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.

The Mechanism Underlying the Protective Effects of Tannic Acid Against Isoproterenol-Induced Myocardial Fibrosis in Mice

“…Sirius red staining has been reported as the most appropriate stain in the evidentiation of MF (Cowling et al, 2019). Sirius red stained heart sections from the control group were observed under the microscope ( Figure 5).…”

The anti‐fibrotic actions of relaxin are mediated through AT2R‐associated protein phosphatases via RXFP1‐AT2R functional crosstalk in human cardiac myofibroblasts

“…Cardiac fibrosis results from an aberrant wound‐healing response to heart tissue injury and is a hallmark of several cardiovascular diseases regardless of etiology 1,2 . It is characterized by the proliferation and differentiation of extracellular matrix (ECM)‐producing fibroblasts into activated myofibroblasts, whereby excessive myofibroblast‐induced ECM production in the cardiac muscle can lead to myocardial and heart valve stiffening and the inability of the heart to effectively pump blood 1,2 . Several factors are known to stimulate myofibroblast‐induced ECM production, the most recognized being transforming growth factor (TGF)‐β1 3,4 .…”

Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

“…This was indicated by mitochondrial dysfunction, inflammation, altered energy metabolism ( Figure 1 and Figure 2 ), and the structural modifications observed in the tissue ( Figure 5 ). Fibrotic lesions are primarily caused by fibroblasts [ 45 , 49 ] and accompanied by a metabolic switch to activate glycolysis [ 50 ]. Increased collagen production, as observed in the Raman maps ( Figure 5 ), and increased stiffness can be attributed to fibroblast activation and sustained fibrosis [ 51 ].…”

“…This region is particularly diagnostic for the presence of collagen, which has a characteristic pattern between 800 and 1000 cm −1 . Excessive deposition of extracellular matrix (ECM) proteins like collagen plays a central role in cardiac fibrosis and relates to metabolic stress (e.g., senescence, nutritional supply, or diabetes) as well as altered cardiac performance [45,46]. The spectra of Danon samples showed a different pattern with respect to spectra of controls.…”