Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (W.Z., X.W., D.B.H., T.W., K.A., R.C.K.).
Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China (X.W.).
Circulation. 2019 Apr 23;139(17):2003-2011. doi: 10.1161/CIRCULATIONAHA.118.037487.
Ceramides have been implicated in the pathophysiology of HIV infection and cardiovascular disease. However, no study, to our knowledge, has evaluated circulating ceramide levels in association with subclinical cardiovascular disease risk among HIV-infected individuals.
Plasma levels of 4 ceramide species (C16:0, C22:0, C24:0, and C24:1) were measured among 398 women (73% HIV+) and 339 men (68% HIV+) without carotid artery plaques at baseline from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. We examined associations between baseline plasma ceramides and risk of carotid artery plaque formation, assessed by repeated B-mode carotid artery ultrasound imaging over a median 7-year follow-up.
Plasma levels of C16:0, C22:0, and C24:1 ceramides were significantly higher in HIV-infected individuals compared with those without HIV infection (all P<0.001), and further analysis indicated that elevated ceramide levels were associated with antiretroviral therapy use, particularly protease inhibitor use, in HIV-infected individuals (all P<0.001). All 4 ceramides were highly correlated with each other ( r=0.70-0.94; all P<0.001) and significantly correlated with total-cholesterol ( r=0.42-0.58; all P<0.001) and low-density lipoprotein cholesterol ( r=0.24-0.42; all P<0.001) levels. Of note, C16:0 and C24:1 ceramides, rather than C22:0 and C24:0 ceramides, were more closely correlated with specific monocyte activation and inflammation markers (eg, r=0.30 between C16:0 ceramide and soluble CD14; P<0.001) and surface markers of CD4 T-cell activation. A total of 112 participants developed carotid artery plaques over 7 years, and higher levels of C16:0 and C24:1 ceramides were significantly associated with increased risk of carotid artery plaques (relative risk [95% CI]=1.55 [1.29, 1.86] and 1.51 [1.26, 1.82] per standard deviation increment, respectively; both P<0.001), after adjusting for demographic and behavioral factors. After further adjustment for cardiovascular disease risk factors and immune activation markers, these associations were attenuated but remained significant. The results were consistent between men and women and between HIV-infected and HIV-uninfected participants.
In 2 HIV cohorts, elevated plasma levels of C16:0 and C24:1 ceramides, correlating with immune activation and inflammation, were associated with antiretroviral therapy use and progression of carotid artery atherosclerosis.
神经酰胺已被牵涉到 HIV 感染和心血管疾病的病理生理学中。然而，据我们所知，没有研究评估过 HIV 感染者的循环神经酰胺水平与亚临床心血管疾病风险之间的关系。
在 Women's Interagency HIV Study 和 Multicenter AIDS Cohort Study 中，我们在基线时测量了 398 名女性（73%为 HIV+）和 339 名男性（68%为 HIV+）中 4 种神经酰胺（C16:0、C22:0、C24:0 和 C24:1）的血浆水平，这些人没有颈动脉斑块。我们通过中位 7 年的重复 B 型颈动脉超声成像检查，评估了基线时血浆神经酰胺与颈动脉斑块形成风险之间的关联。
与未感染 HIV 的个体相比，HIV 感染者的 C16:0、C22:0 和 C24:1 神经酰胺血浆水平明显更高（均 P<0.001），进一步的分析表明，升高的神经酰胺水平与 HIV 感染者的抗逆转录病毒治疗使用有关，特别是蛋白酶抑制剂的使用（均 P<0.001）。所有 4 种神经酰胺彼此之间高度相关（r=0.70-0.94；均 P<0.001），并且与总胆固醇（r=0.42-0.58；均 P<0.001）和低密度脂蛋白胆固醇（r=0.24-0.42；均 P<0.001）水平显著相关。值得注意的是，C16:0 和 C24:1 神经酰胺与特定的单核细胞激活和炎症标志物（例如，C16:0 神经酰胺与可溶性 CD14 之间的 r=0.30；P<0.001）和 CD4 T 细胞激活的表面标志物更为密切相关，而不是 C22:0 和 C24:0 神经酰胺。共有 112 名参与者在 7 年内出现颈动脉斑块，C16:0 和 C24:1 神经酰胺水平升高与颈动脉斑块风险增加显著相关（每标准偏差增加的相对风险[95%CI]分别为 1.55[1.29, 1.86]和 1.51[1.26, 1.82]；均 P<0.001），调整人口统计学和行为因素后仍如此。进一步调整心血管疾病危险因素和免疫激活标志物后，这些关联虽然减弱，但仍然显著。这些结果在男性和女性以及 HIV 感染者和 HIV 未感染者之间是一致的。
在 2 个 HIV 队列中，与免疫激活和炎症相关的 C16:0 和 C24:1 神经酰胺的血浆水平升高与抗逆转录病毒治疗的使用和颈动脉粥样硬化的进展有关。
