Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities

Abstract

Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients.

Keywords: Acute myocardial infarction; Acute myocardial ischemia and reperfusion injury; Chemokines; Cytokines; Dendritic cells; Inflammation; Innate immunity; Lymphocytes; Macrophages; Monocytes.

Fig. 1

Overview of the inflammatory response to acute myocardial infarction. This schema depicts the initial pro-inflammatory and the subsequent anti-inflammatory reparative phase following AMI. Dying cardiomyocytes during acute myocardial ischemia induce the pro-inflammatory response through the production of DAMPS, ROS, and complement, which through the release of cytokines (such as IL-1β, IL-18, IL-1α, IL-6, CCL2, CCL5), mediate the accumulation of a variety of cells including neutrophils, monocytes, macrophages, B lymphocytes and CD8⁺ T cells into the infarct zone. The subsequent anti-inflammatory reparative phase, mediates the resolution of the inflammatory response through the production of anti-inflammatory factors (such as IL-10, IL6, TGF-β), and changes in monocytes and macrophages, and the recruitment of Tregs, CD4⁺ T cells and dendritic cells.

Fig. 2

The pro-inflammatory response induced by DAMPs. Following AMI, the release of damage-associated molecular patterns or DAMPs (such as ATP, mtDNA, RNA, and HMBGB1) induce a pro-inflammatory response which mediates cardiomyocyte death through Toll-like receptors (TLRs) and the recruitment of leukocytes into the infarct zone, the release of cytokines, mitochondrial dysfunction (calcium overload and ROS production), and NLRP3-inflammasome formation.

Fig. 3

The anti-inflammatory reparative phase following acute myocardial infarction. Following the pro-inflammatory response of AMI, the anti-inflammatory reparative phase allows the resolution of inflammation. (1) Bone marrow and circulating monocytes are reported to differentiate into dendritic cells that prevent LV remodeling by the exosome activation of CD4⁺ leukocytes. (2) PS expression of apoptotic neutrophils induces M2 macrophage polarization and the secretion of anti-inflammatory and pro-fibrotic cytokines such as IL-10 and TGF-β that suppress inflammation and promote tissue repair. (3) A switch from pro-inflammatory Ly6C^hi monocytes and M1 macrophages localized at the MI zone in response to increased myocardial CCL-2/MCP-1 expression during the initial pro-inflammatory phase to anti-inflammatory Ly6C^low monocytes and M2 macrophages, possibly mediated by Nr4a1 and in the case of macrophages mediated by IRF5.