Compliance and Genetic Variability Are Determinants of the Success of <scp>l</scp> -Arginine/ <scp>l</scp> -Citrulline Supplementation in High Altitude—A Pilot Study

00:00-00, 2026. BACKGROUND: Asymmetric dimethylarginine (ADMA) is a risk biomarker of high-altitude pulmonary hypertension (HAPH). ADMA is inactivated by dimethylarginine dimethylaminohydrolase (DDAH)1 and 2. Single nucleotide polymorphisms in these genes contribute to genetic predisposition for HAPH. Supplementation with l-arginine may reverse ADMA's inhibitory effect and, thus, HAPH. We conducted a pilot study to test whether supplementation with l-arginine/l-citrulline (A/C) during chronic intermittent hypoxia (CIH) limits the increase in pulmonary arterial pressure (PAP) as compared to placebo. METHODS: Twenty male volunteers were randomly assigned to receive 6 months of A/C or placebo; PAP was assessed by echocardiography. RESULTS: l-Arginine increased in the A/C group at month 1, which subsided until month 6 due to poor compliance with the study supplement. Individuals with 2 or more alleles of a previously described DDAH1/2 haplotype showed a higher increase in ADMA during CIH. A/C caused a trend toward a diminished increase in PAP. However, these findings should be interpreted as exploratory, consistent with the low adherence to treatment in this pilot study. The increase in l-arginine blood levels was attenuated in carriers of a previously described ARG1/2 haplotype. CONCLUSION: Our data show that A/C supplementation may offer an opportunity to alleviate the altitude-induced increase in PAP; however, long-term compliance and genetic factors may affect outcome.