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

描述（由申请人提供）：在过去50年中，与动脉粥样硬化性心血管疾病（CVD）相关的发病率和死亡率显著下降，部分原因是风险因素的识别、相关治疗方法的开发、临床试验中的评估以及患者和医生广泛采用这些治疗方法。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还是结果。在具有相同传统危险因素水平的个体中，CVD的风险差异很大，而这种事件发生率差异的部分原因可能是影响动脉粥样硬化发生和进展的先天性和适应性免疫炎症反应的类型和强度的个体间差异。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的具体作用。本研究的目的是前瞻性评价特异性淋巴细胞亚群的密度是否为心肌梗死（MI）发生率以及MI和新发心绞痛（ANG）复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）和动脉粥样硬化多种族研究（MESA）中。几项试点研究表明，CHS和MESA的冷冻保存样本非常适合研究目的。利用流式细胞术表征来自低温保存细胞的先天和适应性免疫淋巴细胞（1998-99年的CHS和2000-02年的MESA），我们将在1200名MESA和1200名CHS参与者中检测16种不同的淋巴细胞亚群。在对多项检测进行调整后，主要目的是评估16种淋巴细胞亚群与心肌梗死和首次心肌梗死与新发ANG的组合这两个主要结局之间的关系。16个淋巴细胞亚群可分为三类：1)在动脉粥样硬化中起直接作用的高水平促炎细胞会增加CVD事件的风险；2)高水平的慢性适应性免疫激活会增加CVD事件的风险；3)具有抗动脉粥样硬化活性的高水平抗炎细胞可降低心血管疾病事件的风险。例如，第1组中的所有t细胞亚群在动脉粥样硬化、斑块进展或斑块不稳定中都有直接作用：事实上，在血管壁中，它们不是生物标志物，而是动脉粥样硬化的活性因子。在初级预防人群中提出的病例队列研究将使我们能够评估16种淋巴细胞亚群不仅与冠心病事件有关，而且与其他结果有关。该研究具有出色的动力。尽管针对免疫系统的治疗已经改善了类风湿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发现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.