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 过渡期会显著增加心血管疾病的风险，使绝经后妇女成为一个特殊的人群， 关注人们越来越关注对环境化学品的接触，特别是持久性 有机污染物（POP），破坏人体内分泌环境，对心血管健康产生不利影响。的 持久性有机污染物在整个生命周期内的生物累积会对健康产生重大的长期影响，特别是在老年人中 人口然而，持久性有机污染物对亚临床动脉粥样硬化进展的长期影响， 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 尚未在美国人群中评估动脉粥样硬化进展。据我们所知，没有纵向 已经进行了一项研究来调查POP混合物和动脉粥样硬化进展的影响。唯一的 报告特定类别持久性有机污染物、全氟烷基和多氟烷基物质的不利影响的纵向研究 （PFAS），增加颈动脉内膜中层厚度（IMT，超声）超过10年，来自瑞典 高年级学生为了填补我们理解的空白，我们将研究血浆中的长期关联， 绝经后妇女中持久性有机污染物浓度和动脉粥样硬化进展的一个独特队列;早期vs 采用5年纵向测量亚临床颈动脉的Eclamping晚期干预试验（ELITE） 动脉粥样硬化，包括金标准超声测量（IMT，回声和硬度）和冷冻 血浆样本，以分析来自四个主要类别（多氯化物）的60种持久性有机污染物绝对浓度 联苯（PCB）、多溴联苯醚（PBDEs）、有机氯农药（OCPs），以及 （PFASs）。ELITE是一项随机临床试验，包括596例早期（绝经后<6年）和晚期（绝经后≥ 10年）患者 绝经后妇女比较5年内动脉粥样硬化进展率 随机接受激素治疗（HT）和安慰剂治疗的女性之间的差异。除了调查影响的目标之外 POP混合物对动脉粥样硬化进展的影响，我们将研究POP混合物对危险因素的影响 动脉粥样硬化包括代谢（脂质，葡萄糖，HbA 1c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（HT和安慰剂，绝经早期和晚期 组），肥胖，吸烟，饮食和体力活动将在分析中进行调整。评估 在绝经后妇女的不同亚组中，POP暴露的不良反应的普遍性，我们 将在随机接受HT的女性亚组中评估POP与动脉粥样硬化进展的相关性， 安慰剂，以及早期和晚期绝经后组。这项研究将为长期- POP混合物对动脉粥样硬化进展及相关代谢和炎症的长期影响 绝经后妇女中CVD高风险的病理生理学。这项研究的结果将有助于 确定持久性有机污染物的主要个体和亚群，作为管制、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.