Extracellular matrix remodeling in the heart is an active and highly complex process orchestrated by matrix-degrading MMPs and their TIMP inhibitors. MMPs constitute a com plex family of enzymes of the protease group, of which at least 28 members have been identified (indicated by progressive numbers from MMP-1 to MMP28), classified according to the nature of the most important functional groups in their catalytic site, which requires the presence of metal ions as cofactors (zinc or cobalt). Four members of the MMP inhibitor family (TIMP-1 to TIMP-4) were identified.
The fibrillar collagen in the heart is predominantly of type I (85%) and type III (11%); the latter provides elasticity to the myocardium, while the former contributes most to the strength and resistance of the myocardium to wall stress and deformation. Collagen undergoes turnover by the action of fibroblasts and myofibroblasts, which respond to mechanical stress and autocrine and paracrine factors (such as angiotensin II, aldosterone, cytokines, and growth factors), partly secreted by monocytes and macrophages. An increase in collagen deposition results from the increased proliferation of fibroblasts/myofibroblasts and their collagen synthesis and secretion rate. Fibrillar collagen is synthesized as pre- procollagen in the endoplasmic reticulum of fibroblasts and transformed into procollagen with a triple helix structure. Procollagen, secreted into the extracellular matrix, is then cut by proteases to form type I and III collagen fibrils that contribute to the extracellular matrix’s structure and the myocardium’s mechanical characteristics.
Although cardiac tissue biopsy is considered the gold standard for diagnosis, some markers of collagen turnover have been proposed for the noninvasive estimation of myocardial fibrosis. Although numerous markers of collagen turnover have been identified and described, the most robust evidence involves PICP (Procollagen type I C-terminal Propeptide), PIIINP (Procollagen type III N-terminal Propeptide), and ICTP (type I Collagen TeloPeptide).
Many studies, especially case-control, measured circulating biomarkers of extracellular matrix turnover in patients with heart failure. However, analytical difficulties limited their use in clinical practice. Additionally, the results of these studies are difficult to compare with each other because they differ in the number and type of biomarkers analyzed, the study design (case–control vs. cohort, prospective or retrospective study), and the number and demographic (especially age and sex) and clinical characteristics of the enrolled patients. Also, the methods used to measure the same biomarker in the different studies present very different analytical characteristics; generally, RIA or ELISA methods were used. In many studies, the main analytical characteristics and performance (sensitivity, reproducibility, and specificity of the antibodies used) of the methods used are not even specified, so it is impossible to compare the data obtained in different studies, even considering the same bio marker. Some authors have suggested that the PICP/ICPT ratio could better estimate type I collagen turnover than a single marker. However, it should be noted that the absolute differences between healthy subjects and patients with heart failure are generally much smaller than those observed in natriuretic peptides, which show differences of the order of 10-fold or more between the median value of a population of patients with heart failure compared to that observed in healthy subjects. This reduced differential between cases and controls reduces the diagnostic and prognostic accuracy of the biomarker, especially in identifying patients with early forms of the disease. This explains why these biomarkers have a much lower diagnostic and prognostic power than BNP and NT-proBNP. In conclusion, although there are many studies on the circulating levels of collagen and extra cellular matrix turnover biomarkers, there is currently insufficient evidence to support their use in clinical practice for the diagnosis, prognosis, or treatment of patients with heart failure.
