Copyright © 2006, European Society of Cardiology
Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted β-adrenergic activation
aDepartment of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University and Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, The Netherlands
bDepartment of Anatomy and Embryology, Experimental and Molecular Cardiology Group, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands
cCenter for Molecular Therapeutics, Columbia University, PH 7W-321, 630 West 168 Street, New York, NY 10032, USA
dDepartment of CardioThoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht University and Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, The Netherlands
eDepartment of Clinical Chemistry, Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, The Netherlands
fLaboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N, 7th Floor, Herestraat 49, B-3000, Leuven, Belgium
gDepartment of Medical Physiology, HLCU, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, The Netherlands
* Corresponding author. Tel.: +31 43 3877350; fax: +31 43 3875104. Email address: p.volders{at}cardio.unimaas.nl
Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including β-adrenergic (β-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 β-adrenergic receptor (β-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. β1-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. β-A enhancement of IKs was reduced. Isoproterenol shortened action-potential duration in control cells, while causing heterogeneous repolarization responses in chronic AVB. β-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 β1-AR expression. Downregulation and blunted β-A activation of IKs contribute to the loss of β-A-induced shortening of ventricular repolarization, favoring proarrhythmia. Provocation testing with isoproterenol identifies repolarization instability based on acquired channelopathy.
KEYWORDS Ion channels; Remodeling; Autonomic nervous system; Membrane potential; Ventricular function
Time for primary review 12 days
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