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过程中的所有风险。最近，研究表明，抑郁症是影响冠心病患者死亡风险的重要因素，抑郁症影响着16%-23%的心脏病发作患者。抑郁症和应激相关的大脑区域可能会导致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的模型，包括前扣带回和海马体，通过皮质醇和交感系统直接或间接途径到达心脏，介导心脏死亡风险的增加。我们已经开发出一种技术，可以同时对心脏和大脑进行成像，并在有或没有抑郁的心脏病患者的压力挑战期间测量应激激素皮质醇和去甲肾上腺素。初步数据显示，患有抑郁症的冠心病患者在应激挑战下，海马区和前扣带回的激活减少。冠心病和抑郁症患者表现出更大的应激性心肌缺血模式。因此，这项建议的具体目的是：1)使用正电子发射断层扫描(PET)和O-15水成像技术测量患有和不患有抑郁症的心脏病患者认知应激挑战的脑部相关性；2)在应激挑战时注射[Tc-99m]Sestamibi，并用单光子发射断层扫描(SPECT)对同一受试者进行心肌灌注成像；3)评估应激对皮质醇和去甲肾上腺素以及心率变异性的影响，这些是脑部影响心肌功能的介质。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，并在T2加权MRI上评估高强度脑白质病变的影响。假设冠心病伴抑郁的患者在应激过程中会表现出海马区和前扣带回功能降低，这与心肌缺血和心率变异性降低有关。公共卫生相关性冠心病抑郁与死亡率增加相关；了解相关机制可能导致新的治疗方法，有可能降低冠心病死亡率。本项目使用正电子发射断层扫描(PET)测量大脑功能，并在压力任务期间使用单光子发射断层扫描(SPECT)成像来观察抑郁症增加心血管疾病(CVD)死亡风险的机制。该项目将测量在应激期间发生的大脑功能变化，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，有可能导致这种疾病的新疗法。

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.