Distinct patterns of atrial electrical and structural remodeling in angiotensin II mediated atrial fibrillation

J Mol Cell Cardiol. 2018 Nov;124:12-25. doi: 10.1016/j.yjmcc.2018.09.011. Epub 2018 Sep 28.

Abstract

Atrial fibrillation (AF) is prevalent in hypertension and elevated angiotensin II (Ang II); however, the mechanisms by which Ang II leads to AF are poorly understood. Here, we investigated the basis for this in mice treated with Ang II or saline for 3 weeks. Ang II treatment increased susceptibility to AF compared to saline controls in association with increases in P wave duration and atrial effective refractory period, as well as reductions in right and left atrial conduction velocity. Patch-clamp studies demonstrate that action potential (AP) duration was prolonged in right atrial myocytes from Ang II treated mice in association with a reduction in repolarizing K+ currents. In contrast, APs in left atrial myocytes from Ang II treated mice showed reductions in upstroke velocity and overshoot, as well as greater prolongations in AP duration. Ang II reduced Na+ current (INa) in the left, but not the right atrium. This reduction in INa was reversible following inhibition of protein kinase C (PKC) and PKCα expression was increased selectively in the left atrium in Ang II treated mice. The transient outward K+ current (Ito) showed larger reductions in the left atrium in association with a shift in the voltage dependence of activation. Finally, Ang II caused fibrosis throughout the atria in association with changes in collagen expression and regulators of the extracellular matrix. This study demonstrates that hypertension and elevated Ang II cause distinct patterns of electrical and structural remodeling in the right and left atria that collectively create a substrate for AF.

Keywords: Action potential; Angiotensin II; Atrial fibrillation; Fibrosis; K(+) current; Na(+) current.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials*
  • Angiotensin II / metabolism*
  • Angiotensin II / pharmacology
  • Animals
  • Atrial Fibrillation / diagnosis*
  • Atrial Fibrillation / etiology*
  • Atrial Remodeling*
  • Biomarkers
  • Blood Pressure
  • Echocardiography
  • Electrocardiography
  • Immunohistochemistry
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism

Substances

  • Biomarkers
  • Angiotensin II