Serum Biomarkers of Cardiovascular Remodelling Reflect Extra-Valvular Cardiac Damage in Patients with Severe Aortic Stenosis

Abstract

In patients with aortic stenosis (AS), a novel staging classification of extra-valvular left and right heart damage with prognostic relevance was introduced in 2017. The aim of the study was to evaluate the biomarkers of cardiovascular tissue remodelling in relation to this novel staging classification. Patients were categorized according to the novel staging classification into stages 0 to 4. The levels of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases 1 (TIMP-1), B and C domain containing tenascin-C (B+ Tn-C, C+ Tn-C), the ED-A and ED-B domain containing fibronectin (ED-A+ Fn, ED-B+ Fn), endothelin 1 (ET-1) and neutrophil gelatinase-associated lipocalin (NGAL) were determined in serum by ELISA. There were significantly decreased serum levels of MMP-9 and increased levels of B+ Tn-C and C+ Tn-C when comparing stages 0 and 1 with stage 2, with no further dynamics in stages 3 and 4. In contrast, for TIMP-1, C+ Tn-C, ED-A+ Fn, ET-1 and NGAL, significantly increased serum levels could be detected in stages 3 and 4 compared to both stages 0 and 1 and stage 2. ED-A+ Fn and ET-1 could be identified as independent predictors of the presence of stage 3 and/or 4. To the best of our knowledge, this is the first study identifying novel serum biomarkers differentially reflecting the patterns of left and right heart extra-valvular damage in patients suffering from AS. Our findings might indicate a more precise initial diagnosis and risk stratification.

Serum Liberation of Fetal Fibronectin Variants in Patients with Pulmonary Hypertension: ED-A+ Fn as Promising Novel Biomarker of Pulmonary Vascular and Right Ventricular Myocardial Remodeling

“…When comparing ED-A + and ED-B + Fn serum levels in PH patients and healthy controls, we observed significantly increased levels for ED-A + but not for ED-B + Fn qualifying ED-A + Fn as a promising biomarker in PH. This goes in line with recent findings of our group showing a strong re-expression of the molecule in human tissue and serum samples from patients suffering from, e.g., coronary artery disease, aortic stenosis, heart failure of different aetiology or rejection after heart transplantation [26][27][28]30,33,36]. Moreover, we could report similar findings in several preclinical models of cardiac allograft vasculopathy or PH, respectively [29,31,32,37].…”

“…In a very recent study, including elderly patients suffering from severe symptomatic aortic stenosis, our group investigated a panel of biomarkers with respect to their association to the novel staging classification of extra-valvular cardiac damage [38]. Interestingly, ED-A + Fn was significantly increased in aortic stenosis patients additionally exhibiting PH with or without consecutive right heart failure, compared to patients in which the disease was restricted to the left side of the heart [36]. In contrast to ED-A + Fn, a variety of studies investigating ED-B + Fn revealed that its re-expression is strongly linked to cancer development and tumour-associated angiogenesis and not to non-neoplastic chronic inflammatory diseases [39][40][41].…”

Prediction of one- and two-year mortality after transcatheter aortic valve implantation: proposal of a fast sum-score system integrating a novel biomarker of cardiac extracellular matrix accumulation and fibrosis

“…Despite the availability of various studies investigating the value of novel biomarkers of cardiovascular remodeling for improving the diagnosis or estimating the prognosis of AS patients [22,25,26,37], to our best knowledge, none of these markers has ever been implemented into a long-term mortality risk prediction model after TAVI. Thus, the JMS presented here, might fill this gap by integrating circulating levels of TIMP-1, which is a well-known biomarker of cardiovascular ECM accumulation and fibrosis [22,[38][39][40].…”

“…For the following biomarkers, commercially available assays were used according to the instructions of the manufacturer: matrix metalloproteinase 9 (MMP-9; assay: Human MMP-9 Immunoassay, R&D Systems GmbH, Wiesbaden, Germany), tissue inhibitor of metalloproteinase 1 (TIMP-1, assay: Human TIMP-1 Immunoassay, R&D Systems GmbH, Wiesbaden, Germany), B domain containing tenascin-C (B + Tn-C, assay: Tenascin-B Large (FNIII-B) ELISA, IBL International GmbH, Hamburg, Germany), endothelin 1 (ET-1, assay: Endothelin-1 Immunoassay, R&D Systems GmbH, Wiesbaden, Germany) and neutrophil gelatinase-associated lipocalin (NGAL, assay: Human Lipocalin-2/NGAL Immunoassay, R&D Systems, Wiesbaden, Germany). For the serum quantification of extra domain A containing fibronectin (ED-A + Fn) and extra domain B containing fibronectin and (ED-B + Fn), we applied protocols, which were recently established and validated in our group [22,32,33] because commercial ELISA assays are not available at present.…”

“…To reach the goal of defining a risk prediction model fulfilling all these requirements, one has to expand conventional scoring parameters by the integrative implementation of further prognostic determinants derived from, e.g., individual frailty assessment, imaging modalities or circulating reflectors of cardiovascular tissue remodeling. Especially the latter aspect was largely neglected in the past causing that those novel biomarkers, which have been shown to be prognostic in representative cohorts, are not implemented in TAVI risk prediction tools yet [10,[18][19][20][21][22][23][24][25][26][27].…”