The pathogenesis of cardiac fibrosis

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 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.

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…82 Moreover, fibrosis increases the risk of arrhythmias, 83 and fibrotic remodeling may cause cardiomyocyte slippage, thus affecting systolic function. 84 Cardiac fibrosis results from changes in the cellular and extracellular environment and is mainly regulated by activated fibroblasts (discussed below). However, several cell populations contribute to the profibrotic state by secreting fibrogenic factors, including immune cells, cardiomyocytes and vascular cells.…”

“…However, several cell populations contribute to the profibrotic state by secreting fibrogenic factors, including immune cells, cardiomyocytes and vascular cells. 84 The alterations in ECM turnover underlying fibrosis result from a disturbance of the balance between synthetic and degradative processes. Thus, in addition to the increased ECM synthesis by cardiac fibroblasts, the levels and activity of the matrix degrading matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are important determinants of fibrosis.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In health, the cardiac ECM does not simply serve as a mechanical scaffold, but may also transduce signals that are important for cell survival and function. Most cardiac pathologic conditions are associated with expansion of the cardiac interstitial matrix and with marked alterations in its composition (2,3); these changes perturb cardiac systolic and diastolic function. In myocardial infarction, sudden death of up to a billion cardiomyocytes overwhelms the extremely limited regenerative capacity of the adult mammalian heart.…”

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

“…In heart tissue, a number of diverse disorders, including hypertrophic cardiomyopathy and heart failure, are associated with excessive deposition of fibrotic tissue (1). Whereas Wnt-mediated signaling is well established as a participant in maladaptive fibrotic responses in most tissues, including the heart (2), selective Wnt-signaling-targeted agents have been elusive, thus hampering efforts to pharmacologically exploit this understanding for intervention in heart disease.…”