Böger Rainer H, Sullivan Lisa M, Schwedhelm Edzard, Wang Thomas J, Maas Renke, Benjamin Emelia J, Schulze Friedrich, Xanthakis Vanessa, Benndorf Ralf A, Vasan Ramachandran S
Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Circulation. 2009 Mar 31;119(12):1592-600. doi: 10.1161/CIRCULATIONAHA.108.838268. Epub 2009 Mar 16.
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated.
We related plasma ADMA, l-arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence (P>0.10).
In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.
不对称二甲基精氨酸（ADMA）是一氧化氮合酶的内源性抑制剂，可导致内皮功能障碍。尽管在转诊样本中，ADMA升高与心血管疾病事件和死亡风险增加相关，但ADMA在社区中的预后意义尚未得到充分评估。
我们将3320名弗雷明汉后代研究参与者（1769名女性；平均年龄59岁）的血浆ADMA、L-精氨酸（Arg）以及Arg与ADMA的比值与心血管疾病（致命或非致命性心肌梗死、冠状动脉供血不足、心绞痛、中风或短暂性脑缺血发作、间歇性跛行或心力衰竭）和死亡的发生率进行关联分析。在10.9年的随访期内，2956名基线时无心血管疾病的个体中有281人发生了心血管疾病，285名参与者死亡。在调整了既定风险因素和其他生物标志物（B型利钠肽、肾素、同型半胱氨酸、尿白蛋白排泄和C反应蛋白）的多变量模型中，ADMA以及Arg与ADMA的比值与全因死亡率显著相关（每增加1个标准差的调整后风险比[HR]分别为1.21；95%CI，1.07至1.37；以及每增加1个标准差的HR为0.80；95%CI，0.69至0.93），而Arg则不然（每增加1个标准差的HR为0.89；95%CI，0.77至1.02）。我们注意到糖尿病状态存在效应修饰作用；ADMA与无糖尿病个体的死亡相关（每增加1个标准差的调整后HR为1.30；95%CI，1.13至1.50），但与糖尿病个体的死亡无关（每增加1个标准差的调整后HR为0.85；95%CI，0.62至1.16）。ADMA、Arg以及Arg与ADMA的比值与心血管疾病发生率无关（P>0.10）。
在我们这个基于社区的大样本中，ADMA与全因死亡率显著相关，尤其是在非糖尿病个体中。
