Circulating levels of Persistent Organic Pollutants and Subclinical Atherosclerosis progression in Postmenopausal women

摘要 心血管疾病(CVD)是美国和全球女性死亡的主要原因。更年期 更年期显著增加了患心血管疾病的风险，使绝经后妇女成为特殊人群 请注意。人们越来越关注环境化学品的暴露，尤其是持续性的 有机污染物(POPs)，扰乱人类内分泌环境，对心血管健康造成不利影响。这个 持久性有机污染物在一生中的生物积累会导致重大的长期健康影响，特别是在老年人中 人口。然而，POPS对亚临床动脉粥样硬化进展的长期影响，早期 CVD的病理特征，在绝经后妇女中尚未得到很好的研究。此外，持久性有机污染物的影响 在美国人群中还没有对动脉粥样硬化的进展进行评估。据我们所知，没有纵向的 已经进行了研究，以调查POP混合物和动脉粥样硬化进展的影响。唯一的 一项纵向研究，报告了一类特定类别的持久性有机污染物、全氟烷基和多氟烷类物质的不良影响 (PFASs)，关于10年来颈动脉内膜-中层厚度(IMT，超声)增加的研究来自一名瑞典人 高年级组。为了填补我们理解上的空白，我们将研究血浆的长期联系 绝经后妇女中POPs浓度和动脉粥样硬化进展的独特队列；早期与 雌激素(ELITE)对亚临床颈动脉5年纵向测量的晚期干预试验 动脉粥样硬化，包括金标准超声测量(IMT、回声和僵硬)和冷冻 分析来自四个主要类别(多氯化)的60种持久性有机污染物的绝对浓度的血浆样本 多氯联苯、多溴联苯醚、有机氯农药以及 (全氟丙烷)。Elite是一项随机临床试验，包括596项早期(绝经后6年)和晚期(≥10年)的临床试验 绝经后妇女5年内动脉粥样硬化进展率比较 在随机接受激素治疗(HT)和安慰剂的女性之间。超越了调查影响的目标 关于POP混合物对动脉粥样硬化进展的影响，我们将调查POP混合物对危险因素的影响 动脉粥样硬化包括代谢(血脂、血糖、糖化血红蛋白和胰岛素抵抗)和炎症 生物标志物。重要的协变量包括设计因素(羟色胺和安慰剂，绝经早期和晚期 在分析中，肥胖、吸烟、饮食和体力活动将被调整。要评估 POP暴露的不良影响在绝经后妇女不同亚组中的概括性，我们 将在随机接受高血压和高血压治疗的妇女亚组中评估POPS与动脉粥样硬化进展的相关性 安慰剂，以及绝经后早期和晚期组。这项研究将为长期研究提供重要的证据。 POP合剂对动脉粥样硬化进展及相关代谢和炎症的长期效应 心血管疾病高危绝经后妇女的病理生理学研究。这项研究的发现将会有所帮助 确定持久性有机污染物的关键个体和亚群，作为监管、补救和预防心血管疾病的目标。

ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in women in the US and globally. Menopausal transition poses remarkably elevated risk of CVD making postmenopausal women a population of special attention. There is an increasing concern about the exposure to environmental chemicals, particularly persistent organic pollutants (POPs), that disrupt human endocrine milieu and adversely affect cardiovascular health. The bioaccumulation of POPs over lifetime induces significant long-term health impact, especially among older population. However, the long-term effect of POPs on subclinical atherosclerosis progression, an early pathological feature of CVD, has not been studied well in postmenopausal women. In addition, the effect of POPs on atherosclerosis progression has not been evaluated in the US population. To our knowledge, no longitudinal study has been conducted to investigate the effects of POP mixtures and atherosclerosis progression. The only longitudinal study reporting an adverse effect of a specific class of POPs, per- and polyfluoroalkyl substances (PFASs), on increased carotid intima-media thickness (IMT, ultrasound) over 10 years was from a Swedish senior cohort. To fill the gaps in our understanding, we will investigate the long-term associations of plasma POPs concentrations and atherosclerosis progression in postmenopausal women in a unique cohort; Early vs Late Intervention Trial with Estradiol (ELITE) with 5-year longitudinal measurements of subclinical carotid atherosclerosis including gold-standard ultrasound measures (IMT, echogenicity, and stiffness) and frozen plasma samples to analyze absolute concentrations of 60 POPs from four main classes (polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorinated pesticides (OCPs), and (PFASs). ELITE is a randomized clinical trial including 596 early (<6years since menopause) and late (≥10years since menopause) postmenopausal women comparing rates of atherosclerosis progression over 5 years between women randomized to hormone therapy (HT) and placebo. Beyond the goal of investigating the effect of POP mixtures on atherosclerosis progression, we will investigate the impact of POP mixtures on risk factors of atherosclerosis including metabolic (lipids, glucose, HbA1c, and insulin resistance) and inflammatory biomarkers. Important covariates including the design factors (HT and placebo, early and late-postmenopausal groups), obesity, smoking, diet, and physical activity will be adjusted for in the analysis. To assess the generalizability of the adverse effect of POP exposure across various subgroups of postmenopausal women, we will evaluate POPs’ associations with atherosclerosis progression in subgroups of women randomized to HT and placebo, as well as early and late postmenopausal groups. This study will provide important evidence on long- term effect of POP mixtures on atherosclerosis progression and related metabolic and inflammatory pathophysiology among postmenopausal women who are at high risk of CVD. Findings from this study will help identify key individual and subgroups of POPs as targets for regulations, remediations, and CVD prevention.