Biomarkers of Mental Stress Induced Myocardial Ischemia and CHD Prognosis

描述（由申请人提供）：尽管缺血性心脏病（IIHD）的治疗取得了进展，但这种疾病的死亡率和发病率仍然很高。人们越来越认识到，心理社会压力通过各种机制促进了IHD的发展和过程。其中一种机制被认为是应激引起的生理变化导致心肌缺血。精神应激性心肌缺血（MSIMI）在IHD患者中普遍存在。MSIMI在临床上也很重要，因为它已被证明与预后不良风险增加相关，独立于传统的危险因素。MSIMI的确切生化机制尚不清楚，但有证据表明血清素能失调可能起作用。加强对MSIMI分子基础的了解将有助于开发更有效的药物治疗方法。该建议利用了NHLBI资助的REMIT研究中产生的现有数据，该研究调查了选择性5 -羟色胺再摄取抑制剂（SSRI）对MSIMI的影响。作为筛选过程的一部分，我们收集了310名患者的人口统计学、心理测量数据、心血管对精神压力的反应和血液样本，并在人群的一个子集（30名患有/不患有MSIMI的患者[N=15/每个]）中进行了代谢组学初步研究。数据显示，这两组MSIMI患者之间的代谢物存在明显差异，其中最突出的是来自色氨酸、酪氨酸和嘌呤途径的化合物。拟议的研究将通过使用两个互补的代谢组学平台分析整个REMIT人群的样本，从而扩展该试点研究的新发现。试点研究中使用的电化学平台将用于定量色氨酸、酪氨酸、嘌呤和硫氨基酸途径中的化合物，这些生物化学领域已被证明在CNS介导的应激反应研究中很重要，包括MSIMI。我们还将使用基于质谱的平台来分析中间代谢的化合物，包括氨基酸，脂肪酸，酰基肉碱和有机酸。该平台已成功应用于心脏代谢疾病的研究，并为IHD的新机制提供了见解。这些平台的输出将用于识别和验证代谢组学特征：(a)区分患有和不患有MSIMI的患者；(b)区分对艾司西酞普兰反应良好或不良的患者；(c)与不良事件相关。

DESCRIPTION (provided by applicant): Despite advancements in treating ischemic heart disease (IIHD), the mortality and morbidity rates from this disease remain high. It is becoming increasingly recognized that psychosocial stress contributes to the development and course of IHD through various mechanisms. One such mechanism is thought to be stress induced physiological changes resulting in myocardial ischemia. Mental stress induced myocardial ischemia (MSIMI) is prevalent in patients with IHD.MSIMI is also clinically important as it has been shown to be associated with increased risk of poor prognosis, independent of conventional risk factors. The precise biochemical mechanisms underlying MSIMI are poorly known, but there is evidence that serotonergic dysregulation may play a role. Enhanced knowledge of the molecular basis of MSIMI will help inform the development of more effective pharmacotherapy for its treatment. This proposal takes advantage of existing data generated through NHLBI funded REMIT study that investigated the effect of selective serotonin reuptake inhibitor (SSRI) on MSIMI. As a part of the screening process, we collected demographic, psychometric data, cardiovascular responses to mental stress, and blood samples from 310 patients, and conducted a metabolomic pilot study in a subset of the population (30 patients with/without MSIMI [N=15/each]). Data revealed several strong metabolite differences between these groups of patients with/out MSIMI, the most prominent of which involved compounds from the tryptophan, tyrosine, and purine pathways. The proposed study will expand on the novel findings of this pilot study by profiling samples from the entire REMIT population using two complementary metabolomics platforms. An electrochemistry based platform, the one used in the pilot study, will be used to quantitate compounds from the tryptophan, tyrosine, purine, and sulphur amino acid pathways, areas of biochemistry that have been shown to be important in the study CNS mediated stress responses including MSIMI. We will also use a mass spectrometry based platform to profile compounds of intermediary metabolism including amino acids, fatty acids, acylcarnitines, and organic acids. This platform has been successfully applied to the study of cardiometabolic disease and has yielded insights into novel mechanisms of IHD. The output of these platforms will be used to identify and validate metabolomic profiles that: (a) that discriminate between patients with and without MSIMI (b) discriminate between patients showing a good or a poor response to escitalopram and (c) are associated with adverse events.