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Mechanisms of cardiac collagen deposition in experimental models and human disease

Published:March 26, 2019DOI:https://doi.org/10.1016/j.trsl.2019.03.004

      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.

      Abbreviations:

      Ang II (angiotensin II), AT1R (angiotensin II type 1 receptor), CITP (type I collagen C-terminal telopeptide), CMR (cardiac MRI), Col I (collagen I), Col III (collagen III), COL1A1 (collagen type I alpha 1 chain), COL3A1 (collagen type III alpha 1 chain), CTGF (connective tissue growth factor), ECM (extracellular matrix), ECV (extracellular volume), EDA (extra domain A), EMT (epithelial-to-mesenchymal transition), EndMT (endothelial-to-mesenchymal transition), ET-1 (endothelin-1), Gal-3 (galectin-3), HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction), hsTn (highly sensitive cardiac troponin), IL (interleukin), LAP (TGF-β latency associated protein), LGE (late gadolinium enhancement), LOX (lysyl oxidase), MAPK (mitogen-activated protein kinase), MI (myocardial infarction), miRNA (microRNA), MMP (matrix metalloproteinase), MRI (magnetic resonance imaging), MRTF-A (myocardin-related transcription factor-A), ST2 (suppression of tumorigenicity 2), ST2L (transmembrane ST2), sST2 (soluble ST2), TAC (transverse aortic constriction), Tcf21 (transcription factor 21), TGF-β (transforming growth factor-β), TIMP (tissue inhibitor of metalloproteinases), α-SMA (α-smooth muscle actin)
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