tranilast and Embolism

1. Coronary microembolisation (CME) is associated with progressive myocardial dysfunction, and mast cells (MC) might have an important role in myocardial apoptosis after CME. We investigated whether the MC stabilizer tranilast suppresses the accumulation and degranulation of MC while reducing cardiomyocyte apoptosis after CME. 2. We induced CME in miniswine by selective infusion of 15 x 10(4) microspheres (diameter 45 microm) into the left anterior descending artery. Some CME-induced miniswine were treated with the MC stabilizer tranilast (50 mg/kg, p.o., b.d.) beginning 2 weeks before CME, and thereafter throughout the experimental period; others received tranilast without CME; and sham-operated animals without CME served as controls. After 30 days, we assessed cardiomyocyte apoptosis by TUNEL assay and by the total number of MC and the number of degranulating MC using histology and transmission electron microscopy. The wall motion score index and left ventricular ejection fraction were studied by dobutamine stress echocardiography. 3. Coronary microembolisation was associated with increases in the total number of MC, the number of degranulating MC, and myocyte apoptosis. The number of total MC and degranulating MC and apoptotic cardiomyocytes over the anterior embolized myocardium after CME were significantly higher than those over the posterior control myocardium and anterior segments per animal without CME (P < 0.01). Tranilast administration to CME miniswine suppressed cardiomyocyte apoptosis while maintaining regional and global function, which was associated with reductions in the accumulation and degranulation of MC. 4. These findings suggest that tranilast suppresses the accumulation and degranulation of MC while reducing cardiomyocyte apoptosis after CME.

Topics: Animals; Apoptosis; Cell Degranulation; Coronary Vessels; Disease Models, Animal; Echocardiography, Stress; Embolism; Female; In Situ Nick-End Labeling; Male; Mast Cells; Microscopy, Electron, Transmission; Myocytes, Cardiac; ortho-Aminobenzoates; Swine; Swine, Miniature

Coronary microembolization (CME) is associated with progressive myocardial dysfunction despite restoration of coronary flow reserve (CFR). The potential pathophysiological role of mast cells (MCs) remains unclear. Therefore, we induced CME in 18 miniswines and determined whether MC accumulation occurs and their effects on local cytokine secretion [interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-alpha)]; cardiomyocyte apoptosis; and collagen formation at day 1 (D1), day 7 (D7), and day 30 (D30) after CME. Four sham-operated animals without CME (controls) and six animals treated with a MC stabilization agent (tranilast) for 30 days after CME were also studied. CFR decreased at D1 but returned to baseline level at D7 and D30. Coronary sinus levels of IL-6, IL-8, and TNF-alpha increased significantly at D1 and D7 (p<0.01 vs baseline). Levels of IL-6 and IL-8 at D30 returned to baseline level, but not those of TNF-alpha. The numbers of total and degranulating MCs, % apoptotic cardiomyocytes, and collagen volume fraction (CVF) over CME myocardium at D1, D7, and D30 were significantly higher than controls (p<0.01). Treatment with tranilast significantly reduced the serum level of TNF-alpha, numbers of total and degranulating MCs, % apoptotic cardiomyocytes, and CVF at D30 (all p<0.05). There was a significant positive correlation between the numbers of MCs with % apoptotic cardiomyocytes (r = 0.77, p<0.001) and CVF (r = 0.75, p<0.001) over the CME myocardium. Despite restoration of CFR, cardiomyocyte apoptosis persisted after CME and was positively correlated with the number of MCs but was prevented with tranilast treatment. These findings suggest that MCs contribute to cardiomyocyte apoptosis after CME.

Topics: Animals; Apoptosis; Collagen; Coronary Circulation; Coronary Vessels; Embolism; Female; Interleukin-6; Interleukin-8; Male; Mast Cells; Microscopy, Electron, Transmission; Myocardium; Myocytes, Cardiac; ortho-Aminobenzoates; Swine; Swine, Miniature; Tumor Necrosis Factor-alpha