The diagnostic and prognostic significance of methylated arginine metabolites (ADMA, SDMA, L-NMMA) in patients with obstructive sleep apnea syndrome

Abstract

In obstructive sleep apnea syndrome (OSAS), changes in the levels of methylated arginine derivatives have been observed due to intermittent hypoxia. While intermittent hypoxia initially increases the activity of the enzyme dimethylarginine dimethylaminohydrolase (DDAH), thereby reducing the levels of methylated arginine derivatives, prolonged hypoxia can disrupt this mechanism and trigger vascular damage. Therefore, methylated arginine metabolites play a critical role in the pathophysiology of OSAS. This study investigates the relationship between the L-arginine-nitric oxide (NO) pathway and methylated arginine metabolites-asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethyl-L-arginine (L-NMMA)-in newly diagnosed OSAS patients without comorbidities, aiming to evaluate their potential as diagnostic and prognostic biomarkers. This observational case-control study included a total of 122 participants, consisting of 31 healthy controls and 91 patients with OSAS. OSAS patients were stratified by disease severity into 30 mild, 30 moderate, and 31 severe cases. Serum levels of methylated arginine metabolites (ADMA, SDMA, and L-NMMA) and arginine were measured using mass spectrometry. The analyses were performed with an AB Sciex API 3200 triple quadrupole mass spectrometer (USA) equipped with an electrospray ionization (ESI) source operating in positive ion mode, coupled to a Shimadzu LC-20AD liquid chromatography system (Kyoto, Japan). Compared to the control group, OSAS patients showed statistically significant lower levels of ADMA, L-NMMA, arginine, and total methylated arginine load (TMAL) (P < .001). SDMA levels were similar across groups. In OSAS patients without comorbidities, a reduction in TMAL may suggest the activation of compensatory mechanisms in response to sleep-related intermittent hypoxia. This could reflect a shift in the arginine pathway towards enhanced nitric oxide synthesis to mitigate hypoxia-induced vasoconstriction through vasodilation. The reduced arginine levels are likely due to increased utilization, while diminished synthesis of methylated arginine derivatives (ADMA, L-NMMA) may result from this metabolic shift. These findings imply that decreased arginine and methylated arginine levels may serve as potential diagnostic markers and could aid in identifying candidates for polysomnography (PSG), which is both costly and time-consuming, thereby contributing to more efficient patient selection and reducing the overall clinical burden.

Keywords: ADMA; L-NMMA; NO; OSAS; SDMA; TMAL; intermittent hypoxia.

Figure 1.

STROBE flow diagram showing the inclusion and stratification of all 122 participants in the study. All patients who applied to the PSG (polysomnography) clinic were evaluated. Screening was performed to identify patients with exclusion criteria including central sleep apnea, abnormal laboratory findings (e.g., hemoglobin, liver/kidney/thyroid function, homocysteine, folic acid), and comorbid conditions (e.g., cardiovascular disease, diabetes, hypertension, obesity). Patients without exclusion criteria were deemed eligible and included in the study. Participants were allocated to a control group (n = 31) or an OSAS group (n = 91), with the OSAS group further stratified by severity into mild (n = 30), moderate (n = 30), and severe (n = 31). OSAS = obstructive sleep apnea syndrome.

Figure 2.

The boxplot of methylated arginine metabolites–asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethyl-L-arginine (L-NMMA)–and arginine, and total methylated arginine load (TMAL) parameters in study groups.