Mechanisms of Depression in CVD

描述（申请人提供）：冠心病（CHD）是美国最常见的死亡原因。传统的风险因素，如吸烟和高血压，并不能解释心脏病发展的所有风险。最近，研究表明，抑郁症是影响冠心病患者死亡风险的一个重要因素，它影响着16-23%的心脏病患者。参与抑郁和压力的大脑区域可能介导抑郁症患者心脏死亡风险的增加。我们已经开发了一个大脑区域模型，包括前扣带和海马体，通过皮质醇和交感神经系统直接或间接的途径到达心脏，介导心脏死亡风险的增加。我们已经开发了一种技术，可以同时对心脏和大脑进行成像，以及测量压力激素皮质醇和去甲肾上腺素，在心脏病患者的压力挑战中，有或没有抑郁症。初步数据显示，冠心病合并抑郁症患者海马和前扣带激活随着应激挑战而降低。冠心病合并抑郁症患者表现出更大的应激性心肌缺血模式。因此，本提案的具体目的是：1)使用正电子发射断层扫描（PET）和O-15水来测量患有和不患有抑郁症的心脏病患者的应激性认知挑战的大脑相关因素；2)同一受试者在应激刺激时注射[Tc-99m]sestamibi，用单光子发射断层扫描（SPECT）成像心肌灌注；3)评估应激对皮质醇和去甲肾上腺素的影响以及心率变异性作为大脑对心肌功能影响的中介。次要目的是评估早期生活创伤对脑和心脏激活的影响，比较精神应激和运动应激引起的心肌缺血，评估高强度白质病变对T2加权MRI的影响。假设伴有抑郁的冠心病患者在应激时海马和前扣带功能下降，这与心肌缺血和心率变异性降低有关。冠心病患者抑郁与死亡率增加相关了解其中的机制可能会带来新的治疗方法，有可能降低冠心病的死亡率。本项目使用正电子发射断层扫描（PET）测量脑功能和单光子发射断层扫描（SPECT）成像心脏功能在一个有压力的任务来观察抑郁症增加心血管疾病（CVD）死亡风险的机制。该项目将测量在压力下发生的脑功能变化，以及这些变化可能影响心血管疾病和抑郁症患者心肌缺血的方式，以及可能介导这些影响的神经激素变化。了解抑郁症增加心血管疾病死亡率的基于大脑的机制，有可能为这种疾病带来新的治疗方法。

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the most common cause of death in the United States. Traditional risk factors, such as smoking and hypertension, do not account for all of the risks in the development of heart disease. Recently, research has demonstrated that depression, which affects 16-23% of patients suffering heart attacks, is an important factor that affects the risk of death in patients with coronary heart disease. Brain regions involved in depression and stress may mediate the increased risk of cardiac mortality in depression. We have developed a model of brain areas including anterior cingulate and hippocampus, through either direct or indirect pathways through cortisol and the sympathetic system to the heart, mediating an increased risk for cardiac mortality. We have developed techniques to perform simultaneous imaging of the heart and brain, as well as measurement of the stress hormones cortisol and norepinephrine, during a stress challenge in patients with heart disease, with and without depression. Preliminary data shows decreased hippocampal and anterior cingulate activation with a stressful challenge in CHD patients with depression. Patients with CHD and depression showed a pattern of greater stress induced myocardial ischemia. Specific Aims of this proposal are therefore to: 1) Use positron emission tomography (PET) and O-15 water to measure brain correlates of a stressful cognitive challenge in patients with heart disease, with and without depression; 2) Inject [Tc-99m]sestamibi at the time of the stress challenge and image myocardial perfusion with single photon emission tomography (SPECT) in the same subjects; 3) Assess the effects of stress on cortisol and norepinephrine as well as heart rate variability as mediators of the effects of the brain on myocardial function. Secondary aims are to assess the effects of early life trauma on brain and heart activation, to compare mental stress and exercise stress induced myocardial ischemia, and to assess the effects of high intensity white matter lesions on T2 weighted MRI. Hypotheses are that CHD patients with depression will show decreased hippocampal and anterior cingulate function during stress which will be associated with myocardial ischemia and decreased heart rate variability. PUBLIC HEALTH RELEVANCE Depression in CHD is associated with increased mortality; understanding mechanisms involved may lead to new treatments with the potential to reduce CHD mortality. Narrative This project uses positron emission tomography (PET) measurement of brain function and single photon emission tomography (SPECT) imaging of heart function during a stressful task to look at mechanisms by which depression increases the risk of mortality from cardiovascular disease (CVD). The project will measure changes in brain function that occur during stress and the way these may affect myocardial ischemia in patients with CVD and depression, as well neurohormonal changes that may mediate these effects. Understanding brain-based mechanisms by which depression increases mortality from CVD has the potential to lead to new treatments for this disorder.