Biomarkers of Mental Stress Induced Myocardial Ischemia and CHD Prognosis

精神压力引起的心肌缺血和冠心病预后的生物标志物

• 批准号: 8696550
• 负责人: WEI JIANG
• 金额: $ 60.54万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696550
• 关键词: 5-Hydroxytryptophan; Adverse event; Aftercare; Amino Acids; Area; Biochemical; Biochemical Pathway; Biochemistry; Biological Markers; Blood specimen; Branched-Chain Amino Acids; Cardiac; Cardiovascular system; Cessation of life; Clinical Trials; Data; Development; Disease; Electrochemistry; Enrollment; Escitalopram; Event; Excitatory Amino Acids; Fatty Acids; Funding; Future; Heart Diseases; Homovanillic Acid; Hydroxyindoleacetic Acid; Intervention; Knowledge; Kynurenine; Left Ventricular Function; Levodopa; Mass Spectrum Analysis; Mediating; Melatonin; Metabolic; Metabolism; Methionine; Molecular; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Names; National Heart, Lung, and Blood Institute; Output; Participant; Pathway interactions; Patients; Pharmacotherapy; Phase; Physiological; Pilot Projects; Placebos; Play; Population; Procedures; Process; Psyche structure; Psychometrics; Psychosocial Stress; Purines; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Selective Serotonin Reuptake Inhibitor; Serotonin; Serum; Stress; Stress Tests; Sulfur Amino Acids; Technology; Testing; Tryptophan; Tyrosine; Unstable angina; Uric Acid; Variant; Vital Status; Work; acylcarnitine; base; biological adaptation to stress; cohort; defined contribution; follow-up; improved; insight; metabolomics; mortality; novel; novel therapeutic intervention; organic acid; outcome forecast; public health relevance; purine; response; screening; therapeutic target

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.

描述（由申请人提供）：尽管治疗缺血性心脏病（IIHD）方面取得了进步，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，社会心理压力通过各种机制有助于IHD的发展和过程。一种这种机制被认为是压力引起的生理变化，导致心肌缺血。心理压力诱导的心肌缺血（MSIMI）在IHD.MSIMI患者中普遍存在临床上很重要，因为已证明它与预后不良的风险增加有关，而与常规危险因素无关。 MSIMI的确切生化机制是鲜为人知的，但有证据表明5-羟色胺能力障碍可能起作用。增强对MSIMI分子基础的知识将有助于告知开发更有效的药物治疗。该提案利用了通过NHLBI资助的ROMIT研究产生的现有数据，该研究研究了选择性5-羟色胺再摄取抑制剂（SSRI）对MSIMI的影响。作为筛查过程的一部分，我们收集了人口统计学，心理测量数据，对精神压力的心血管反应以及来自310名患者的血液样本，并在一部分人群中进行了代谢小组试验研究（30名患有/不含MSIMI的患者[n = 15/每个））。数据显示，这些/OUT/OUT MSIMI的患者组之间有几种强大的代谢物差异，其中最突出的涉及色氨酸，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对整个职权群体的样本进行分析，从而扩展这项试点研究的新发现。基于电化学的平台（试点研究中的一个平台）将用于定量色氨酸，酪氨酸，嘌呤和硫氨基酸途径的化合物，这是在研究CNS介导的应激反应中很重要的生物化学区域，包括MSIMI在内。我们还将使用基于质谱的平台来介绍中间代谢的化合物，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，并对IHD的新机制产生了见解。这些平台的输出将用于识别和验证：（a）区分有和没有msimi的患者（b）区分对依他斯普兰和（c）反应良好或不良反应的患者与不良事件有关。