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

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 benefi ts. Soluble ST2 (sST2), a biomarker of fi brosis 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 effi cacy of ARNI in HFpEF patients, as measured by changes in estimated glomerular fi ltration 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 fi xed-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 signifi cant 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 signifi cant 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 confi rmed 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 effi cacy of ARNI in HFpEF patients. Routine monitoring of sST2 may facilitate personalized HFpEF management.