We have previously shown that circulating levels of tetrahydrobiopterin (HB) function as a robust biomarker for aortic aneurysms in several independent animal models. In the present study, we examined diagnostic and predictive values of circulating HB levels in human patients of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) for the first time, while clinically applicable biomarkers for aortic aneurysms have never been previously available. Ninety-five patients scheduled for TAA repair surgeries and 53 control subjects were recruited at University of California Los Angeles (UCLA) Ronald Regan Medical Center, while 44 control subjects and 29 AAA patients were recruited through National Institute of Health (NIH) National Disease Research Interchange (NDRI) program. We had intriguing observations that circulating HB levels were substantially lower in TAA and AAA patients, linearly correlated with aortic HB levels (blood: R = 0.8071, p < 0.0001, n = 75; plasma: R = 0.7983, p < 0.0001, n = 75), and associated with incidence of TAA (blood: adjusted OR 0.495; 95% CI 0.379–0.647; p < 0.001; plasma: adjusted OR 0.501; 95% CI 0.385–0.652; p < 0.001) or AAA (blood: adjusted OR 0.329; 95% CI 0.125–0.868; p = 0.025) after adjustment for other factors. Blood or plasma HB levels below 0.2 pmol/μg serve as an important threshold for prediction of aortic aneurysms independent of age and gender (for TAA risk - blood: adjusted OR 419.67; 95% CI 59.191–2975.540; p < 0.001; plasma: adjusted OR 206.11; 95% CI 40.956–1037.279; p < 0.001). This threshold was also significantly associated with incidence of AAA (p < 0.001 by Chi-square analysis). In addition, we observed previously unrecognized inverse association of Statin use with TAA, and an association of AAA with arrhythmia. Taken together, our data strongly demonstrate for the first time that circulating HB levels can serve as a first-in-class, sensitive, robust and independent biomarker for clinical diagnosis and prediction of TAA and AAA in human patients, which can be rapidly translated to bedside to fundamentally improve clinical management of the devastating human disease of aortic aneurysms.

中文翻译：

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循环四氢生物蝶呤水平作为胸腹主动脉瘤患者新型生物标志物的诊断和预测价值


我们之前已经在几个独立的动物模型中证明，四氢生物蝶呤（HB）的循环水平可以作为主动脉瘤的强有力的生物标志物。在本研究中，我们首次检查了胸主动脉瘤（TAA）和腹主动脉瘤（AAA）人类患者循环HB水平的诊断和预测价值，而临床上适用的主动脉瘤生物标志物以前从未获得过。加州大学洛杉矶分校 (UCLA) 罗纳德·里根医学中心招募了 95 名计划进行 TAA 修复手术的患者和 53 名对照受试者，同时通过美国国立卫生研究院 (NIH) 国家疾病研究所招募了 44 名对照受试者和 29 名 AAA 患者交换 (NDRI) 计划。我们有有趣的观察结果，TAA 和 AAA 患者的循环 HB 水平显着降低，与主动脉 HB 水平线性相关（血液：R = 0.8071，p < 0.0001，n = 75；血浆：R = 0.7983，p < 0.0001，n = 75)，并与 TAA 的发生率相关（血液：调整后 OR 0.495；95% CI 0.379–0.647；p < 0.001；血浆：调整后 OR 0.501；95% CI 0.385–0.652；p < 0.001）或 AAA（血液：调整后调整其他因素后，OR 0.329；95% CI 0.125–0.868；p = 0.025。血液或血浆 HB 水平低于 0.2 pmol/μg 是预测主动脉瘤的重要阈值，与年龄和性别无关（对于 TAA 风险 - 血液：调整后 OR 419.67；95% CI 59.191–2975.540；p < 0.001；血浆：调整后OR 206.11；95% CI 40.956–1037.279；p < 0.001）。该阈值也与 AAA 的发生率显着相关（卡方分析 p < 0.001）。 此外，我们观察到以前未被认识到的他汀类药物使用与 TAA 的负相关性，以及 AAA 与心律失常的相关性。总而言之，我们的数据首次强有力地证明，循环 HB 水平可以作为人类患者 TAA 和 AAA 临床诊断和预测的一流、敏感、稳健和独立的生物标志物，并且可以快速转化为床边从根本上改善主动脉瘤这一毁灭性人类疾病的临床管理。