The inflammatory response in myocardial injury, repair, and remodelling

Abstract

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.

The extracellular matrix in myocardial injury, repair, and remodeling

“…In contrast, early nonselective MMP inhibition with doxycycline attenuated progression to dilative remodeling in patients with STEMI and left ventricular dysfunction (133). The conflicting findings may reflect the pathophysiological heterogeneity of human myocardial infarction; successful implementation of matrix modulation strategies may require development of biomarkers or imaging approaches to identify patients with specific alterations in matrix metabolism (134). Moreover, interpretation of the effects of therapies targeting MMPs are complicated by their wide range of actions beyond matrix metabolism involving processing and modulation of bioactive cytokines and growth factors.…”

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

“…In the clinic, post-infarction remodeling and heart failure is pathophysiologically heterogeneous. For the same amount of cardiomyocyte loss, some patients develop dilative remodeling and systolic dysfunction, while others may have extensive fibrosis, accompanied by diastolic heart failure (122). Differences in TGF-β responses between patients may account for the distinct patterns of post-infarction remodeling in various subpopulations.…”

Monocytes and macrophages in cardiac injury and repair

“…Here, macrophages functionally shift from promoting inflammation to supporting repair and produce growth factors that recruit and activate mesenchymal reparative cells (mainly myofibroblasts and vascular cells) (33). This transitioning from inflammatory to reparative macrophages resembles in vitro polarization from the so-called "M1" to "M2" macrophages.…”