The Biological Basis for Cardiac Repair After Myocardial Infarction

Abstract

In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post-infarction heart failure.

The Structure-function remodeling in rabbit hearts of myocardial infarction

“…The Masson trichrome staining (Prabhu and Frangogiannis 2016; Talman and Ruskoaho 2016) showed a huge amount of tissues with fibrosis at border zones of rabbit hearts at postoperative 12 weeks given post‐MI inflammation (Anker and von Haehling 2004). An increase in cardiac fibrosis altered the constitutive relation of myocardium and further increased the ventricle wall shear, which impaired coronary vasculature (e.g., a vascular rarefaction) at border zones and contributed to the vicious cycle of ischemia and HF with time.…”

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…The cellular events involved in repair of the infarcted heart can be divided in three distinct, but overlapping phases: the inflammatory phase, the proliferative phase and the maturation phase (12,13). During the inflammatory phase, release of alarmins by necrotic cardiomyocytes activates innate immune pathways, leading to recruitment of leukocytes in the infarcted myocardium (14). Clearance of the infarct from dead cells and matrix debris by professional phagocytes activates anti-inflammatory cascades leading to suppression of the inflammatory response and transition to the proliferative phase of infarct healing (15).…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In myocardial infarction, sudden death of up to a billion cardiomyocytes overwhelms the extremely limited regenerative capacity of the adult mammalian heart. As a result, the infarcted ventricle heals through activation of a superbly orchestrated cellular response that clears the wound of dead cells and matrix debris, ultimately leading to formation of a collagen-based scar (4). In conditions associated with pressure or volume overload, dynamic alterations in the ECM network may affect cardiomyocyte survival and may regulate the response of interstitial cells to mechanical stress.…”