Background:It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS).Methods:Patients meeting Framingham criteria for HF with EF<50% were enrolled (N=1017) and plasma underwent SOMAscan profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and NT-proBNP (N-terminal pro-B-type natriuretic peptide), then was tested in the validation cohort. Risk stratification improvement was evaluated by C statistic, integrated discrimination index, continuous net reclassification index, and median improvement in risk score for 1-year and 3-year mortality.Results:Participants’ mean age was 68 years, 48% identified as Black, 35% were female, and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio, 2.27 [95% CI, 1.84–2.82], P=6.3×10^-14), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (P=2.2×10^-6), and it remained significant after adjustment for clinical score and NT-proBNP (hazard ratio, 1.37 [95% CI, 1.05–1.79], P=0.021). The HFrEF-PRS improved metrics of risk stratification (C statistic change, 0.009, P=0.612; integrated discrimination index, 0.041, P=0.010; net reclassification index=0.391, P=0.078; median improvement in risk score=0.039, P=0.016) and associated with cardiovascular death and HF phenotypes (eg, 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF.Conclusions:A plasma multiprotein score improved risk stratification in patients with HFrEF and identified novel candidates.

中文翻译：

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血浆蛋白质组学特征预测射血分数降低的心力衰竭患者的存活率

背景：目前尚不清楚血浆蛋白质组是否对射血分数降低的心力衰竭 (HF) (HFrEF) 的既定预测因子增加了价值。我们试图推导和验证 HFrEF 患者生存的血浆蛋白质组学风险评分 (PRS) (HFrEF-PRS)。方法：纳入符合 Framingham HF 标准且 EF<50% 的患者 (N=1017)，血浆接受 SOMAscan分析（4453 个目标）。患者以 2:1 的比例随机分为推导组和验证组。HFrEF-PRS 是使用根据临床评分和 NT-proBNP（N 末端前 B 型利钠肽）调整的全因死亡率的 Cox 回归得出的，然后在验证队列中进行测试。通过 C 统计量、综合辨别指数、连续净重分类指数、和 1 年和 3 年死亡率风险评分的中位数改善。结果：参与者的平均年龄为 68 岁，48% 为黑人，35% 为女性，296 人死亡。在推导中（n=681），128 种蛋白质与死亡率相关，8 种包含优化的 HFrEF-PRS。在验证（n=336）中，HFrEF-PRS 与死亡率相关（风险比，2.27 [95% CI，1.84–2.82]，P =6.3×10 ^-14），Kaplan-Meier 曲线在 HFrEF-PRS 四分位数之间有显着差异（P =2.2×10 ^-6），在调整临床评分和 NT-proBNP 后仍然显着（风险比，1.37 [95 % CI, 1.05–1.79], P = 0.021)。HFrEF-PRS 改进了风险分层指标（C 统计变化，0.009，P = 0.612；综合辨别指数，0.041，P = 0.010；净重新分类指数 = 0.391，P = 0.078；风险评分中位数改善 = 0.039，P= 0.016）并与心血管死亡和心衰表型相关（例如，6 分钟步行距离、EF 变化）。大多数 HFrEF-PRS 蛋白与 HFrEF 的联系鲜为人知。结论：血浆多蛋白评分改善了 HFrEF 患者的风险分层并确定了新的候选者。