Regional alterations in protein expression in the dyssynchronous failing heart.
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.
Spragg
David D
DD
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Leclercq
Christophe
C
Loghmani
Morteza
M
Faris
Owen P
OP
Tunin
Richard S
RS
DiSilvestre
Deborah
D
McVeigh
Elliot R
ER
Tomaselli
Gordon F
GF
Kass
David A
DA
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
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