title: Regional alterations in protein expression in the dyssynchronous failing heart.
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.
  
  
  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 Ca2+-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.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Spragg
authors.forename: Christophe
authors.initials: C
authors.lastname: Leclercq
authors.forename: Morteza
authors.initials: M
authors.lastname: Loghmani
authors.forename: Owen P
authors.initials: OP
authors.lastname: Faris
authors.forename: Richard S
authors.initials: RS
authors.lastname: Tunin
authors.forename: Deborah
authors.initials: D
authors.lastname: DiSilvestre
authors.forename: Elliot R
authors.initials: ER
authors.lastname: McVeigh
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D006329:Heart Conduction System / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction; D011506:Proteins / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000503:physiopathology*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D018031:Connexin 43; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban