatically associated channels: Kv7.1

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

Authors: Milan Stengl, Christian Ramakers, Dirk W Donker, Ashish Nabar, Andrew V Rybin, Roel L H M G Spätjens, Theo van der Nagel, Will K W H Wodzig, Karin R Sipido, Gudrun Antoons, Antoon F M Moorman, Marc A Vos, Paul G A Volders

Journal, date & volume: Cardiovasc. Res., 2006 Oct 1 , 72, 90-100

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16934787

Abstract
Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including beta-adrenergic (beta-A)-sensitive IKs. 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 IKs downregulation from acute to chronic hypertrophy; and (2) concomitant changing responses of repolarization to beta-adrenergic receptor (beta-AR) stimulation.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. beta1-AR mRNA and protein decreased more gradually to 53 +/- 8% at 7 days. In chronic-AVB LV myocytes, IKs -tail density was reduced: 1.4 +/- 0.3 pA/pF versus 2.6 +/- 0.4 pA/pF in controls. beta-A enhancement of IKs 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 QTc at SR (by -8 +/- 3% from 295 ms), left it unaltered at 3 days AVB (+1 +/- 3% from 325 ms) and prolonged QTc at 30 days (+6 +/- 3% from 365 ms).Profound decrease of KCNQ1 occurs within days after AVB induction and is followed by a more gradual decrease of beta1-AR expression. Downregulation and blunted beta-A activation of IKs 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.