Beyond Vasodilation in Pulmonary Arterial Hypertension: Integrating Remodeling-Directed Therapies into Risk-Guided Management

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Abstract
Background/Objectives: Pulmonary arterial hypertension (PAH) management is evolving beyond conventional vasoactive therapies toward strategies targeting pathways implicated in pulmonary vascular remodeling. Despite advances in combination therapy, substantial residual risk persists. The clinical introduction of sotatercept, targeting activin signaling, has expanded the therapeutic landscape. This narrative review critically evaluates the evidence supporting remodeling-directed treatment and examines how established recommendations, individualized therapeutic considerations, and investigational strategies can be distinguished within risk-guided PAH management. Methods: Clinical, translational, and mechanistic evidence was narratively synthesized, prioritizing randomized controlled trials, prospective investigations, major guidelines, and relevant mechanistic studies. Particular attention was given to differences in trial populations, endpoints, background treatment, safety, and evidence maturity. Results: Sotatercept has demonstrated incremental clinical benefits across functional, hemodynamic, and clinical-outcome measures in studied PAH populations, although trial heterogeneity limits indirect comparisons and long-term disease modification remains unproven. Other remodeling-directed approaches, including growth-factor inhibition, BMPR2 restoration, immune modulation, and metabolic targeting, remain investigational, with variable and frequently preliminary evidence. The proposed synthesis distinguishes guideline-supported therapeutic escalation from individualized clinical considerations and research hypotheses, emphasizing residual risk, treatment tolerability, and demonstrated incremental benefit. Conclusions: Remodeling-directed therapy expands the treatment options for PAH but does not replace established vasoactive treatment or risk-based escalation. Future priorities include defining optimal therapeutic sequencing, identifying responsive patient populations, and determining whether sustained clinical improvements translate into modification of disease progression.

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