Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes.
OBJECTIVE
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-beta1 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.
Tsuda
Takeshi
T
Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA. takeshi.tsuda@jefferson.edu
Gao
Erhe
E
Evangelisti
Lucia
L
Markova
Dessislava
D
Ma
Xinliang
X
Chu
Mon-Li
ML
D000818:Animals; D003094:Collagen / Q000032:analysis; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005355:Fibrosis; D006339:Heart Rate; D006439:Hemodynamics; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000032:analysis; D020257:Ventricular Remodeling
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen