Background: Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined.

Methods and Results: Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes (P=0.001, 0.012, and 0.009 for the 3 outcomes, respectively).

Conclusions: Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes.

Clinical Trial Registration : URL: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.

背景：可溶性ST2（sST2）与心脏重塑和纤维化有关。在慢性心力衰竭中，尚未在包含NT-proBNP（N端pro-B型利尿钠肽）和hs-TnT（高敏感性心肌肌钙蛋白T）的模型中评估sST2的预测价值。试验对治疗产生重大影响。因此，在PARADIGM-HF试验（ARNI与ACEI进行前瞻性比较以确定对全球死亡率和心力衰竭的影响的前瞻性比较）中，治疗对sST2水平的影响，sST2与预后之间的关系以及各种sST2分区值的预后效用被检查了。

方法和结果：比较治疗组之间的基线（n = 2002），1个月（n = 1936）和8个月随机化（n = 1758）sST2水平（（屈特尔/缬沙坦与依那普利）。使用限制性三次样条模型评估了基线sST2与（1）心力衰竭住院，（2）心血管死亡和（3）合并心力衰竭住院与心血管死亡之间的关系。调整后的Cox比例风险模型用于检验从基线到1个月sST2变化对经历每种结局的危害的影响。与依那普利相比，沙比特比/缬沙坦导致sST2水平下降更多，而上升较少。在调整了包括NT-proBNP和hs-TnT在内的其他预测因素后，基线sST2仍然是结果的独立预测因素。基线sST2与结果之间的关联是线性的。对于3个结果，P分别为0.001、0.012和0.009）。

结论：与依那普利相比，沙比特比/缬沙坦导致sST2水平的降低更大，而上升幅度则较小。没有特定的阈值与风险相关，因为观察到基线sST2与结果之间存在线性关系。从基线到1个月sST2的变化与结局风险独立相关。

临床试验注册：URL：https://www.clinicaltrials.gov。唯一标识符：NCT01035255。