Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on I-Ks downregulation and blunted beta-adrenergic activation

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

45 Citations (Web of Science)

Abstract

Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including beta-adrenergic (beta-A)-sensitive I-Ks. 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 I-Ks 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. beta 1-AR mRNA and protein decreased more gradually to 53 +/- 8% at 7 days. In chronic-AVB LV myocytes, I-Ks-tail density was reduced: 1.4 +/- 0.3 pA/pF versus 2.6 +/- 0.4 pA/pF in controls. beta-A enhancement of I-Ks 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 QT(c) at SR (by -8 +/- 3% from 295 ms), left it unaltered at 3 days AVB (+1 +/- 3% from 325 ms) and prolonged QT(c) 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 beta 1-AR expression. Downregulation and blunted beta-A activation of I-Ks 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.
Original languageEnglish
Pages (from-to)90-100
JournalCardiovascular Research
Volume72
Issue number1
DOIs
Publication statusPublished - 1 Oct 2006

Keywords

  • ion channels
  • remodeling
  • autonomic nervous system
  • membrane potential
  • ventricular function

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