Abstract Body (Do not enter title and authors here): Background: Selexipag is an established oral therapy for pulmonary arterial hypertension (PAH). In some patients, it enables withdrawal from continuous prostacyclin infusion. However, the mechanisms underlying inter-individual differences in treatment response remain unclear.
Objective: To identify clinical and molecular determinants associated with selexipag responsiveness in patients with PAH.
Methods: We evaluated 21 patients aged ≥16 years with PAH who received selexipag at Hokkaido University Hospital between 2021 and 2024. Patients who had undergone lung transplantation, were on hemodialysis, or initiated selexipag concurrently with other vasodilators were excluded; 15 patients remained eligible. Clinical data—including NYHA class, right heart catheterization, 6-minute walk distance, cardiac MRI, and echocardiography—were collected before and after treatment. Based on composite improvement in these measures, patients were classified into responder (n = 8) and non-responder (n = 7) groups. Whole-exome sequencing and plasma metabolomics profiling (CE-TOFMS and LC-TOFMS) were conducted, targeting 281 ionic and 189 lipid metabolites. Statistical analyses included t-tests, chi-square tests, and Fisher’s exact tests (p < 0.05). For metabolite comparisons, Wilcoxon rank sum tests were performed, and p-values were adjusted using the Benjamini–Hochberg method to control the false discovery rate (adjusted p < 0.1). This study was approved by the institutional ethics committee (No. 023-0073).
Results: A pathogenic ACVRL1 variant was identified in one non-responder. Rare variants in PTGIS (n = 1) and RNF213 (n = 2) were found in non-responders, and one RNF213 variant was found in a responder. Acylcarnitine levels were significantly higher in responders than in non-responders (adjusted p = 0.088). The rs1799821 AA genotype in CPT2 was significantly more frequent in responders (p = 0.003). Upstream metabolic pathway analysis revealed downregulation of ATP citrate lyase (p = 0.004) and fatty acid synthase (p = 0.026), and upregulation of CPT1C (p = 0.005) in responders.
Conclusion: The rs1799821 AA genotype in CPT2 may contribute to impaired mitochondrial fatty acid oxidation and suppressed endogenous prostacyclin production, potentially leading to increased responsiveness to selexipag. Altered expression of ATP citrate lyase, fatty acid synthase, and CPT1C may further affect lipid metabolism and contribute to inter-individual variability in treatment response.