Genotypic Impact on Outcomes after CABG Surgery

描述（由申请人提供）： 体外循环（CPB）和冠状动脉旁路移植术（CABG）手术后凝血和纤溶途径的激活可能导致特定的不良临床出血和动脉血栓形成临床（ATC）结局。越来越多的证据表明，特定基因型与CPB后器官特异性结局相关，包括认知功能障碍、肾损害和死亡。然而，同种异型凝血和纤溶基因变异在决定不良出血和ATC结局（包括围手术期出血、MI、冠状动脉移植物衰竭和CABG术后心源性死亡）频率中的作用知之甚少。本提案的总体目的是研究特定凝血和纤溶基因型和表型是否与接受需要CPB的CABG手术的人中特定不良事件、围手术期出血和ATC结局的发生率增加相关。为了实现这一总体目标，提出了三个具体目标。具体目标1：建立一个强大的围手术期血液样本库和接受需要CPB的CABG手术的患者的不良临床结局数据库。具体目标#2：确定特定凝血和纤溶表型是否可预测接受需要CPB的CABG手术的患者的不良、围手术期出血和ATC结局。具体目标#3：在接受CABG手术的患者中建立凝血和纤溶同种异型与不良、围手术期出血和ATC结局之间的关系。申请人是一名心胸麻醉医师，在心脏病患者的临床管理方面拥有12年经验，具有统计学和临床试验设计和执行背景。为了为未来的独立研究奠定基础，除了基本分子技术的直接经验和培训外，申请人还将在哈佛公共卫生学院攻读公共卫生硕士学位。这将包括1）生物统计学，2）疾病流行病学，3）生物信息学，4）人类遗传学的统计方法和5）研究伦理学的教学。总体目标是掌握遗传流行病学和统计方法，评估遗传对不良结局的影响，并利用这些技能进行创新的以患者为导向的临床研究。职业发展和研究计划将利用布里格姆妇女医院和哈佛医学院独特的统计、流行病学和基因组技能以及实验室资源，特别是心血管疾病方面的资源。在接受需要CPB的CABG手术的人群中，识别与特定不良事件、围手术期出血和ATC结局发生率增加相关的特定凝血和纤溶基因型和表型，可改善术前患者风险分层、预防性治疗和术后资源利用。

DESCRIPTION (provided by applicant): Activation of the coagulation and fibrinolytic pathways following cardiopulmonary bypass (CPB) and coronary artery bypass graft (CABG) surgery may result in specific, adverse clinical bleeding and arterial thrombotic clinical (ATC) outcomes. Accumulating evidence suggests that specific genotypes are associated with organ-specific outcomes after CPB, including cognitive dysfunction, renal compromise, and death. However, little is known of the role of allotypic coagulation and fibrinolytic gene variation in determining the frequency of adverse bleeding and ATC outcomes, including perioperative hemorrhage, MI, coronary artery graft failure and cardiac death following CABG surgery. The general aim of this proposal is to investigate whether specific coagulation and fibrinolytic genotypes and phenotypes are associated with an increased incidence of specific adverse, perioperative bleeding and ATC outcomes in humans undergoing CABG surgery requiring CPB. In order to accomplish this general aim, 3 specific aims are proposed. Specific Aim #1: Establish a robust perioperative blood sample repository and adverse clinical outcomes database of patients undergoing CABG surgery requiring CPB. Specific Aim #2: Establish whether specific coagulation and fibrinolytic phenotypes are predictive of adverse, perioperative bleeding and ATC outcomes in patients undergoing CABG surgery requiring CPB. Specific Aim #3: Establish the relationship between coagulation and fibrinolytic allotypes and adverse, perioperative bleeding and ATC outcomes in patients undergoing CABG surgery. The Applicant is a Cardiothoracic Anesthesiologist with twelve years experience in clinical management of cardiac patients, with a background in statistics and clinical trial design and execution. To build a foundation for future independent research, in addition to direct experience and training in basic molecular techniques, the Applicant will undertake a Master of Public Health degree at the Harvard School of Public Health. This will include didactic teaching in 1) Biostatistics, 2) Epidemiology of disease, 3) Bioinformatics, 4) Statistical methods in human genetics, and 5) Research ethics. The overall objective is to master genetic epidemiology and statistical methods for assessment of hereditary influences upon adverse outcomes and utilize these skills to conduct innovative patient-oriented clinical research. The career development and research plans will take advantage of the unique collection of statistical, epidemiological and genomic skills, and laboratory resources, notably in cardiovascular diseases, available within Brigham and Women's Hospital and the Harvard Medical School. Identification of specific coagulation and fibrinolytic genotypes and phenotypes associated with an increased incidence of specific adverse, perioperative bleeding and ATC outcomes in humans undergoing CABG surgery requiring CPB may improve preoperative patient risk stratification, preventative therapy and postoperative resource utilization..