Extracellular Matrix in Ischemic Heart Disease, Part 4/4: JACC Focus Seminar

Abstract

Myocardial ischemia and infarction, both in the acute and chronic phases, are associated with cardiomyocyte loss and dramatic changes in the cardiac extracellular matrix (ECM). It has long been appreciated that these changes in the cardiac ECM result in altered mechanical properties of ischemic or infarcted myocardial segments. However, a growing body of evidence now clearly demonstrates that these alterations of the ECM not only affect the structural properties of the ischemic and post-infarct heart, but they also play a crucial and sometimes direct role in mediating a range of biological pathways, including the orchestration of inflammatory and reparative processes, as well as the pathogenesis of adverse remodeling. This final part of a 4-part JACC Focus Seminar reviews the evidence on the role of the ECM in relation to the ischemic and infarcted heart, as well as its contribution to cardiac dysfunction and adverse clinical outcomes.

Keywords: biomarker; collagen; fibroblast; heart failure; ischemic heart disease.

Figure 1.. Generation of matrix fragments and formation of a plasma-derived provisional matrix during the inflammatory phase of cardiac repair.

A. Immunohistochemistry for fibrinogen/fibrin (black) shows deposition of plasma-derived proteins (including fibrin and fibronectin) that enrich the cardiac ECM during the early stages of infarct healing (arrows). Counterstained with eosin. Scalebar=120μm. Data from our own work in a canine model of reperfused MI (13). B. Schematic cartoon illustrating the dramatic changes in the interstitial ECM network during the inflammatory phase of infarct healing. Rapid activation and induction of proteases, such as MMPs and cathepsins, in the infarcted myocardium generates ECM fragments (matrikines and matricryptins) that modulate the phenotype of fibroblasts, macrophages (Ma) and endothelial cells (EC). MMPs have a wide range of substrates and process cytokines and chemokines, regulating their pro-inflammatory actions. Recruitment and migration of leukocytes (L), fibroblasts and vascular cells in the infarcted heart requires interactions between cell surface integrins (ITG) and provisional matrix proteins (such as fibrin and fibronectin). Thus, the provisional matrix plays an important role in regulation of inflammatory, fibrogenic and angiogenic responses.

Figure 2.. The time course of collagen deposition in the healing infarct.

Staining of canine infarct border zones with picrosirius red to identify collagen fibers at 3, 14 and 28 days after reperfused MI (1h of coronary occlusion followed by reperfusion). Collagen is identified by the red staining, with cardiomyocytes in light brown. Note the early disruption of the collagen network, accompanied by limited de novo synthesis at 3 days (A). After 14 days, extensive collagen deposition is noted in the healing infarct (B). The mature scar (28 days - C) exhibits a dense matrix network, typically associated with collagen cross-linking. Data from our own work in a canine model of reperfused MI (13). Scalebar=100μm.

Central Illustration.. Matricellular proteins regulate inflammatory, reparative, angiogenic and fibrogenic cellular responses during the proliferative phase of infarct healing.

A. Immunohistochemical staining using a peroxidase-based strategy (black) shows expression of the matricellular proteins osteopontin (OPN–top panel) and thrombospondin (TSP)-1 (lower panel) in the infarcted myocardium. Counterstained with eosin. Scalebar=100μm. Data are from our own work in a canine model of reperfused MI (13,152). Each matricellular protein shows a unique pattern of localization, likely reflecting distinct cellular sources and mechanisms of regulation. OPN is predominantly expressed by macrophages (top-arrows), whereas TSP-1 is deposited in the infarct border zone (bottom-arrows). B. Schematic cartoon illustrating the complex matrix environment in the proliferative phase of infarct healing. Cell-derived fibronectin, hyaluronan, and a wide range of matricellular proteins (OPN, TSP-1, TNC/tenascin-C, periostin, SPARC, osteoglycin and members of the CCN family) and proteoglycans enrich the infarct ECM and regulate assembly of the collagen-based structural matrix, while modulating a variety of cellular responses in cardiomyocytes, fibroblasts, macrophages and vascular cells.