T-cell subsets as CVD risk factors in CHS and MESA

描述(申请人提供)：在过去的50年里，与动脉粥样硬化性心血管疾病(CVD)相关的发病率和死亡率急剧下降，部分原因是风险因素的确定、相关疗法的开发、临床试验中的评估以及患者和医生对这些疗法的广泛采用。前瞻性队列研究提供了一些最可靠的证据，证明风险因素可能是疾病的原因或后果。在具有相同水平的传统危险因素的个体中，心血管疾病的风险差异很大，这种发病率差异的部分原因可能是影响动脉粥样硬化的发展和进展的内在和适应性免疫炎症反应的类型和强度的个体间差异的结果。血管生物学的进展已经确定了各种淋巴细胞亚群在称为动脉粥样硬化的慢性炎症性疾病中所起的特定作用。本研究的目的是前瞻性地评价特定淋巴细胞亚群密度是否是心肌梗死(MI)及其与新发心绞痛(Ang)的组合的新的独立危险因素。拟议的病例队列研究嵌套在心血管健康研究(CHS)和动脉粥样硬化的多种族研究(MESA)中。几项初步研究表明，来自CHS和MESA的超低温保存样品非常适合研究目标。用流式细胞术分析冷冻保存细胞(1998-99在CHS和2000-02在MESA)中的固有免疫和获得性免疫淋巴细胞，我们将分析1200名MESA和1200名CHS参与者的16个不同的淋巴细胞亚群。通过对多项检测进行调整，主要目的是评估16个淋巴细胞亚群中的每一个与两种主要结果-MI以及首次MI和新发ANG的组合的相关性。16个淋巴细胞亚群分为三组：1)高水平的促炎细胞直接参与动脉粥样硬化将增加CVD事件的风险；2)高水平的慢性适应性免疫激活将增加CVD事件的风险；以及3)高水平的具有抗动脉粥样硬化活性的抗炎细胞将降低CVD事件的风险。例如，组1中的所有T细胞亚群在动脉粥样硬化形成、斑块进展或斑块不稳定性中都有直接作用：事实上，在血管壁中，它们不是生物标记物，而是动脉粥样硬化的活性物质。在一级预防人群中拟议的病例队列研究将使我们能够评估16个淋巴细胞亚群不仅与发生的冠状动脉事件，而且与其他结果的相关性。这项研究具有很强的说服力。尽管针对免疫系统的治疗已经改善了类风湿性关节炎和癌症等严重疾病的治疗选择，但心血管医学中免疫相关疗法的开发和使用仍有待进一步发现。这项病例队列研究的结果可能会产生新的免疫靶点和新的治疗方法。

DESCRIPTION (provided by applicant): The dramatic decline in the morbidity and mortality associated with atherosclerotic cardiovascular disease (CVD) in the last 50 years is attributable in part to the identification of risk factors, the development of relevant therapies, their evaluaton in clinical trials, and the widespread adoption of those treatments by patients and physicians. Prospective cohort studies have provided some of the most reliable evidence about whether risk factors are likely to be a cause or a consequence of disease. Among individuals with the same levels of traditional risk factors, the risk of CVD varies widely, and part of this variation in evnt rates is likely to be the result of inter-individual variation in the type and intensity of the innte and adaptive- immune inflammatory responses that influence the development and progression of atherosclerosis. Advances in vascular biology have identified the specific roles that various lymphocyte subsets have in the chronic inflammatory disease called atherosclerosis. The goal of this research is to evaluate prospectively whether the densities of specific lymphocyte subsets are novel independent risk factors for the incidence of myocardial infarction (MI) and the composite of MI and new-onset angina (ANG). The proposed case- cohort study is nested within the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Several pilot studies have demonstrated that the cryopreserved samples from CHS and MESA are well suited to the study aims. Using flow cytometry to characterize the innate and adaptive-immune lymphocytes from cryopreserved cells (1998-99 in CHS and 2000-02 in MESA), we will assay 16 different lymphocyte subsets in 1200 MESA and 1200 CHS participants. With adjustment for multiple testing, the primary aim is to evaluate the association of each of the 16 lymphocyte subsets with the two primary outcomes, MI and the composite of first MI and new-onset ANG. The 16 lymphocyte subsets cluster into three groups: 1) high levels of pro-inflammatory cells with direct roles in atherosclerosis will increase the risk of CVD events 2) high levels of chronic adaptive-immune activation will increase the risk of CVD events; and 3) high levels of anti-inflammatory cells with antiatherogenic activity will decrease the risk of CVD events. All the T-cell subsets in Group 1, for instance, have a direct role in atherogenesis, plaque progression or plaque instability: indeed, in the vessel wall, they are not biomarkers, but the active agents of atherosclerosis. The proposed case-cohort study in a primary-prevention population will enable us to evaluate the associations of 16 lymphocyte subsets not only with incident coronary events but also with other outcomes. The study has excellent power. Although treatments targeting the immune system have improved the therapeutic options for serious conditions such as rheumatoid arthritis and cancer, the development and use of immune-related therapies in cardiovascular medicine awaits further discovery. Findings from this case-cohort study may yield novel immune targets and new therapeutic approaches.