Abstract 613 Profibrotic Biomarkers correlate with clinical presentation and outcome in cardiac Transthyretin amyloidosis

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Profibrotic Biomarkers correlate with clinical presentation and outcome in cardiac Transthyretin amyloidosis
S. Hein¹, M. Knoll², F. aus dem Siepen¹, J. Furkel², S. Schönland³, U. Hegenbart³, H. A. Katus¹, A. V. Kristen⁴, N. Frey¹, M. Konstandin¹
¹Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; ²Abteilung für Radioonkologie und Strahlentherapie, Universitätsklinikum Heidelberg, Heidelberg; ³Medizinische Klinik V, Universitätsklinik Heidelberg, Heidelberg; ⁴Kardiovaskuläres Zentrum Darmstadt, Darmstadt;
AIM: In cardiac transthyretin amyloidosis (ATTR-CM) aggregated protein fibrils are deposited in the heart leading to myocardial thickening with interstitial and subendocardial fibrosis. Recently, in vitro studies revealed direct effects of transthyretin on fibroblasts’ structure, function and gene expression. We therefore hypothesized that biomarkers known to modulate fibrotic processes might be of clinical value in ATTR-CM. METHOD: In 61 patients with hereditary (vATTR) and 43 with wildtype ATTR (ATTRwt) amyloidosis as well as 21 healthy controls fourteen fibrosis markers (EN-RAGE, IGFBP 1, 2, 3, 4 and 6, FGF23, MMP2, 7, 9 and 13, TIMP2 and 4, RAGE-AGE) were analyzed using Luminex multiplex assay. Statistical analyses were performed using parametric survival regression models and cluster analysis to correlate biomarker levels with clinical presentation and outcome (decompensation (DMP) or transplantation/death (HTX)). RESULTS: Significant differences were found in ATTR patients with cardiac affection compared to controls or ATTR patients without cardiac involvement for IGFBP 1, 2, 3, 4 and 6, FGF-23, MMP-2 and -7, TIMP-2 and -4, as well as RAGE-AGE plasma levels. Univariate analyses revealed significant association of MMP-7, RAGE-AGE, MMP-2, IGFBP-1, IGFBP-2, FGF-23 and TIMP-2 for both endpoints. Univariate analyses for IGFBP-3 and TIMP-4 revealed significant association with HTX but not DMP. Upon hierarchical clustering patients were divided in two groups. Individuals falling into cluster 1 were significantly older, had lower GFR, EDD and MAPSE. Myocardial wall thickness, leukocyte count, CRP, hsTNT and NTproBNP levels were significantly higher. In the multivariate analysis IGFBP-6, IGFBP-1 and TIMP-4 showed significant association with Htx, whereas FGF-23 was independently associated with DMP independent of established risk markers. Patients in cluster 2 showed lowest risk for the endpoint Htx (HR 0.02; CI 0-0,2; p<0.001) being the strongest predictor of all tested risk markers. CONCLUSION: Assessment of profibrotic biomarkers might help stratification of ATTR-CM patients in addition to established risk markers.
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