Regional alterations in protein expression in the dyssynchronous failing heart

David D. Spragg, Christophe Leclercq, Morteza Loghmani, Owen P. Faris, Richard S. Tunin, Deborah DiSilvestre, Elliot R. McVeigh, Gordon F. Tomaselli, David A. Kass

Research output: Contribution to journalArticlepeer-review

224 Scopus citations

Abstract

Background - Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. Methods and Results - Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca 2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial-paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. Conclusions - LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.

Original languageEnglish (US)
Pages (from-to)929-932
Number of pages4
JournalCirculation
Volume108
Issue number8
DOIs
StatePublished - Aug 26 2003
Externally publishedYes

Keywords

  • Heart failure
  • Molecular biology
  • Pacing
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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