Boyd Anders, Boccara Franck, Meynard Jean-Luc, Ichou Farid, Bastard Jean-Philippe, Fellahi Soraya, Samri Assia, Sauce Delphine, Haddour Nabila, Autran Brigitte, Cohen Ariel, Girard Pierre-Marie, Capeau Jacqueline
Inserm UMR_S1136, Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Paris, France.
Department of Cardiology, AP-HP, Hôpital Saint-Antoine, Paris, France.
Open Forum Infect Dis. 2019 Dec 6;6(12):ofz516. doi: 10.1093/ofid/ofz516. eCollection 2019 Dec.
HIV-infected individuals undergoing effective antiretroviral therapy (ART) present an increased risk of atherosclerotic cardiovascular disease. We identified serum metabolites associated with carotid intima-media thickness (c-IMT) and its evolution.
One hundred forty-three hydrophilic serum metabolites were measured by ultraperformance liquid chromatography coupled with high-resolution mass spectrometry in 49 HIV+ ART+, 48 HIV+ ART-naïve and 50 HIV-negative, age-matched, never-smoking male triads. Metabolites differentially altered between groups ("features") were defined as having a Benjamini-Hochberg-adjusted value <.05 from a test and >0.25 log absolute mean fold change in metabolite levels. c-IMT was measured across 12 sites at inclusion in all individuals and at the carotid artery (cca) after a median of 5.1 years in 32 HIV+ ART+ individuals. The difference in c-IMT (cross-sectional analysis) and slope of cca-IMT regression/progression per year (longitudinal analysis) for each log (area) increase in metabolite level were estimated with linear regression.
Compared with HIV-, metabolite features of HIV+ ART+ were increased N6,N6,N6-trimethyl-L-lysine and decreased ferulate and 5-hydroxy-L-tryptophan, whereas features of HIV+ ART-naïve were increased malate, kynurenine, 2-oxoglutarate, and indole-3-acetate and decreased succinate and 5-hydroxy-L-tryptophan. In HIV+ ART+ individuals, quinolinate and/or indole-3-acetate were positively associated with c-IMT (.03), cca-IMT (.03), and cca-IMT progression (.008). These associations were not observed in HIV+ ART-naïve or HIV-negative individuals. In HIV+ ART+ individuals, the metabolites xanthosine and uridine, from nucleotide metabolism, and g-butyrobetaine, from lysine/dietary choline degradation, were also positively or negatively associated with c-IMT and/or cca-IMT (all .01), but not its evolution.
In these highly selected HIV-positive ART-controlled males, 2 novel metabolites derived from tryptophan catabolism, indole-3-acetate and quinolinate, were associated with c-IMT and its progression.
接受有效抗逆转录病毒疗法（ART）的HIV感染者患动脉粥样硬化性心血管疾病的风险增加。我们确定了与颈动脉内膜中层厚度（c-IMT）及其演变相关的血清代谢物。
采用超高效液相色谱-高分辨率质谱法测定了49例HIV+ ART+、48例HIV+未接受ART治疗以及50例年龄匹配、从不吸烟的HIV阴性男性三组人群中的143种亲水性血清代谢物。组间差异改变的代谢物（“特征”）定义为经Benjamini-Hochberg校正的P值<0.05（来自t检验）且代谢物水平的绝对平均倍数变化>0.25 log。在所有个体入组时在12个部位测量c-IMT，在32例HIV+ ART+个体中，中位随访5.1年后在颈动脉（cca）测量。代谢物水平每增加一个对数（面积），通过线性回归估计c-IMT的差异（横断面分析）和cca-IMT回归/进展的斜率（纵向分析）。
与HIV阴性者相比，HIV+ ART+者的代谢物特征为N6,N6,N6-三甲基-L-赖氨酸增加，阿魏酸和5-羟基-L-色氨酸减少，而HIV+未接受ART治疗者的特征为苹果酸、犬尿氨酸、2-氧代戊二酸和吲哚-3-乙酸增加，琥珀酸和5-羟基-L-色氨酸减少。在HIV+ ART+个体中，喹啉酸和/或吲哚-3-乙酸与c-IMT（P=0.03）、cca-IMT（P=0.03）和cca-IMT进展（P=0.008）呈正相关。在HIV+未接受ART治疗者或HIV阴性个体中未观察到这些关联。在HIV+ ART+个体中，核苷酸代谢产生的代谢物黄苷和尿苷以及赖氨酸/膳食胆碱降解产生的γ-丁甜菜碱也与c-IMT和/或cca-IMT呈正相关或负相关（均P<0.01），但与c-IMT的演变无关。
在这些经过高度选择的HIV阳性且ART控制良好的男性中，2种源自色氨酸分解代谢的新型代谢物，吲哚-3-乙酸和喹啉酸，与c-IMT及其进展相关。
