Mechanisms of Platelet Activation in Depression and Acute Coronary Syndromes

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，其适当的预防和治疗是巨大的公共卫生问题。抑郁症已被证明可以预测心肌梗死恢复期患者发病率和死亡率的增加，与心脏疾病的严重程度无关。抑郁症和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-HT）介导的血小板反应性增加被认为是抑郁症与急性冠状动脉综合征（ACS）联系的主要机制。我们自己的初步研究表明，ACS患者的抑郁情绪与5-HT激活的血小板聚集增强有关。该建议的中心假设是，5-HT信号增强的血小板从ACS抑郁症患者。设计了三个具体目标来系统地检验这一假设：1）通过测量5-HT增强的血小板聚集和5-HT诱导的1 IIb 23表达来确定5-HT对血小板活化的作用，2）确定血小板对5-HT的摄取，3）确定ACS和具有不同严重程度抑郁的稳定CAD患者的血小板上的5-HT受体密度。为了探索5-HT转运蛋白功能和5-HT结合的改变与抑郁症和ACS相关的可能性，将对患者进行三种特定5-HT基因多态性的基因分型：a）5-HT转运蛋白多态性，5-HTTLPR短和长，B）5-HTTLPR插入内新识别的A对G单核苷酸多态性，和c）位于5-HT受体的非编码DNA区的102位的T取代为C。将在基线和一个月随访时测量血小板功能和抑郁。将通过评估ACS和稳定型CAD患者首次入组后12个月内发生的主要和次要不良心脏事件，探讨5-HT信号传导、5-HT多态性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，招募患有ACS和稳定型CAD的受试者，将使用DSM-IV-R（SCID）的结构化临床访谈（用于诊断重度抑郁症）和Beck抑郁量表（BDI）评估抑郁症状，以提供抑郁症状的连续测量。将根据SCID标准对患有和未患有重度抑郁症的患者的血小板进行比较，并通过BDI评分的类别进行探索。心血管风险和抑郁症之间的逻辑联系是血小板5-HT信号系统，因为5-HT在抑郁症中起着核心作用，并且大脑和血小板5-HT受体和转运蛋白之间具有相似性。阐明特定的血小板活化途径及其与不良心脏事件的联系将提供高度临床相关和重要的信息。鉴于ACS和抑郁症患者的死亡率显著增加，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，并可能提高生存率。 公共卫生相关性：重度抑郁症是心血管疾病死亡率和发病率的独立危险因素。抑郁症和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积极的治疗，并可能提高生存率。

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.