Mechanisms of Platelet Activation in Depression and Acute Coronary Syndromes

描述(申请人提供)：抑郁症和心血管疾病是西方世界最大的两个公共卫生问题，它们的适当预防和治疗是巨大的公共卫生问题。抑郁已被证明可以预测心肌梗死康复期患者的发病率和死亡率的增加，与心脏疾病的严重程度无关。抑郁症与心血管风险增加之间的确切机制仍然知之甚少。5-羟色胺(5-羟色胺)介导的血小板反应性升高被认为是抑郁症与急性冠脉综合征(ACS)联系的主要机制。我们自己的试点工作表明，在急性冠脉综合征患者中，抑郁的情绪与增强的5-羟色胺激活的血小板聚集有关。这一建议的中心假设是，患有抑郁症的急性冠脉综合征患者的血小板中5-羟色胺信号增强。为了系统地验证这一假说，我们设计了三个特定的目标：1)通过测定5-羟色胺促进的血小板聚集和5-羟色胺诱导的1IIb23的表达来确定5-羟色胺对血小板活化的影响；2)测定血小板对5-羟色胺的摄取；3)测定不同抑郁程度的急性冠脉综合征患者和稳定期冠心病患者的血小板上5-羟色胺受体密度。为了探讨5-羟色胺转运体功能和5-羟色胺结合的改变与抑郁症和急性冠脉综合征的关系，我们将对患者进行三种特殊的5-羟色胺转运体基因多态的基因分型：a)5-羟色胺转运体基因多态，5-HTTLPR短和长，b)新发现的A代表5-HTTLPR插入内的G单核苷酸多态，c)位于5-HTTLPR非编码DNA区域102位的T代表C替代。将在基线和一个月的随访中测量血小板功能和抑郁程度。通过评估在最初登记的急性冠脉综合征和稳定的冠心病患者12个月内发生的主要和轻微不良心脏事件，将探索5-羟色胺信号、5-羟色胺基因多态和不良心脏结局之间的关系。这将在一项病例对照研究中进行，招募有急性冠脉综合征和稳定型冠心病的受试者，他们的抑郁症状将使用DSM-IV-R结构化临床访谈(SCID)来诊断重度抑郁，并使用贝克抑郁问卷(BDI)来提供抑郁症状的持续衡量。根据SCID标准对患有和不患有严重抑郁症的患者的血小板进行比较，并根据BDI评分的类别进行探索。考虑到5-羟色胺在抑郁症中发挥的核心作用，以及大脑和血小板5-羟色胺受体和转运体之间的相似之处，心血管风险和抑郁之间的逻辑联系是血小板5-羟色胺信号系统。阐明特定的血小板激活途径及其与不良心脏事件的联系将提供具有高度临床相关性和重要性的信息。鉴于急性冠脉综合征和抑郁症患者死亡率的显著增加，更好地了解导致风险增加的机制可以导致更有针对性和积极的治疗，并有可能提高存活率。 公共卫生相关性：抑郁症是心血管疾病死亡率和发病率的独立危险因素。抑郁症与心血管风险增加之间的确切机制仍然知之甚少。更好地理解导致风险增加的机制可能会导致更有针对性和侵略性的治疗，并有可能提高存活率。

DESCRIPTION (provided by applicant): Depression and cardiovascular disease are the two largest public health problems in the Western world, and their appropriate prevention and treatment are enormous public health issues. Depression has been shown to predict increased morbidity and mortality among patients recovering from a myocardial infarction, independent of the severity of cardiac illness. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Increased serotonin (5-HT) mediated platelet reactivity has been postulated to be a major mechanism linking depression to acute coronary syndromes (ACS). Our own pilot work has shown that depressed mood is associated with enhanced 5-HT activated platelet aggregation in patients with ACS. The central hypothesis of this proposal is that 5-HT signaling is enhanced in platelets from ACS patients with depression. Three specific aims have been designed to systematically test this hypothesis: 1) Determine the effect of 5-HT on platelet activation by the measurement of 5-HT-augmented platelet aggregation and 5-HT- induced 1IIb23 expression, 2) Determine platelet uptake of 5-HT and 3) Determine 5-HT receptor density on platelets from ACS and stable CAD patients with varying severity of depression. To explore the possibility that alterations in 5-HT transporter function and 5-HT binding are linked to depression and ACS, patients will be genotyped for three specific 5-HT gene polymorphisms: a) 5-HT transporter polymorphism, 5-HTTLPR short and long, b) a newly recognized A for G single nucleotide polymorphism within the 5-HTTLPR insertion, and c) a T for C substitution at position 102 located in a non-coding DNA region of the 5-HT receptor. Platelet function and depression will be measured at baseline and at a one-month follow up. Examination of the relationship between 5-HT signaling, 5-HT polymorphisms, and adverse cardiac outcomes will be explored by assessing both major and minor adverse cardiac events that occur within a 12-month period after initial enrollment in both ACS and stable CAD patients. This will be conducted in a case controlled study recruiting subjects presenting with ACS and stable CAD whose symptoms of depression will be assessed using the Structured Clinical Interview for DSM-IV-R (SCID) to diagnose major depression and the Beck Depression Inventory (BDI) to provide a continuous measure of depressive symptoms. Comparisons will be made on platelets obtained from patients who have and do not have major depression by SCID criteria, and explored by categories of the BDI scores. A logical link between cardiovascular risk and depression is the platelet 5-HT signaling system given the central role that 5-HT plays in depression and the similarities between brain and platelet 5-HT receptors and transporters. Elucidation of the specific platelet activation pathways and their link to adverse cardiac events will provide information that is highly clinically relevant and important. Given the significant increased mortality in patients with ACS and depression, a better understanding of mechanisms leading to increased risk can lead to more targeted and aggressive therapy and potentially improved survival. PUBLIC HEALTH RELEVANCE: Major depression is an independent risk factor for cardiovascular mortality and morbidity. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Better understandings of mechanisms leading to increased risk will likely lead to more targeted and aggressive therapy and potentially improved survival.