title: Alterations in myofilament function contribute to left ventricular dysfunction in pigs early after myocardial infarction.
abstract: Myocardial infarction (MI) initiates cardiac remodeling, depresses pump function, and predisposes to heart failure. This study was designed to identify early alterations in Ca2+ handling and myofilament proteins, which may contribute to contractile dysfunction and reduced beta-adrenergic responsiveness in postinfarct remodeled myocardium. Protein composition and contractile function of skinned cardiomyocytes were studied in remote, noninfarcted left ventricular (LV) subendocardium from pigs 3 weeks after MI caused by permanent left circumflex artery (LCx) ligation and in sham-operated pigs. LCx ligation induced a 19% increase in LV weight, a 69% increase in LV end-diastolic area, and a decrease in ejection fraction from 54+/-5% to 35+/-4% (all P<0.05), whereas cardiac responsiveness to exercise-induced increases in circulating noradrenaline levels was blunted. Endogenous protein kinase A (PKA) was significantly reduced in remote myocardium of MI animals, and a negative correlation (R=0.62; P<0.05) was found between cAMP levels and LV weight-to-body weight ratio. Furthermore, SERCA2a expression was 23% lower after MI compared with sham. Maximal isometric force generated by isolated skinned myocytes was significantly lower after MI than in sham (15.4+/-1.5 versus 19.2+/-0.9 kN/m2; P<0.05), which might be attributable to a small degree of troponin I (TnI) degradation observed in remodeled postinfarct myocardium. An increase in Ca2+ sensitivity of force (pCa50) was observed after MI compared with sham (DeltapCa50=0.17), which was abolished by incubating myocytes with exogenous PKA, indicating that the increased Ca2+ sensitivity resulted from reduced TnI phosphorylation. In conclusion, remodeling of noninfarcted pig myocardium is associated with decreased SERCA2a and myofilament function, which may contribute to depressed LV function. The full text of this article is available online at http://circres.ahajournals.org.
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. j.vandervelden@vumc.nl
authors.forename: J
authors.initials: J
authors.lastname: van der Velden
authors.forename: D
authors.initials: D
authors.lastname: Merkus
authors.forename: B R
authors.initials: BR
authors.lastname: Klarenbeek
authors.forename: A T
authors.initials: AT
authors.lastname: James
authors.forename: N M
authors.initials: NM
authors.lastname: Boontje
authors.forename: D H W
authors.initials: DH
authors.lastname: Dekkers
authors.forename: G J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: J M J
authors.initials: JM
authors.lastname: Lamers
authors.forename: D J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D017079:Exercise Tolerance; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology; D007537:Isometric Contraction; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D009638:Norepinephrine / Q000097:blood; D009929:Organ Size; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013318:Stroke Volume; D034421:Sus scrofa; D019210:Troponin I / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D020257:Ventricular Remodeling; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019210:Troponin I; D000099211:Phospholamban