Molecular remodeling of Cx43, but not structural remodeling, promotes arrhythmias in an arrhythmogenic canine model of nonischemic heart failure

J Mol Cell Cardiol. 2021 Sep:158:72-81. doi: 10.1016/j.yjmcc.2021.05.012. Epub 2021 May 31.

Abstract

Background: Both gap junctional remodeling and interstitial fibrosis have been linked to impaired electrical conduction velocity (CV) and fatal ventricular arrhythmias in nonischemic heart failure (HF). However, the arrhythmogenic role of the ventricular gap junctional Cx43 in nonischemic HF remains in debate. Here, we assessed this in a newly developed arrhythmogenic canine model of nonischemic HF.

Methods and results: Nonischemic HF was induced in canines by combined aortic valve insufficiency and aortic constriction. Left ventricular (LV) myocardium from HF dogs showed similar pathological changes to that of humans. HF dogs had reduced LV function, widened QRS complexes, and spontaneous nonsustained ventricular tachycardia. CV was measured in intact LV epicardium with high-density grid mapping. Total (Cx43-T) and nonphosphorylated Cx43 (Cx43-NP) and histological interstitial fibrosis were assessed from these mapped LV tissues. Longitudinal CV, which was slowed in HF (49 ± 1 vs. 65 ± 2 cm/s in Ctl), was positively correlated with reduced total junctional Cx43 and negatively correlated with markedly increased junctional Cx43-NP (2-fold) in HF. Cx43 dephosphorylation in HF was associated with enhanced colocalization of PP2A at the level of Cx43. Unchanged action potential upstroke and transverse CV were associated with unaltered Cx43 lateralization and interstitial fibrosis in the nonischemic HF canine LV.

Conclusion: Our unique arrhythmogenic canine model of HF resembles human nonischemic HF (prior to the end stage). Cx43 remodeling occurs prior to the structural remodeling (with lack of fibrosis) in HF and it is crucial in slowed CV and ventricular arrhythmia development. Our findings suggest that altered Cx43 alone is arrhythmogenic and modulation of Cx43 has the anti-arrhythmic therapeutic potential for HF patients.

Keywords: Conduction velocity; Dephosphorylation; Fibrosis; Heart failure; connexin43 remodeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials
  • Animals
  • Connexin 43 / metabolism*
  • Disease Models, Animal
  • Dogs
  • Electric Conductivity
  • Female
  • Fibrosis
  • Gap Junctions / metabolism
  • Heart Conduction System / physiopathology
  • Heart Failure / complications*
  • Heart Failure / metabolism*
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Male
  • Phosphorylation
  • Tachycardia, Ventricular / complications*
  • Tachycardia, Ventricular / metabolism*
  • Ventricular Dysfunction, Left / complications*
  • Ventricular Dysfunction, Left / metabolism*
  • Ventricular Fibrillation / complications*
  • Ventricular Fibrillation / metabolism*
  • Ventricular Function, Left

Substances

  • Connexin 43