Serum and tissue biomarkers in aortic stenosis

Abstract

Background: Calcific aortic valve stenosis (CAVS) is seen in a large proportion of individuals over 60 years. It is an active process, influenced by lipid accumulation, mechanical stress, inflammation, and abnormal extracellular matrix turnover. Various biomarkers (BMs) are studied, as regards mechanisms, diagnosis and prognosis. Methods: In the calcified valves calcium deposition, elastin fragmentation and disorganization of cellular matrix were assessed, together with expression of OPN, OPG, osteocalcin (OCN) and RL2.We prospectively studied the following serum BMs in 60 patients with CAVS and compared them to 20 healthy controls, free from any cardiac disease: Matrix metalloproteinases (MMP) 2 and 9 and tissue inhibitor of metalloproteinase 1 (TIMP1), which regulate collagen turnover, inflammatory factors, i.e. tumor necrosis factor a (TNFa), interleukin 2 (IL2), transforming growth factor β1 (TGF-β1) which regulates fibrosis, fetuin-A (fet-A), osteopontin (OPN), osteoprotegerin (OPG), sclerostin (SOST), and relaxin-2 (RL2) which positively or negatively regulate calcification. Monocyte chemoattractant protein 1 (MCP-1) which regulates migration and infiltration of monocytes/macrophages was also studied as well as malondialdehyde (MDA) an oxidative marker. Results: Extent of tissue valve calcification (Alizarin Red stain) was negatively correlated with tissue elastin, and RL2, and positively correlated with tissue OCN and serum TIMP1 and MCP-1 and negatively with MMP9.Tissue OCN was positively correlated with OPN and negatively with the elastin. Tissue OPN was negatively correlated with elastin and OPG. Tissue OPN OPG and RL2 were not correlated with serum levels In the serum we found in patients statistically lower TIMP1, fet-A and RL2 levels, while all other BMs were higher compared to the healthy group. Positive correlations between SOST and IL2, OPG and MDA but negative with TNFa and OPN were found; also MMP9 was negatively correlated with TNFa and MCP-1 was negatively correlated with TIMP1. Conclusion: We found that many BMs expressing calcification, collagen breakdown, or formation, and inflammation are increased in the valve tissue and in the serum of patients with CAVS as compared with healthy group. Our findings may give new insights towards diagnosis but also therapy. Thus antisclerostin, and antiflammatory agents could be tried for preventing aortic calcification progression.

Biomarkers in Aortic Stenosis: A Systematic Review

“…[36][37][38] Inflammatory cells such as macrophages and lymphocytes that have been recruited to the fibrosa release inflammatory cytokines and matrix metalloproteinases, leading to degradation of cusp collagen and proteoglycans. [39][40][41][42] These biological events lead to osteoblastic transition of valve interstitial cells and active cusp calcification.- 37,38 As a result, with time the calcified valve becomes increasingly rigid and stenotic.…”

“…87 MDA levels appear to be increased in patients with AS and were shown to be predictive of worse outcomes, including increased risk of dying after TAVR. 39,42 In these studies, MDA levels provided incremental value over the EuroSCORE for risk prediction.…”

“…These include transforming growth factor β1, 40,42,89 collagen-derived peptides, 90 matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMP). [39][40][41][42] Both TIMP1 and MMP2 appear to have incremental value over established clinical risk models for prediction of the Valve Academic Research Consortium combined safety endpoint at 30 days after TAVR, while MMP2 also improved the prediction of a combined endpoint (defined as the occurrence of any clinical [safety or efficacy] endpoint, wherein efficacy includes allcause mortality after 30 days, hospitalization for symptoms of valve-related or cardiac decompensation, and prosthetic heart valve dysfunction) throughout 1 year of follow-up. 39 Important limitations of these biomarkers include uncertainties in regard to their specificity for cardiac disease [91][92][93][94] and their route of clearance.…”

Bone Metabolism Markers in Aortic Stenosis and the Role of Vitamin D Deficiency

“…Данный биомаркер играет важную роль в ремоделировании костной ткани, а также принимает участие в эктопи-ческой кальцификации, активируя дифференцировку миофибробластов в остеобласты [23,24]. Ранее Yu PJ, [23,25]. Аналогичные результаты проведенного нами иссле-дования также подтверждают возможное участие остеопонтина в развитии АС, вероятно, за счет акти-вации процессов воспаления.…”

Imaging of Myocardial Fibrosis and Its Functional Correlates in Aortic Stenosis: A Review and Clinical Potential

“…First of all, GLS was found to be related to biomarkers of myocardial fibrosis such as those expressing calcification, collagen formation, or breakdown and inflammation [42, 43]. Several studies have also reported significant associations between LV systolic function and both FMF and DMF at CMR or myocardial histology [3, 14, 15, 18, 19, 24, 29, 44-46] (Table 2).…”