TY - JOUR
T1 - Temporal patterns of electrical remodeling in canine ventricular hypertrophy
T2 - Focus on IKs downregulation and blunted β-adrenergic activation
AU - Stengl, Milan
AU - Ramakers, Christian
AU - Donker, Dirk W.
AU - Nabar, Ashish
AU - Rybin, Andrew V.
AU - Spätjens, Roel L.H.M.G.
AU - van der Nagel, Theo
AU - Wodzig, Will K.W.H.
AU - Sipido, Karin R.
AU - Antoons, Gudrun
AU - Moorman, Antoon F.M.
AU - Vos, Marc A.
AU - Volders, Paul G.A.
N1 - Funding Information:
This study was supported by The Netherlands Organization for Health and Development, The Hague (ZonMw 906-02-068 to P.G.A.V.), The Netherlands Heart Foundation, The Hague (NHS 98.042 to C.R.), the ‘Stichting Hartsvrienden Rescar’, Maastricht, The Netherlands (to P.G.A.V.), and the United States National Heart, Lung, and Blood Institute (USPHS-NHLBI grant HL-67101 to A.V.R.). Monique M.J. de Jong, Departments of Cardiology and CardioThoracic Surgery, Maastricht, and Jet D.M. Beekman, Department of Medical Physiology, University Medical Center Utrecht, The Netherlands provided excellent technical assistance. Michel E.F.H. Pereboom, Department of Clinical Chemistry, Academic Hospital Maastricht, performed the catecholamine analyses. The primers for canine KCNQ1 and KCNE1 genes were kindly provided by Robert Dumaine, PhD, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, University of Sherbrooke, QC, Canada. The authors are grateful to Jos G. Maessen, MD, PhD, Department of CardioThoracic Surgery, Cardiovascular Research Institute Maastricht and Academic Hospital Maastricht for his role in establishing the serial-biopsy technique.
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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.
AB - 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.
KW - Autonomic nervous system
KW - Ion channels
KW - Membrane potential
KW - Remodeling
KW - Ventricular function
UR - https://www.scopus.com/pages/publications/33748918547
U2 - 10.1016/j.cardiores.2006.07.015
DO - 10.1016/j.cardiores.2006.07.015
M3 - Article
C2 - 16934787
AN - SCOPUS:33748918547
SN - 0008-6363
VL - 72
SP - 90
EP - 100
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -