Soluble ST2 dynamic changes predict the cardiorenal protective efficacy of arni in patients with heart failure with preserved ejection fraction: a meta-analysis

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of HF cases, predominantly affecting older adults with comorbidities such as hypertension, diabetes, and obesity. Despite the breakthrough provided by angiotensin receptor-neprilysin inhibitors (ARNI), approximately 30% of HFpEF patients do not derive cardiorenal benefits. Soluble ST2 (sST2), a biomarker of fibrosis and ventricular stress, avoids confounders associated with traditional markers (e.g., NT-proBNP) and may serve as a predictor of ARNI response. Objectives: To evaluate whether dynamic changes in sST2 can predict the cardiorenal protective efficacy of ARNI in HFpEF patients, as measured by changes in estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and left ventricular diastolic function (E/e' ratio). Methods: We searched CENTRAL, The Cochrane Library, Embase, PubMed, Science Citation Index (SCI), and Social Science Citation Index (SSCI) for randomized controlled trials (RCTs) and cohort studies (prospective/retrospective) without language or date restrictions. Eligible studies included HFpEF patients (EF ≥ 50% per 2016 ESC or 2022 AHA/ACC/HFSA guidelines) receiving ARNI for ≥ 1 month with dynamic sST2 monitoring (baseline + post-treatment). Two independent reviewers performed study selection, data extraction, and risk of bias assessment (RoB-2 for RCTs; Newcastle-Ottawa Scale [NOS] for cohort studies). Heterogeneity was evaluated using the I² statistic, with fixed-effect models (I² ≤ 50%) or random-effect models (I² > 50%) for data synthesis. Sensitivity analysis and publication bias assessment (funnel plots, Egger’s test) were conducted using Stata 17.0. Results: A total of 12 studies (4 RCTs, 8 cohort studies) involving 2,863 HFpEF patients were included. Patients with a significant sST2 decrease (≥ 20% from baseline) showed a smaller decline in eGFR (mean difference [MD]  =  3.21 mL/min/1.73m², 95% CI: 1.89–4.53, I²  =  38%), greater reduction in UACR (standardized mean difference [SMD]  =  -0.57, 95% CI: -0.79 to -0.35, I²  =  45%), and more improved E/e' ratio (MD  =  -1.83, 95% CI: -2.56 to -1.10, I²  =  42%) compared to those with no significant sST2 decrease. Subgroup analysis revealed consistent results across ARNI dosages (200-400 mg/day sacubitril/valsartan) and follow-up durations (3–12 months). Sensitivity analysis confirmed the stability of outcomes, and publication bias was not detected (Egger’s test P > 0.05 for all outcomes). Conclusions: Dynamic changes in sST2 (≥ 20% reduction from baseline) reliably predict the cardiorenal protective efficacy of ARNI in HFpEF patients. Routine monitoring of sST2 may facilitate personalized HFpEF management.