title: Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure.
abstract: End-stage heart failure (HF) is characterized by changes in conduction velocity (CV) that predispose to arrhythmias. Here, we investigate the time course of conduction changes with respect to alterations in connexin 43 (Cx43) properties and mechanical function during the development of HF. We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21 days of rapid pacing to produce variable degrees of remodeling. CV is compared with an index of mechanical function [left ventricular end-diastolic pressure (LVEDP)] and with dynamic changes in the expression, distribution, and phosphorylation of Cx43. In contrast to repolarization, CV was preserved during early stages of remodeling (3 and 7 days) and significantly reduced at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained downregulation of pan-Cx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated Cx43 isoform to over twofold baseline levels in end-stage HF, and a late abrupt increase in pan-Cx43, but not dephosphorylated Cx43, lateralization. These data demonstrate that 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of pan-Cx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event that coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.
authors: Division of Cardiology and Institute for Computational Medicine, Johns Hopkins University, 720 Rutland Ave., Ross 844, Baltimore, MD 21205, USA. akar@jhu.edu
authors: Fadi G
authors: FG
authors: Akar
authors: Robert D
authors: RD
authors: Nass
authors: Samuel
authors: S
authors: Hahn
authors: Eugenio
authors: E
authors: Cingolani
authors: Manish
authors: M
authors: Shah
authors: Geoffrey G
authors: GG
authors: Hesketh
authors: Deborah
authors: D
authors: DiSilvestre
authors: Richard S
authors: RS
authors: Tunin
authors: David A
authors: DA
authors: Kass
authors: Gordon F
authors: GF
authors: Tomaselli
mesh_terms: D000200:Action Potentials; D000818:Animals; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D017629:Gap Junctions / Q000378:metabolism*; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D018031:Connexin 43; D020033:Protein Isoforms