on June 23, 2003
Published online before print June 23, 2003, doi: 10.1161/01.CIR.0000074225.62168.68
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Submitted on December 31, 2002
From the Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan; and the Department of Food Science (T.F.), Kyoto Women's University, Kyoto, Japan. * To whom correspondence should be addressed. E-mail: gifuim-gif{at}umin.ac.jp.
Background--Granulation tissue cells at the subacute stage of myocardial infarction (MI) are eliminated by apoptosis to finally make a scar at the chronic stage. We hypothesized that postinfarct inhibition of apoptosis might preserve myofibroblasts and endothelial cells in granulation and modulate chronic left ventricular (LV) remodeling and heart failure. Methods and Results--A pancaspase inhibitor, Boc-Asp-fmk (BAF, 10 µmol/kg per day), or vehicle (control) was given to rats with experimental large MI. The treatment was started on the third day after MI and continued until 4-week-old MI. Two weeks later, the apoptosis of granulation tissue cells was significantly reduced and conversely, the cell population was greater in BAF. Twelve weeks later, BAF showed significantly greater survival rates (84% versus 42%) with significantly smaller LV cavity, lower LV end-diastolic pressure and central venous pressure, and higher LV dP/dt, which indicated improvement of LV remodeling and dysfunction. A scar was established in old infarct of control subjects, but in BAF, the infarct wall was thicker because of greater old infarct area, which contained abundant myofibroblasts and vessels. Surprisingly, many of the Conclusions--The postinfarct treatment with BAF improved LV remodeling and dysfunction through inhibition of granulation tissue cell apoptosis. These findings imply a new therapeutic strategy against postinfarct heart failure.
Revised on March 17, 2003
Accepted on March 21, 2003
Inhibition of Granulation Tissue Cell Apoptosis During the Subacute Stage of Myocardial Infarction Improves Cardiac Remodeling and Dysfunction at the Chronic Stage
Kenji Hayakawa MD,
-smooth muscle actin-positive myofibroblast-like cells in BAF, making bundles and running parallel to the survived cardiomyocytes, were ultrastructurally mature smooth muscle cells with contractile phenotype. Cardiomyocyte apoptosis in the infarct area was equally rare in each group.
Key words: apopstosis • heart failure • myocardial infarction • remodeling
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