Mechanisms involved in postinfarction remodeling

Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, include dilation, hypertrophy, and the formation of a discrete collagen scar.

Myocyte hypertrophy is initiated by neurohumoral activation, myocardial stretch, activation of the local tissue renin-angiotensin system, and paracrine/autocrine factors. Postinfarction hypotension stimulates the renin-angiotensin-aldosterone axis, catecholamine production, spillover from sympathetic nerve terminals, and natriuretic peptide secretion. Serine proteases activate the local renin-angiotensin system in the noninfarcted myocardium, causing increased local angiotensin-converting enzyme (ACE) activity, resulting in the local production of angiotensin II, the probable stimulus of hypertrophy in noninfarcted myocardium. Moreover, there appears a tight bidirectional relationship between wall stress and myocyte hypertrophy. Mechanical stretch results in the secretion of angiotensin II from cytoplasmic granules and this stretch-induced hypertrophic response is mediated by angiotensin II type 1 (ATt) receptors.

Interstitial breakdown begins within 3 hours of infarction and is induced by serine proteases such as plas-min and the release of matrix metalloproteinase 8 (MMP8) from neutrophils. The initial digestion of collagen intercellular struts is responsible for the slippage of the necrotic myofilaments that causes infarct expansion.

Tissue repair is initiated by the formation of a fibrin-fibronectin matrix, which precedes collagen synthesis, to which myofibroblasts become adherent. A complex costimulatory relationship exists between aldosterone, atrial natriuretic peptide (ANP), endothelin, bradykinin, and transforming growth factor (3j (TGFPj) in the regulation of collagen synthesis. Aldosterone is synthesized by myofibroblasts and stimulates the transcription of collagen types I and III mRNA. Deposition of collagen types I and III occurs predominantly in the infarct zone; however, it also occurs in noninfarcted myocardium when intercellular signaling is potentiated by extensive myocyte necrosis.

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