Bolca Emrah, Ergün Dilek, Ergün Recai, Kanat Fikret, Ünlü Ali, Onmaz Duygu Eryavuz, Körez Muslu Kazim
Department of Pulmonary Medicine, Konya City Hospital, Konya, Türkiye.
Department of Pulmonary Medicine, Faculty of Medicine, Selçuk University, Konya, Türkiye.
Medicine (Baltimore). 2025 Aug 8;104(32):e43903. doi: 10.1097/MD.0000000000043903.
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.
在阻塞性睡眠呼吸暂停综合征（OSAS）中，由于间歇性缺氧，已观察到甲基化精氨酸衍生物水平的变化。虽然间歇性缺氧最初会增加二甲基精氨酸二甲胺水解酶（DDAH）的活性，从而降低甲基化精氨酸衍生物的水平，但长期缺氧会破坏这一机制并引发血管损伤。因此，甲基化精氨酸代谢产物在OSAS的病理生理学中起着关键作用。本研究调查了新诊断的无合并症OSAS患者中L-精氨酸-一氧化氮（NO）途径与甲基化精氨酸代谢产物——不对称二甲基精氨酸（ADMA）、对称二甲基精氨酸（SDMA）和N-单甲基-L-精氨酸（L-NMMA）之间的关系，旨在评估它们作为诊断和预后生物标志物的潜力。这项观察性病例对照研究共纳入122名参与者，包括31名健康对照者和91名OSAS患者。OSAS患者按疾病严重程度分为30例轻度、30例中度和31例重度病例。使用质谱法测量甲基化精氨酸代谢产物（ADMA、SDMA和L-NMMA）和精氨酸的血清水平。分析使用配备电喷雾电离（ESI）源并以正离子模式运行的AB Sciex API 3200三重四极杆质谱仪（美国）进行，并与岛津LC-20AD液相色谱系统（日本京都）联用。与对照组相比，OSAS患者的ADMA、L-NMMA、精氨酸和总甲基化精氨酸负荷（TMAL）水平在统计学上显著降低（P < 0.001）。各组之间的SDMA水平相似。在无合并症的OSAS患者中，TMAL的降低可能表明机体激活了代偿机制以应对与睡眠相关的间歇性缺氧。这可能反映了精氨酸途径向增强一氧化氮合成的转变，以通过血管舒张减轻缺氧诱导的血管收缩。精氨酸水平降低可能是由于利用率增加，而甲基化精氨酸衍生物（ADMA、L-NMMA）合成减少可能是这种代谢转变的结果。这些发现表明，精氨酸和甲基化精氨酸水平降低可能作为潜在的诊断标志物，并有助于识别多导睡眠图（PSG）检查的候选者，PSG检查既昂贵又耗时，从而有助于更有效地选择患者并减轻总体临床负担。
