Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure

Fadi G. Akar, Robert D. Nass, Samuel Hahn, Eugenio Cingolani, Manish Shah, Geoffrey G. Hesketh, Deborah DiSilvestre, Richard S. Tunin, David A. Kass, Gordon F. Tomaselli

Research output: Contribution to journalArticle

127 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number2
DOIs
StatePublished - Aug 1 2007
Externally publishedYes

Fingerprint

Connexin 43
Gap Junctions
Heart Failure
Protein Isoforms
Blood Pressure
Phosphorylation
Left Ventricular Function
Cardiac Arrhythmias
Down-Regulation
Dogs

Keywords

  • Arrhythmias
  • Connexin
  • Electrical remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. / Akar, Fadi G.; Nass, Robert D.; Hahn, Samuel; Cingolani, Eugenio; Shah, Manish; Hesketh, Geoffrey G.; DiSilvestre, Deborah; Tunin, Richard S.; Kass, David A.; Tomaselli, Gordon F.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 2, 01.08.2007.

Research output: Contribution to journalArticle

Akar, Fadi G. ; Nass, Robert D. ; Hahn, Samuel ; Cingolani, Eugenio ; Shah, Manish ; Hesketh, Geoffrey G. ; DiSilvestre, Deborah ; Tunin, Richard S. ; Kass, David A. ; Tomaselli, Gordon F. / Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 293, No. 2.
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AU - Hesketh, Geoffrey G.

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AB - 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.

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