Gina LaRocca1,2, Thor Aspelund3,4, Anders M Greve1, Gudny Eiriksdottir3, Tushar Acharya1, Gudmundur Thorgeirsson4, Tamara B Harris5, Lenore J Launer5, Vilmundur Gudnason3,4, Andrew E Arai1. 1. Department of Health and Human Services, National Heart, Lung, and Blood, National Institutes of Health, Building 10, Room B1D416, MSC 1061, 10 Center Drive, Bethesda, MD 20892-1061, USA. 2. Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1030, New York, NY 10029, USA. 3. Icelandic Heart Association, Holtasmari 1, Kopavogur, Iceland. 4. University of Iceland, 101 Reykjavik, Reykjavik, Iceland. 5. Department of Health and Human Services, National Institute on Aging, 31 Center Drive, MSC 2292, Bethesda, MD 20892, USA.
Abstract
BACKGROUND: Fibrosis is a key pathological process in many chronic inflammatory disease states. AIMS: We hypothesized that tissue inhibitor metalloproteinase-1 and matrix metalloproteinase-9 (TIMP-1 and MMP-9), biomarkers of fibrosis, would predict all-cause mortality and we assessed the incremental value of these biomarkers when adjusting for clinical and other biomarkers. METHODS: The cohort included 5511 community-dwelling participants in the AGES-Reykjavik Study. The baseline Cox proportional hazards regression model was based on the Framingham Risk Score variables; we added TIMP-1, MMP-9, serum high-sensitivity C-reactive protein (hsCRP), and estimated glomerular filtration rate (eGFR). The primary outcome was all-cause 10-year mortality. Cause of death was categorized as cardiovascular death (CVD), cancer death, and other causes. RESULTS: Participants averaged 76 years and 43% were male. Ten-year mortality was 41% (2263 deaths). Of these, 915 (16.6%) died of cardiovascular disease (CVD), 543 (9.9%) with cancer, and 805 (14.6%) from other causes. For 10-year mortality, age was the strongest predictor (log likelihood χ2 = 798.7, P < 0.0001), followed by TIMP-1 (χ2 = 125.2, P < 0.0001), female gender, current smoker, diabetes mellitus, total cholesterol, eGFR (χ2 16.7, P < 0.0001), body mass index, and hsCRP (χ2 11.3, P = 0.0008) in that order. TIMP-1 and hsCRP had the highest continuous net reclassification improvement over the baseline model for 5-year survival [net reclassification index (NRI) 0.28 and 0.19, respectively, both P < 0.0001] and for 10-year survival (NRI 0.19 and 0.11, respectively, both statistically significant). CONCLUSION: TIMP-1 is the strongest predictor of all-cause mortality after age. The metabolic pathways regulating extracellular matrix homeostasis and fibrogenic processes appear pathologically relevant and are prognostically important. Published by Oxford University Press on behalf of the European Society of Cardiology 2017. This work is written by US Government employees and is in the public domain in the US.
BACKGROUND: Fibrosis is a key pathological process in many chronic inflammatory disease states. AIMS: We hypothesized that tissue inhibitor metalloproteinase-1 and matrix metalloproteinase-9 (TIMP-1 and MMP-9), biomarkers of fibrosis, would predict all-cause mortality and we assessed the incremental value of these biomarkers when adjusting for clinical and other biomarkers. METHODS: The cohort included 5511 community-dwelling participants in the AGES-Reykjavik Study. The baseline Cox proportional hazards regression model was based on the Framingham Risk Score variables; we added TIMP-1, MMP-9, serum high-sensitivity C-reactive protein (hsCRP), and estimated glomerular filtration rate (eGFR). The primary outcome was all-cause 10-year mortality. Cause of death was categorized as cardiovascular death (CVD), cancer death, and other causes. RESULTS: Participants averaged 76 years and 43% were male. Ten-year mortality was 41% (2263 deaths). Of these, 915 (16.6%) died of cardiovascular disease (CVD), 543 (9.9%) with cancer, and 805 (14.6%) from other causes. For 10-year mortality, age was the strongest predictor (log likelihood χ2 = 798.7, P < 0.0001), followed by TIMP-1 (χ2 = 125.2, P < 0.0001), female gender, current smoker, diabetes mellitus, total cholesterol, eGFR (χ2 16.7, P < 0.0001), body mass index, and hsCRP (χ2 11.3, P = 0.0008) in that order. TIMP-1 and hsCRP had the highest continuous net reclassification improvement over the baseline model for 5-year survival [net reclassification index (NRI) 0.28 and 0.19, respectively, both P < 0.0001] and for 10-year survival (NRI 0.19 and 0.11, respectively, both statistically significant). CONCLUSION: TIMP-1 is the strongest predictor of all-cause mortality after age. The metabolic pathways regulating extracellular matrix homeostasis and fibrogenic processes appear pathologically relevant and are prognostically important. Published by Oxford University Press on behalf of the European Society of Cardiology 2017. This work is written by US Government employees and is in the public domain in the US.
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