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Review
. 2014 Feb;71(4):549-74.
doi: 10.1007/s00018-013-1349-6. Epub 2013 May 7.

The pathogenesis of cardiac fibrosis

Ping Kong  1 , Panagiota Christia, Nikolaos G Frangogiannis
Affiliations
Review

The pathogenesis of cardiac fibrosis

Ping Kong et al. Cell Mol Life Sci. 2014 Feb.

Abstract

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 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.

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Figures

Fig. 1
Fig. 1
Types of cardiac fibrosis (histopathologic images show Sirius-red stained sections of samples from mouse models of fibrosis to identify the collagen network). a Myocardial infarction results in sudden loss of a large number of cardiomyocytes leading to replacement fibrosis. b Interstitial fibrosis is associated with increased deposition of collagen in the cardiac interstitial space in the absence of significant cardiomyocyte loss. c Perivascular fibrosis is characterized by expansion of the vascular adventitial matrix. d The fibrotic heart exhibits expansion of the interstitial space associated with deposition of collagens and other matrix proteins. Myofibroblasts (MF) are the main effector cells in cardiac fibrosis; however, macrophages, lymphocytes, mast cells, vascular endothelial cells, and cardiomyocytes may also participate in the process
Fig. 2
Fig. 2
Origin of the myofibroblast in fibrotic hearts. Resident cardiac fibroblasts (abundant in adult mammalian hearts), circulating and resident fibroblast progenitors (including fibrocytes), epicardial epithelial cells undergoing epithelial to mesenchymal transition (EMT), and endothelial cells undergoing endothelial to mesenchymal transdifferentiation (EndMT) are documented sources of myofibroblasts in fibrotic hearts. Their relative contribution to the myofibroblast population likely depends on the underlying cause of fibrosis. Pericytes may represent an additional source of myofibroblasts in the fibrotic myocardium; however, their role in fibrotic remodeling of the ventricle has not been elucidated
Fig. 3
Fig. 3
Mast cells in cardiac fibrosis. Cardiac mast cell numbers increase in failing and remodeling hearts. Mast cell degranulation results in release of a wide range of fibrogenic mediators, leading to activation, proliferation, and differentiation of cardiac fibroblasts
Fig. 4
Fig. 4
Matricellular proteins are induced in the fibrotic heart and modulate cellular responses. Upregulation and deposition of matricellular proteins in the cardiac interstitium is a hallmark of the fibrotic response. a Immunohistochemical staining shows deposition of the prototypical matricellular protein tenascin-C (arrows) in the border zone and remodeling myocardium in reperfused mouse infarcts. b Periostin is also expressed in myofibroblasts and deposited in the infarct matrix (arrows). c, d Both tenascin-C (c) and periostin (d) are upregulated in the murine pressure overloaded heart (arrows)
Fig. 5
Fig. 5
Cellular effects of TGF-β in cardiac fibrosis. TGF-β is a key fibrogenic mediator that may affect all cell types involved in the cardiac fibrotic response
Fig. 6
Fig. 6
Remodeling and fibrosis in the pressure-overloaded heart. Animal models of cardiac pressure overload exhibit rapid development of concentric myocardial hypertrophy and fibrosis associated with diastolic dysfunction, followed by chamber dilation and systolic dysfunction. The protease/antiprotease balance plays an important role in remodeling of the pressure overloaded heart. During the early stages of the response to pressure overload, angiotensin II and TGF-β may promote matrix preservation, stimulating collagen and TIMP synthesis. Although the events associated with decompensation are poorly understood, increased MMP synthesis may be involved in transition to the dilative phase. Lower panel The histopathological images show Sirius red staining in a mouse model of transverse aortic constriction to illustrate the typical alterations of the cardiac interstitium in the pressure-overloaded heart: perivascular (left) and interstitial (right) fibrosis
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