Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts

David D. Spragg, Fadi G. Akar, Robert H. Helm, Richard S. Tunin, Gordon F. Tomaselli, David A. Kass

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Background: Cardiac dyssynchrony due to intraventricular conduction delay produces heterogeneous regional wall stress and worsens arrhythmia susceptibility in failing hearts. We examined whether chronic dyssynchrony per se induces regionally heterogeneous electrophysiological remodeling. Methods and results: Adult dogs (n = 9) underwent left bundle branch radiofrequency ablation (QRS duration increased from 50 ± 7 to 104 ± 7 ms); 6 untreated dogs served as controls. A subset of ablated (n = 3) and control (n = 4) dogs underwent tagged MR imaging to confirm ablation-induced left ventricular (LV) dyssynchrony. Four weeks later, hearts were excised and early (anterior)- and late (lateral)-activated myocardial segments were isolated. Conduction velocity (CV), action potential duration (APD), and refractory period (RP) of paced, arterially perfused myocardial wedges were studied by extracellular and optical mapping, and arrhythmia susceptibility was assessed by programmed stimulation. Regional stress-response kinase, calcium cycling, and gap junction protein expression were assayed by Western blotting, and the subcellular distribution of connexin43 was analyzed by immunofluorescence microscopy. CV, APD, and RP were significantly reduced in the late-activated, lateral wall of dyssynchronous hearts compared to the anterior wall. Normal differences in CV (endocardial > epicardial) were reversed in the dyssynchronous lateral LV. While the total expression of connexin43 was unaltered in dyssynchronous models, its subcellular location was redistributed in late-activated myocardium from intercalated discs to lateral myocyte membranes. Arrhythmias were rare in tissue from normal and dyssynchronous models. Total expression of calcium-cycling proteins (sarcoplasmic reticulum Ca 2 +-ATPase and phospholamban) and the stress-response kinase phospho-ERK did not vary regionally in either model. Conclusions: Dyssynchrony even in the absence of LV dysfunction induces regionally specific changes in conduction and repolarization. These changes support a novel mechanism linking mechanical dyssynchrony to persistent electrophysiological remodeling and heterogeneity.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalCardiovascular Research
Volume67
Issue number1
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

Fingerprint

Cardiac Arrhythmias
Myocardium
Connexin 43
Dogs
Action Potentials
Phosphotransferases
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Calcium
Connexins
Left Ventricular Dysfunction
Fluorescence Microscopy
Muscle Cells
Western Blotting
Membranes
Proteins
phospholamban

Keywords

  • Action potential duration
  • Arrhythmia
  • Conduction velocity
  • Ventricular dyssynchrony

ASJC Scopus subject areas

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

Cite this

Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. / Spragg, David D.; Akar, Fadi G.; Helm, Robert H.; Tunin, Richard S.; Tomaselli, Gordon F.; Kass, David A.

In: Cardiovascular Research, Vol. 67, No. 1, 01.07.2005, p. 77-86.

Research output: Contribution to journalArticle

Spragg, David D. ; Akar, Fadi G. ; Helm, Robert H. ; Tunin, Richard S. ; Tomaselli, Gordon F. ; Kass, David A. / Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. In: Cardiovascular Research. 2005 ; Vol. 67, No. 1. pp. 77-86.
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AU - Tunin, Richard S.

AU - Tomaselli, Gordon F.

AU - Kass, David A.

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AB - Background: Cardiac dyssynchrony due to intraventricular conduction delay produces heterogeneous regional wall stress and worsens arrhythmia susceptibility in failing hearts. We examined whether chronic dyssynchrony per se induces regionally heterogeneous electrophysiological remodeling. Methods and results: Adult dogs (n = 9) underwent left bundle branch radiofrequency ablation (QRS duration increased from 50 ± 7 to 104 ± 7 ms); 6 untreated dogs served as controls. A subset of ablated (n = 3) and control (n = 4) dogs underwent tagged MR imaging to confirm ablation-induced left ventricular (LV) dyssynchrony. Four weeks later, hearts were excised and early (anterior)- and late (lateral)-activated myocardial segments were isolated. Conduction velocity (CV), action potential duration (APD), and refractory period (RP) of paced, arterially perfused myocardial wedges were studied by extracellular and optical mapping, and arrhythmia susceptibility was assessed by programmed stimulation. Regional stress-response kinase, calcium cycling, and gap junction protein expression were assayed by Western blotting, and the subcellular distribution of connexin43 was analyzed by immunofluorescence microscopy. CV, APD, and RP were significantly reduced in the late-activated, lateral wall of dyssynchronous hearts compared to the anterior wall. Normal differences in CV (endocardial > epicardial) were reversed in the dyssynchronous lateral LV. While the total expression of connexin43 was unaltered in dyssynchronous models, its subcellular location was redistributed in late-activated myocardium from intercalated discs to lateral myocyte membranes. Arrhythmias were rare in tissue from normal and dyssynchronous models. Total expression of calcium-cycling proteins (sarcoplasmic reticulum Ca 2 +-ATPase and phospholamban) and the stress-response kinase phospho-ERK did not vary regionally in either model. Conclusions: Dyssynchrony even in the absence of LV dysfunction induces regionally specific changes in conduction and repolarization. These changes support a novel mechanism linking mechanical dyssynchrony to persistent electrophysiological remodeling and heterogeneity.

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