Effect of Sotatercept on Right Ventricular-Pulmonary Arterial Coupling in Pulmonary Hypertension

BACKGROUND: Right ventricular failure is the proximate cause of death in pulmonary hypertension (PH). No approved therapy had restored right ventricular-pulmonary arterial (RV-PA) coupling across WHO Group 1 and Group 2 PH before sotatercept. TAPSE/sPAP carries independent prognostic significance (HR 1.87/unit decrease, 95% CI 1.35-2.59; p<0.001) and is a 2022 ESC/ERS risk-stratification criterion. Whether sotatercept restores coupling mechanistically across divergent PH phenotypes had not been formally examined. METHODS: Systematic review of MEDLINE, Embase, Cochrane CENTRAL, Scopus, ClinicalTrials.gov through March 2026. Eligible: placebo-controlled RCTs reporting echocardiographic TAPSE/sPAP with sotatercept at 24 weeks. Effect estimates from published tables (STELLAR: ANCOVA; CADENCE: Hodges-Lehmann) or WebPlotDigitizer v5+Wan 2014 conversion (PULSAR). Pooled via inverse-variance random-effects model (DerSimonian-Laird). Pre-specified sensitivity analysis excluded CADENCE. Dual-reviewer extraction and ROB 2.0 bias assessment were performed. RESULTS Three RCTs, 509 patients: PULSAR (WHO Group 1, Phase 2; n=106), STELLAR post-hoc (Group 1, Phase 3; n=275/323), CADENCE (WHO Group 2 CpcPH-HFpEF, Phase 2; n=164). Baseline TAPSE/sPAP 0.23-0.32 mm/mmHg across all trials, within the intermediate-risk zone (<0.19 high; >0.32 low risk, 2022 ESC/ERS). Pooled estimate: +0.14 mm/mmHg (95% CI 0.11-0.16; p<0.001; I2=0%; Q=2.26, df=3; t2=0). TAPSE unchanged in all arms (all NS). sPAP fell 18-28 mmHg vs near-zero placebo change (STELLAR -18.52 mmHg, p<0.0001; CADENCE 0.3 mg/kg -18.59 mmHg; CADENCE 0.7 mg/kg -27.86 mmHg). PULSAR: directional PASP reduction (Figure 2). Sensitivity analysis (PULSAR+STELLAR): +0.133 mm/mmHg (95% CI 0.105-0.161; I2=29%), confirming robustness. CONCLUSIONS Sotatercept improves RV-PA coupling by +0.14 mm/mmHg (95% CI 0.11-0.16; p<0.001; I2=0%) across three RCTs spanning WHO Groups 1 and 2. Preserved TAPSE with profound sPAP reduction establishes afterload reduction as the exclusive mechanism, distinct from all approved vasodilators. Baseline TAPSE/sPAP rises to 0.42 mm/mmHg, crossing the validated low-risk threshold >0.32 mm/mmHg associated with mortality HR 1.87 and improved 3-year event-free survival (n=659). I2=0% across populations differing by 25 years in age and 12 mmHg in PAWP establishes a population-agnostic class effect. Sotatercept is the first therapy shown to restore RV-PA coupling to a low-risk echocardiographic threshold across WHO Group 1 PAH and Group 2 CpcPH-HFpEF through reversal of afterload excess, providing mechanistic context for survival benefit.