Inhibition of Granulation Tissue Cell Apoptosis During the Subacute Stage of Myocardial Infarction Improves Cardiac Remodeling and Dysfunction at the Chronic Stage

Abstract

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 mol/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 ␣-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. 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.

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

“…The difference in the proportions of cardiomyocyte apoptosis have been reported in the previous studies, 10,[29][30][31] and the difference between the studies might have been due to differences in the tissue samples taken or the method used for analysis of myocardial tissue. 7,32 However, a previous literature by van Empel et al reviewed a prevalence of cardiomyocyte apoptosis ranging from 0.12 to 0.70% in myocardial biopsy specimens obtained from patients with NYHA classes III-IV heart failure, 30,[33][34][35][36][37][38][39][40] which was similar to the figure obtained in the present study. Therefore, the variation in the prevalence of cardiomyocyte apoptosis between the reported studies may not have been due to differences in the myocardial tissue samples used for analysis.…”

“…In contrast, another study has recently shown that inhibition of apoptosis in granulation tissue in the infarcted region formed thicker walls, which contributed to ventricular remodeling. 7 Although the time course and type of apoptosis varies in patients with heart failure, the lack of stage-specific expression of granulation tissue apoptosis in the present study indicates that antiapoptotic therapy in patients with heart failure might have profound effects on inhibiting apoptosis in cardiomyocytes, leading to a decrease in ventricular remodeling and heart failure. 44 In the present study, the temporal and spatial distribution of TNF-a-positive cardiomyocyte differed from that of ss-DNA-positive cardiomyocyte; the mean SI of cardiomyocytes peaked at stage II and then declined rapidly, whereas the mean TI peaked at stage III and remained constant well into the later stages, as similarly reported previously.…”

“…7 In contrast, another recent study demonstrated that inhibtion of cardiomyocyte apoptosis by a caspase-3 inhibitor (DEVD-CHO) prevented ventricular dilatation. 41 The difference in the level of cardiomyocyte apoptosis between the two studies might have been due to the difference in the methods used for inhibition of apoptosis.…”

“…It is therefore speculated that apoptotic mechanisms may be differently regulated in these cell types that may have higher sensitivity to apoptotic stimuli compared with the other cells. 7 Therefore, small round ss-DNA-positive cells whose origin could not be identified from cardiomyocytes, interstitial cells, or inflammatory cells, were not counted in the statistical analysis. The number of IL-10 or CD68-positive cells was similarly counted in 10 randomly selected fields at  40 magnification, and used to calculate the mean number of positively stained cells per microscopic field.…”

“…[1][2][3][4][5][6] Recent studies have suggested that apoptosis in granulation tissue cells after MI plays an important role in cardiac remodeling during the chronic stages of MI. 7,8 However, there has been little morphological evidence of apoptosis in both cardiomyocytes and granulation tissue cells occurring at different stages of MI in humans. Furthermore, the rate of cardiomyocyte apoptosis in human MI has been reported to vary (0.12-12%).…”