Ancillary Investigation of Mental Stress Biomarkers in Coronary Heart Disease

描述（由申请人提供）： 冠心病患者的心理应激可导致心肌缺血。精神应激诱发的缺血可预测不良心脏事件风险增加，其预后临床意义已超过运动负荷试验期间诱发的缺血。虽然精神应激试验作为临床工具有很大的希望，但精神应激缺血的潜在机制需要确定，并且在其他心脏风险生物标志物中应激诱导的扰动的预后价值尚不清楚。本应用程序是为响应RFA-HL-09-001而开发的，作为即将进行的临床试验的辅助研究，该临床试验包括在压力管理干预前后评估CHD患者中精神压力诱导的心肌缺血。拟定的辅助研究扩展了母研究，重点关注精神负荷试验期间血管内皮功能和心脏自主调节的一过性损伤。这些心血管调节系统的短暂性损害可能是缺血活动表现的原因，也可能独立地导致不良临床结局的风险。以心率变异性（HRV）为指标的副交感神经心脏控制在精神压力期间减弱，导致心脏电不稳定和事件风险增加。通过血流介导的血管扩张（FMD）测量，精神压力也显示对血管内皮功能有不利影响。CHD患者的特征在于内皮功能障碍，即使在静息条件下，并且这种关键的血管调节机制的进一步损害，特别是在冠状动脉血管中，可能引起精神应激性缺血并增加心脏事件的风险。拟定的辅助研究旨在评价这些应激生物标志物是否与心肌缺血的发生相关，并评估其预后价值。通过建立包括临床随访阶段的母临床试验的基础设施，有可能采用具有成本效益的方法来解决以下研究假设：（i）精神应激诱导的HRV和FMD受损将预测精神应激缺血的发生;（ii）精神应激诱导的HRV和FMD受损将预测不良心血管结局;（iii）压力管理干预将导致对精神压力的HRV和FMD反应的改善。辅助研究产生的数据将通过推进精神压力测试在心脏病患者风险分层中的使用而具有重要的临床意义。公共卫生相关性：冠心病（CHD）是美国和全世界的重要健康问题，并且是美国男性和女性的主要死亡原因。这项研究旨在开发精神压力生物标志物，以改善CHD的风险分层，并为临床医生提供评估工具，以更好地优化患者管理。

DESCRIPTION (provided by applicant): Myocardial Ischemia can be induced by mental stress in patients with coronary heart disease (CHD). Mental stress-induced ischemia is predictive of increased risk of adverse cardiac events, and its prognostic clinical significance has been established over and above ischemia induced during exercise stress testing. Although mental stress testing holds much promise as a clinical tool, the mechanisms underlying mental stress ischemia need to be identified, and the prognostic value of stress-induced perturbations in other biomarkers of cardiac risk are unknown. This application was developed in response to RFA-HL-09-001, as an ancillary study to an upcoming clinical trial that includes the assessment of mental stress induced myocardial ischemia in CHD patients, both before and after a stress management intervention. The proposed ancillary study extends the parent study by focusing on transient impairment of vascular endothelial function and autonomic regulation of the heart during mental stress testing. Transient impairment in these cardiovascular regulatory systems may be responsible for the manifestation of ischemic activity, and also may contribute independently to risk of adverse clinical outcomes. Parasympathetic cardiac control, indexed by heart rate variability (HRV), is attenuated during mental stress, resulting in cardiac electrical instability and heightened risk of events. Mental stress also has been shown to have an adverse impact on vascular endothelial function as measured by flow-mediated dilation (FMD). CHD patients are characterized by endothelial dysfunction, even under resting conditions, and further compromise of this critical vascular regulatory mechanism, especially in the coronary vessels, may provoke mental stress ischemia and increase the risk for cardiac events. The proposed ancillary study is designed to evaluate whether these stress biomarkers are related to the occurrence of myocardial ischemia and to assess their prognostic value. By building upon the infrastructure of the parent clinical trial, which includes a clinical follow-up phase, a cost-effective approach to addressing the following research hypotheses is possible: (i) Mental stress-induced impairment of HRV and FMD will predict the occurrence of mental stress ischemia; (ii) Mental stress-induced impairment of HRV and FMD will predict adverse cardiovascular outcomes, and; (iii) a stress management intervention will result in improved HRV and FMD response to mental stress. The data generated by the ancillary study will have important clinical significance by advancing the use of mental stress testing for risk stratification in cardiac patients. PUBLIC HEALTH RELEVANCE: Coronary Heart Disease (CHD) is a significant health problem in the United States and throughout the world, and is the leading cause of death for men and women in the US. This study is designed to develop mental stress biomarkers that will refine risk stratification in CHD, and provide clinicians with assessment tools that will better equip them to optimize patient management.