Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation

Andrea A. Domenighetti, Christophe Boixel, Daniel Cefai, Hugues Abriel, Thierry Pedrazzini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. It predisposes patients to heart failure, QT interval prolongation and ventricular arrhythmias. Angiotensin II (Ang II) exerts direct actions on cardiac tissue inducing cardiomyocyte hypertrophy and electro-mechanical dysfunction. However, a direct association between Ang II and cardiomyocyte electrical remodeling has yet to be demonstrated. Transgenic TG1306/1R (TG) mice with cardiac-specific Ang II overproduction demonstrate blood pressure-independent cardiac hypertrophy and exhibit significant increase in sudden death associated with mechanical dysfunction. The present study makes use of TG mice to evaluate the direct effects of high levels of intracardiac Ang II on cardiac electrophysiology. Surface-limb ECG measurements were recorded on 50- to 60-week-old TG and wild-type (WT) mice. QT interval was significantly prolonged (+ 20%) in TG mice relative to WT. TG mice also showed an increased incidence of ventricular arrhythmias. QT prolongation was associated with prolongation of cardiomyocyte action potential at 90% repolarization (APD90). The change in APD90 correlated with a reduction in IK1 potassium current density in TG vs. WT cardiomyocytes (at - 70 mV: 0.3 ± 0.1 pA/pF vs. 0.8 ± 0.2 pA/pF, P < 0.05). In TG mice, reduction in IK1 was associated with a significant reduction (- 50%) of the mRNA encoding Kir2.1 and Kir2.2 subunits of IK1-related KCNJ2 and KCNJ12 potassium channels. These data suggest that cardiac Ang II overproduction leads to the emergence of a long QT syndrome resulting from an IK1-dependent prolongation of the action potential duration through modulation of channel subunit expression.

Original languageEnglish (US)
Pages (from-to)63-70
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Action potential
  • Angiotensin II
  • Arrhythmia
  • Cardiac hypertrophy
  • Electrocardiography
  • Heart failure
  • IK1
  • Long QT syndrome
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation'. Together they form a unique fingerprint.

Cite this