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Title: Temporal patterns of electrical remodeling in canine ventricular hypertrophy: focus on IKs downregulation and blunted beta-adrenergic activation
Authors: Stengl, Milan ×
Ramakers, Christian
Donker, Dirk W
Nabar, Ashish
Rybin, Andrew V
Spätjens, Roel L H M G
van der Nagel, Theo
Wodzig, Will K W H
Sipido, Karin
Antoons, Gudrun
Moorman, Antoon F M
Vos, Marc A
Volders, Paul G A #
Issue Date: Oct-2006
Series Title: Cardiovascular Research vol:72 issue:1 pages:90-100
Abstract: OBJECTIVES: 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. 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. 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). CONCLUSIONS: 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.
URI: 
ISSN: 0008-6363
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Cardiology
Experimental Cardiology
× corresponding author
# (joint) last author

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