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。越来越多的人认识到，心理社会压力通过各种机制促进了IHD的发展和进程。一种这样的机制被认为是导致心肌缺血的应激诱导的生理变化。精神应激诱发的心肌缺血（MSIMI）在IHD患者中很常见，MSIMI在临床上也很重要，因为它已被证明与预后不良的风险增加有关，与传统的风险因素无关。MSIMI的确切生化机制知之甚少，但有证据表明，多巴胺能失调可能发挥作用。增强对MSIMI分子基础的了解将有助于开发更有效的药物治疗。该提案利用了NHLBI资助的REMIT研究产生的现有数据，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例患者的人口统计学、心理测量学数据、心血管对精神压力的反应和血液样本，并在一个亚组人群（30例有/无MSIMI [N=15/例]）中进行了代谢组学初步研究。数据显示，这些MSIMI/非MSIMI患者组之间存在几种强烈的代谢物差异，其中最突出的涉及来自色氨酸、酪氨酸和嘌呤途径的化合物。这项拟议的研究将通过使用两个互补的代谢组学平台对整个REMIT人群的样本进行分析来扩展这项试点研究的新发现。基于电化学的平台（用于初步研究）将用于定量色氨酸、酪氨酸、嘌呤和含硫氨基酸途径的化合物，这些生物化学领域已被证明在研究CNS介导的应激反应（包括MSIMI）中很重要。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、酰基肉毒碱和有机酸。该平台已成功应用于心脏代谢疾病的研究，并对IHD的新机制产生了深刻的见解。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和（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.