Hearts of mice with reduction of function mutation in STAT3 (SA/SA) develop fibrotic collagen foci and reduced systolic function with hypertension. This model was used to determine if fractal dimension and image analysis can provide a quantitative description of myocardial fibrosis using routinely prepared trichome-stained material. Collagen was characterized by relative density [integrated optical density/area (IOD/A)] and fractal dimension (D), an index of complexity. IOD/A of collagen in wild type mice increased with hypertension while D decreased, suggesting tighter collagen packing that could eventually stiffen the myocardium as in diastolic heart failure. Reduced STAT3 function caused modest collagen fibrosis with increased IOD/A and D, indicating more tightly packed, but more disorganized collagen than normotensive and hypertensive controls. Hypertension in SA/SA mice resulted in large regions where myocytes were lost and replaced by fibrotic collagen characterized by decreased density and increased disorder. This indicates that collagen associated with reparative fibrosis in SA/SA hearts experiencing hypertension was highly disorganized and more space filling. Loss of myocytes and their replacement by disordered collagen fibers may further weaken the myocardium leading to systolic heart failure. Our findings highlight the utility of image analysis in revealing importance of a cellular protein for normal and reparative extracellular matrix deposition.

Myofibroblasts are differentiated fibroblasts that hold a key role in wound healing and remodeling following myocardial infarction (MI). A large repertoire of stimuli, such as mechanical stretch, growth factors, cytokines, and vasoactive peptides, induces myofibroblast differentiation. Myofibroblasts are responsible for the production and deposition of collagen, leading to the establishment of a dense extracellular matrix that strengthens the infarcted tissue and minimizes dilatation of the infarct area. In addition, cells contributing to fibrosis act on sites distal from the infarct area and promote collagen deposition in noninfarcted tissue, thus contributing to adverse remodeling and consequently to the development of congestive heart failure (CHF). Current drugs that are used to treat post-MI CHF do influence fibroblasts and myofibroblasts; however, their therapeutic efficacy is far from being regarded as ideal. Novel therapeutic agents targeting (myo)fibroblasts are being developed to successfully prevent the cardiac remodeling of sites remote from the infarct area and therefore hinder the establishment of CHF. The purpose of this review article is to discuss the basic concepts of the myofibroblasts' actions in cardiac wound healing processes, factors that influence them, currently available pharmacological agents, and future challenges in this area.