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.

Kong P, Christia P, Saxena A, Su Y, Frangogiannis NG. Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am J Physiol Heart Circ Physiol 305: H1363-H1372, 2013. First published August 30, 2013; doi:10.1152/ajpheart.00395.2013Understanding the role of fibroblasts in pathologic conditions is hampered by the absence of specific markers. Fibroblast-specific protein (FSP)1 has been suggested as a fibroblast-specific marker in normal and fibrotic tissues; FSP1 reporter mice and FSP1-Cre-driven gene deletion are considered reliable strategies to investigate fibroblast biology. Because fibroblasts are abundant in normal and injured mammalian hearts, we studied the identity of FSP1 ϩ cells in the infarcted and remodeling myocardium using mice with green fluorescent protein (GFP) expression driven by the FSP1 promoter. Neonatal and adult mouse hearts had low numbers of FSP1 ϩ cells. Myocardial infarction induced marked infiltration with FSP1-expressing cells that peaked after 72 h of reperfusion. Using flow cytometry, we identified 50% of FSP1 ϩ cells as hematopoietic cells; many endothelial cells were also FSP1ϩ . Increased infiltration with FSP1 ϩ cells was also noted in the pressure-overloaded myocardium. Although some FSP1 ϩ cells had fibroblast morphology, Ͼ30% were identified as hematopoietic cells, endothelial cells, or vascular smooth muscle cells. In contrast, periostin did not stain leukocytes or vascular cells but labeled spindle-shaped interstitial cells and, as a typical matricellular protein, was deposited in the matrix. CD11b ϩ myeloid cells sorted from the infarcted heart had higher FSP1 expression than corresponding CD11b-negative cells, highlighting the predominant expression by hematopoietic cells. FSP1 is not a specific marker for fibroblasts in cardiac remodeling and fibrosis. cardiac fibrosis; myocardial infarction; fibroblast; cardiac remodeling; periostin FIBROBLASTS ARE THE MOST ABUNDANT noncardiomyocytes in the adult mammalian myocardium and play an important role in cardiac homeostasis and disease (39). In the normal heart, fibroblasts not only secrete extracellular matrix proteins and provide structural support by maintaining the interstitial matrix network but may also interact with cardiomyocytes and vascular cells transducing signals essential for preservation of cardiac function (21, 42). Following myocardial injury, cardiac fibroblasts undergo dynamic changes and actively participate in reparative, fibrotic, and hypertrophic responses (9) by secreting structural and matricellular matrix proteins and by releasing cytokines and growth factors, thus modulating phenotype and function of cardiomyocytes and noncardiomyocytes (23, 41). Because of their abundance in normal and injured hearts, their phenotypic plasticity, and their broad range of secreted mediators, fibroblasts have attracted significant interest as potentially critical cellular effectors of cardiac remodeling. However, understanding of their role in vivo has been hampered by the lack of a reli...

Acute cardiomyocyte necrosis in the infarcted heart generates Damage-Associated Molecular Patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, and triggering an intense inflammatory reaction. Infiltrating leukocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels; the geometric, functional and molecular alterations associated with post-infarction remodeling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the post-infarction inflammatory reaction may be crucial to protect the myocardium from dilative remodeling and progressive dysfunction. Inhibition and resolution of post-infarction inflammation involves mobilization of inhibitory mononuclear cell subsets and requires activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the post-infarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodeling. Given the pathophysiologic complexity of post-infarction remodeling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and Monocyte Chemoattractant Protein-1) may be effective in patients with defective resolution of post-infarction inflammation who exhibit progressive dilative remodeling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies.

Mouse models of myocardial infarction are essential tools for the study of cardiac injury, repair, and remodeling. Our current investigation establishes a systematic approach for quantitative evaluation of the inflammatory and reparative response, cardiac function, and geometry in a mouse model of reperfused myocardial infarction. Reperfused mouse infarcts exhibited marked induction of inflammatory cytokines that peaked after 6 hr of reperfusion. In the infarcted heart, scar contraction and chamber dilation continued for at least 28 days after reperfusion; infarct maturation was associated with marked thinning of the scar, accompanied by volume loss and rapid clearance of cellular elements. Echocardiographic measurements of end-diastolic dimensions correlated well with morphometric assessment of dilative remodeling in perfusion-fixed hearts. Hemodynamic monitoring was used to quantitatively assess systolic and diastolic function; the severity of diastolic dysfunction following myocardial infarction correlated with cardiomyocyte hypertrophy and infarct collagen content. Expression of molecular mediators of inflammation and cellular infiltration needs to be investigated during the first 72 hr, whereas assessment of dilative remodeling requires measurement of geometric parameters for at least four weeks after the acute event. Rapid initiation and resolution of the inflammatory response, accelerated scar maturation, and extensive infarct volume loss are important characteristics of infarct healing in mice.