Introduction: ACVRL1 (ALK1) mutations are critical drivers of pulmonary hypertension, significantly influencing endothelial dysfunction and vascular remodeling. Despite its clinical importance, the precise prognostic impact of ALK1 on disease progression remains insufficiently characterized across diverse populations. This systematic review aims to evaluate the prognostic role of ACVRL1/ALK1 in the development and outcomes of pulmonary hypertension.

Material and methods: This systematic review was conducted according to PRISMA guidelines to evaluate the prognostic role of ACVRL1/ALK1 in pulmonary hypertension. Eligible human studies were systematically identified from international and national databases, screened against predefined inclusion and exclusion criteria, and assessed for methodological quality. Data on study characteristics, sample size, mutation status, hemodynamic parameters, disease progression, survival, and clinical outcomes were extracted using a standardized approach.

Results: Synthesis of 11 studies (n=11; cohort, case-control, and genetic designs) confirms that ACVRL1/ALK1 mutations independently correlate with earlier disease onset and accelerated clinical decline. Carriers exhibited significantly worse hemodynamic profiles (e.g., higher pulmonary arterial pressures) and increased right ventricular strain compared to non-carriers. Qualitative synthesis indicates higher risk stratification scores and diminished survival rates, underscoring ACVRL1 as a pivotal genetic determinant of aggressive pulmonary hypertension phenotypes and poor clinical outcomes.

Conclusion: ACVRL1/ALK1 mutations serve as a critical prognostic biomarker in pulmonary hypertension, identifying a high-risk cohort characterized by early-onset disease and rapid hemodynamic deterioration. Incorporating ACVRL1 genotyping into clinical risk stratification is essential for optimizing surveillance and initiating aggressive, personalized therapeutic interventions. Future prospective multicenter trials are necessary to refine genotype-specific survival estimates and standardize long-term management protocols for this vulnerable patient population.