A second-hit conceptual framework for pulmonary arterial hypertension in adult congenital heart disease: genetics, hemodynamics, and treat-and-repair.

Pulmonary arterial hypertension (PAH) complicates a clinically important subset of adult congenital heart disease (ACHD) and contributes to substantial morbidity and premature mortality. This narrative review synthesizes direct and indirect evidence within a second-hit conceptual framework for ACHD-associated PAH. In this framework, baseline pulmonary vascular susceptibility interacts over time with sustained hemodynamic or hypoxemic exposure and with superimposed biological or clinical stressors. SOX17 has the clearest direct genetic association with ACHD-PAH, whereas evidence involving BMPR2-related metabolic, inflammatory, and proliferative pathways is derived predominantly from heritable PAH, broader PAH populations, and experimental models. Experimental and computational studies also suggest that disturbed flow and mechanobiological signaling may contribute to endothelial dysfunction and endothelial-to-mesenchymal transition, although these mechanisms have not been established as a causal sequence in longitudinal ACHD cohorts. Four-dimensional flow magnetic resonance imaging and cardiopulmonary exercise testing may characterize abnormal flow patterns and impaired pulmonary vascular reserve in research settings, but neither is validated for screening patients with borderline ACHD hemodynamics or for selecting therapy. Evidence supporting treat-and-repair remains observational and defect-specific, with the most developed adult data derived from carefully selected patients with atrial septal defects; these findings should not be extrapolated directly to ventricular septal defects, patent ductus arteriosus, or complex congenital heart disease. Fontan physiology is considered separately as a low-flow, low-reserve pulmonary vascular state rather than as classical high-pressure PAH. The principal contribution of this review is to organize heterogeneous evidence according to its directness, distinguish established clinical practice from investigational approaches, and identify priorities for prospective validation. The second-hit framework should therefore be interpreted as a hypothesis-generating conceptual synthesis rather than as a validated diagnostic or therapeutic algorithm.