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


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.
Stengl
Milan
M
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University and Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, The Netherlands.
Ramakers
Christian
C
Donker
Dirk W
DW
Nabar
Ashish
A
Rybin
Andrew V
AV
Spätjens
Roel L H M G
RL
van der Nagel
Theo
T
Wodzig
Will K W H
WK
Sipido
Karin R
KR
Antoons
Gudrun
G
Moorman
Antoon F M
AF
Vos
Marc A
MA
Volders
Paul G A
PG
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002839:Chromans / Q000494:pharmacology; D004285:Dogs; D015536:Down-Regulation; D004562:Electrocardiography; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D006327:Heart Block; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D002839:Chromans; C420023:HMR 1556; D051657:KCNQ1 Potassium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D013449:Sulfonamides; D007545:Isoproterenol; D004837:Epinephrine