The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction

Abstract

Optimal healing of damaged tissue following myocardial infarction (MI) requires a coordinated cellular response that can be divided into three phases: inflammatory, proliferative/reparative, and maturation. The inflammatory phase, characterized by rapid influx of cytokines, chemokines, and immune cells, is critical to the removal of damaged tissue. The onset of the proliferative/reparative phase is marked by increased proliferation of myofibroblasts and secretion of collagen to replace dead tissue. Lastly, crosslinking of collagen fibers and apoptosis of immune cells marks the maturation phase. Excessive inflammation or fibrosis has been linked to increased incidence of arrhythmia and other MI-related pathologies. This review describes the roles of inflammation and fibrosis in arrhythmogenesis and prospective therapies for anti-arrhythmic treatment.

Keywords: Arrhythmia; Fibrosis; Inflammation; Myocardial infarction.

Figure 1

Optimal post-MI healing is comprised of three phases: inflammatory, reparative/proliferative, and maturation. Timely progression and resolution of each phase is required for proper healing. An overactive inflammatory or reparative phase can lead to ventricular arrhythmia.

Figure 2

Inflammation and Cx43. A) Immunofluorescence images of Cx43 (green) and CD-68 (red, macrophage marker) show abundant macrophage infiltration in the infarct region of an ApoE+MI heart (bottom). Myocytes adjacent to macrophages show internalization of Cx43 (Inset). B) Top: Cx43 (green) normally co-localizes with N-cadherin (N-Cad, red), a marker of the intercalated disc. Arrows indicate examples of obvious co-localization of Cx43 and N-Cad. Bottom: In the infarct region of an ApoE+MI heart, Cx43 expression is observed without corresponding N-Cad staining, indicating Cx43 internalization or lateralization to areas outside of the intercalated disc. Arrows indicate obvious examples of co-localization. Dashed boxes indicate examples of internalization (Cx43 without corresponding N-Cad). C) Quantification of Cx43 and N-Cad co-localization, demonstrating increased Cx43 internalization/lateralization in the infarct compared to remote regions, and in ApoE+MI compared to WT+MI hearts. D–F) ApoE+MI hearts have a ~3-fold increase in IL-1β expression and a corresponding ~2-fold decrease in Cx43 expression. Reprinted with permission from [47].

Figure 3

The temporal progression of collagen deposition through 28 days post-MI. Sections were stained with 1% picosirius red, which stains collagen red. Reprinted with permission from [85].

Figure 4

Sustained VT anchored to compact scar. A) Photograph of post-MI rabbit heart. Arrow indicates infarct. B) Masson trichrome staining of short-axis slices. Blue indicates fibrosis. C) 3D histological reconstruction showing entire infarct region in blue. D) Phase map of stable reentrant VT rotating clockwise, anchored to compact scar. E) Location of phase singularities (center of reentry) corresponds to infarct location. F) Lead I ECG during VT. Reprinted with permission from [57].