Chirinos Julio A, Zhao Lei, Reese-Petersen Alexander L, Cohen Jordana B, Genovese Federica, Richards A Mark, Doughty Robert N, Díez Javier, González Arantxa, Querejeta Ramón, Zamani Payman, Nuñez Julio, Wang Zhaoqing, Ebert Christina, Kammerhoff Karl, Maranville Joseph, Basso Michael, Qian Chenao, Rasmussen Daniel G K, Schafer Peter H, SeifFert Dietmar, Karsdal Morten A, Gordon David A, Ramirez-Valle Francisco, Cappola Thomas P
Hospital of the University of Pennsylvania, Philadelphia.
University of Pennsylvania, Perelman School of Medicine, Philadelphia.
NEJM Evid. 2022 Oct;1(10). doi: 10.1056/evidoa2200091. Epub 2022 Sep 13.
Endotrophin, a collagen type VI-derived peptide, mediates metabolic dysregulation, inflammation, and fibrosis in animal models, but has not been studied in human heart failure (HF).
We examined the association between circulating endotrophin and outcomes in participants suffering from HF with preserved ejection fraction (HFpEF) enrolled in the TOPCAT trial (n=205). Associations were validated in a participant-level meta-analysis (n=810) that included participants with HFpEF from the PHFS study (United States; n=174), PEOPLE cohort (New Zealand; n=168), a randomized trial of vasodilator therapy (United States; n=45), a cohort from Donostia University Hospital and University of Navarra (Spain; n=171), and the TRAINING-HF trial (Spain; n=47). We also assessed associations in HF with reduced ejection fraction in PHFS (n=1,642).
Plasma endotrophin levels at baseline were associated with risk of future death (standardized hazard ratio [HR] = 1.74; 95% confidence interval [CI]=1.36-2.24; P<0.001) and death or HF-related hospital admission (DHFA; standardized HR=2.11; 95% CI= 1.67-2.67; P<0.001) in TOPCAT. Endotrophin improved reclassification and discrimination for these outcomes beyond the MAGGIC risk score and NT-proBNP (N-terminal pro b-type natriuretic peptide). Findings were confirmed in the participant-level meta-analysis. In participants with HF with reduced ejection fraction in PHFS, endotrophin levels were associated with death (standardized HR=1.82; 95% CI=1.66-2.00; P<0.001) and DHFA (standardized HR=1.40; 95% CI=1.31-1.50; P<0.001), but the strength of the latter association was substantially lower than for the MAGGIC risk score (standardized HR=1.93; 95% CI=1.76-2.12) and BNP (standardized HR=1.78; 95% CI=1.66-1.92).
Circulating endotrophin levels are independently associated with future poor outcomes in patients with HF, particularly in HFpEF. (Funded by Bristol Myers Squibb; Instituto de Salud Carlos III [Spain] and European Regional Development Fund; European Commission CRUCIAL project; and the U.S. National Institutes of Health National Heart, Lung, and Blood Institute.).
内营养蛋白是一种源自VI型胶原蛋白的肽，在动物模型中介导代谢失调、炎症和纤维化，但尚未在人类心力衰竭（HF）中进行研究。
我们在TOPCAT试验（n = 205）中纳入的射血分数保留的心力衰竭（HFpEF）参与者中，研究了循环内营养蛋白与预后之间的关联。在一项参与者水平的荟萃分析（n = 810）中验证了这种关联，该分析纳入了来自PHFS研究（美国；n = 174）、PEOPLE队列（新西兰；n = 168）、一项血管扩张剂治疗随机试验（美国；n = 45）、多诺斯提亚大学医院和纳瓦拉大学（西班牙；n = 171）的队列以及TRAINING-HF试验（西班牙；n = 47）的HFpEF参与者。我们还评估了PHFS中射血分数降低的HF患者的关联（n = 1,642）。
在TOPCAT中，基线时血浆内营养蛋白水平与未来死亡风险（标准化风险比[HR]=1.74；95%置信区间[CI]=1.36 - 2.24；P<0.001）以及死亡或HF相关住院（DHFA；标准化HR = 2.11；95%CI = 1.67 - 2.67；P<0.001）相关。除了MAGGIC风险评分和NT - proBNP（N末端前体b型利钠肽）外，内营养蛋白改善了这些预后的重新分类和鉴别能力。这些发现在参与者水平的荟萃分析中得到证实。在PHFS中射血分数降低的HF参与者中，内营养蛋白水平与死亡（标准化HR = 1.82；95%CI = 1.66 - 2.00；P<0.001）和DHFA（标准化HR = 1.40；95%CI = 1.31 - 1.50；P<0.001）相关，但后一种关联的强度明显低于MAGGIC风险评分（标准化HR = 1.93；95%CI = 1.76 - 2.12）和BNP（标准化HR = 1.78；95%CI = 1.66 - 1.92）。
循环内营养蛋白水平与HF患者未来的不良预后独立相关，尤其是在HFpEF患者中。（由百时美施贵宝公司、西班牙卡洛斯三世健康研究所和欧洲区域发展基金、欧盟关键项目以及美国国立卫生研究院国家心肺血液研究所资助。）
