Morphological basis for impact of angiotensin II type 1A receptor Blockade upon myocardial infarct tissue dynamics

Abstract

Blockade of angiotensin II type 1A receptor (AT1) attenuates left ventricular remodeling and heart failure after myocardial infarction (MI). However, the morphological bases for such beneficial effects are not fully elucidated except for prevention of fibrosis in the noninfarcted area. AT1 knockout (KO) mice, compared with wild-type (WT) mice, showed significantly attenuated left ventricular remodeling (dilatation) and dysfunction comprised of excessive fibrosis in noninfarcted area at 4 weeks after large MI, consistent with the earlier studies. Morphometry revealed that the size of infarct scar was comparable between each group, but that the infarct wall thickness was greater while its coronal expansion was less marked in AT1KO mice. The cell population in infarct scar was greater in AT1KO mice, where extravascular a-smooth muscle actin (SMA)-positive cells were abundant. In 1 week-old infarct consisting of granulation tissue, apoptosis of a-SMA-positive cells was less frequent in AT1KO mice than in WT mice while proliferating activity of them was similar between the groups. Thus, in AT1KO mice, the survived myofibroblasts might have contributed to infarct contraction and infarct wall thickening, which consequently altered infarcted tissue geometry to reduce wall stress, and then prevented left ventricular dilatation and dysfunction. Unfavorable infarct tissue dynamics may be an important mechanistic basis for deleterious effects of AT1 signals upon the postinfarction disease process.