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.

中文翻译：

---

由生物标志物组织抑制剂金属蛋白酶 1 测量的纤维化可预测年龄基因环境易感性-雷克雅未克 (AGES-Reykjavik) 研究中的死亡率

背景纤维化是许多慢性炎症性疾病状态的关键病理过程。目的 我们假设组织抑制剂金属蛋白酶 1 和基质金属蛋白酶 9（TIMP-1 和 MMP-9），纤维化的生物标志物，可以预测全因死亡率，我们在调整临床和其他生物标志物时评估了这些生物标志物的增量价值. 方法 该队列包括 AGES-Reykjavik 研究中的 5511 名社区居民。基线 Cox 比例风险回归模型基于 Framingham 风险评分变量；我们添加了 TIMP-1、MMP-9、血清超敏 C 反应蛋白 (hsCRP) 和估计肾小球滤过率 (eGFR)。主要结果是全因 10 年死亡率。死亡原因分为心血管死亡（CVD）、癌症死亡和其他原因。结果 参与者平均年龄为 76 岁，43% 为男性。十年死亡率为 41%（2263 人死亡）。其中，915 人（16.6%）死于心血管疾病（CVD），543 人（9.9%）死于癌症，805 人（14.6%）死于其他原因。对于 10 年死亡率，年龄是最强的预测因子（对数似然 χ2 = 798.7，P < 0.0001），其次是 TIMP-1（χ2 = 125.2，P < 0.0001）、女性、当前吸烟者、糖尿病、总胆固醇、 eGFR (χ2 16.7, P < 0.0001)、体重指数和 hsCRP (χ2 11.3, P = 0.0008) 按此顺序排列。TIMP-1 和 hsCRP 在 5 年生存率[净再分类指数 (NRI) 分别为 0.28 和 0.19，P < 0.0001] 和 10 年生存率 (NRI 0.19 和 0.11) 的基线模型中具有最高的持续净再分类改进，分别具有统计学意义）。结论 TIMP-1 是年龄后全因死亡率的最强预测因子。调节细胞外基质稳态和纤维化过程的代谢途径似乎具有病理相关性并且对预后很重要。