© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes
aDepartment of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA
bDepartment of Pediatrics, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA
cNemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, DE 19899, USA
dDepartment of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA
eDepartment of Emergency Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA
fDepartment of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA
takeshi.tsuda{at}jefferson.edu
* Corresponding author. Tel.: +1-215-503-2067; fax: +1-215-503-5788.
Objectives: Myocardial fibrosis is a major component of ventricular remodeling after large myocardial infarction (MI). The present study tests the hypothesis that post-ischemic myocardial fibrosis can occur independent of hemodynamic changes. Methods: A mouse model of distal left coronary artery ligation was established to induce a small infarct (less than 15% of the left ventricle) in order to avoid significant mechanical overload after permanent myocardial ischemia. Left heart catheterization was performed to evaluate the post-infarct hemodynamics. Tissues from both ischemic and non-ischemic myocardium were examined for mRNA and protein expression at 24, 72 h and 7 days after ligation. Results: Heart/body weight ratio after ligation was increased by approximately 10% over sham control although there is no statistically significant difference in hemodynamic parameters between the two groups. Non-ischemic myocardium distant from the infarct site showed molecular evidence of myocardial fibrosis 72 h and 7 days after ligation. There was marked up-regulation of mRNAs for extracellular matrix (ECM) proteins and their cross-linking enzyme, such as collagens type I, III and VI, and lysyl oxidase. Immunohistochemical study confirmed that the expression of these ECM proteins was significantly increased in the non-ischemic myocardium after 7 days. TGF-β1 was up-regulated after 72 h in both ischemic and non-ischemic myocardium. Conclusions: Molecular and histopathological findings demonstrate that abnormal myocardial fibrosis can be induced by a small infarct independent of secondary hemodynamic changes.
KEYWORDS Extracellular matrix; Fibrosis; Infarction; Hemodynamics; Remodelling
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