Mechanisms of cardiac collagen deposition in experimental models and human disease

Abstract

The inappropriate deposition of extracellular matrix within the heart (termed cardiac fibrosis) is associated with nearly all types of heart disease, including ischemic, hypertensive, diabetic, and valvular. This alteration in the composition of the myocardium can physically limit cardiomyocyte contractility and relaxation, impede electrical conductivity, and hamper regional nutrient diffusion. Fibrosis can be grossly divided into 2 types, namely reparative (where collagen deposition replaces damaged myocardium) and reactive (where typically diffuse collagen deposition occurs without myocardial damage). Despite the widespread association of fibrosis with heart disease and general understanding of its negative impact on heart physiology, it is still not clear when collagen deposition becomes pathologic and translates into disease symptoms. In this review, we have summarized the current knowledge of cardiac fibrosis in human patients and experimental animal models, discussing the mechanisms that have been deduced from the latter in relation to the former. Because assessment of the extent of fibrosis is paramount both as a research tool to further understanding and as a clinical tool to assess patients, we have also summarized the current state of noninvasive/minimally invasive detection systems for cardiac fibrosis. Albeit not exhaustive, our aim is to provide an overview of the current understanding of cardiac fibrosis, both clinically and experimentally.

Fig 1.

Simplified pictorial representation of cardiac fibroblast activation. Actin stress fibers are depicted in the protomyofibroblast as thin lines and contractile α-smooth muscle actin-containing fibers are depicted in the myofibroblast as thick lines (with thick gray arrows denoting contractile tension). Fibroblast activation in the heart involves a complex mix of pathways, but the most important result is the increased deposition of ECM. EDA-Fn, extra domain A fibronectin; ??, questionable contribution, limited contribution, or contribution only in certain contexts.

Fig 2.

Example cardiac magnetic resonance images in common cardiac conditions showing late gadolinium enhancement, native (precontrast) and postcontrast T1 mapping, and calculated extracellular volume (ECV) fractions. Red arrows identify areas of subendocardial delayed enhancement. White arrows identify midwall delayed enhancement. Reproduced, with permission, from Everett et al. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)