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Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine
10:08

Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine

Published on: February 17, 2018

Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure

Fadi G Akar1, Richard C Wu, George J Juang

  • 1Johns Hopkins Univ., School of Medicine, 720 Rutland Ave., Ross 844, Baltimore, MD 21205, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|February 1, 2005
PubMed

Insights

Heart failure reduces cellular repolarization by downregulating K(+) currents. This study finds reduced cKv4.3 expression causes transient outward K(+) current (I(to)) downregulation in heart failure, suggesting posttranslational modification.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Electrophysiology

Background:

  • Heart failure (HF) is associated with prolonged action potential duration and reduced cellular repolarization reserve.
  • K(+) current downregulation significantly contributes to these electrophysiological changes in HF.
  • The precise molecular mechanisms driving K(+) current alterations in HF remain incompletely understood.

Purpose of the Study:

  • To investigate whether altered expression of K(+) channel alpha- and beta-subunits underlies K(+) current downregulation in tachycardia-induced HF.
  • To quantify K(+) channel subunit expression at mRNA and protein levels across left ventricular layers in a canine HF model.

Main Methods:

  • Utilized a canine model of tachycardia-induced heart failure.
  • Quantified mRNA and protein expression of key K(+) channel subunits (cKv4.3, cKv1.4, cKChIP2, cKir2.1, cERG, cKvLQT1, cMinK) in left ventricular epicardial, midmyocardial, and endocardial layers.
  • Compared expression levels between normal and failing hearts.

Main Results:

  • Marked reductions in canine cKv4.3 mRNA and protein were observed in all left ventricular layers in HF, correlating with transient outward K(+) current (I(to)) downregulation.
  • Paradoxical increases in cKv1.4 protein levels were found, while cKChIP2 expression remained unchanged.
  • Inward rectifier K(+) current (I(K1)) reduction occurred without changes in cKir2.1 expression; canine ether-a-go-go-related gene (cERG) protein expression increased, but cKvLQT1 and cMinK levels were unaffected.

Conclusions:

  • Downregulation of I(to) in heart failure is primarily associated with decreased cKv4.3 expression, not cKv1.4 or cKChIP2.
  • Alterations in other K(+) currents (I(K), I(K1)) in nonischemic dilated cardiomyopathy do not stem from changes in the transcript or protein levels of their primary subunits.
  • These findings suggest that posttranslational modifications likely play a significant role in HF-induced alterations of cardiac K(+) currents.

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