One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-alpha release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.

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.

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review manuscript discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of post-infarction remodeling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited remove dead cells and matrix debris by phagocytosis, while setting the stage for scar formation. Timely repression of the inflammatory response is critical for effective healing and followed by activation of infarct myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor-β family are critically involved in suppression of inflammation and activation of a pro-fibrotic program. Translation of these concepts in the clinic requires understanding of the pathophysiologic complexity and heterogeneity of post-infarction remodeling in human patients with myocardial infarction. Individuals with overactive and prolonged post-infarction inflammation might exhibit dilation and systolic dysfunction and benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with exaggerated fibrogenic reactions can develop diastolic heart failure and might require inhibition of the smad3 cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.