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)后凝血和纤溶通路的激活可能导致特定的、不利的临床出血和动脉血栓形成(ATC)结果。越来越多的证据表明，特定的基因类型与CPB后特定器官的结局有关，包括认知功能障碍、肾脏损害和死亡。然而，对于同种异型凝血和纤溶基因变异在决定不良出血和ATC结局中的作用，包括围术期出血、心肌梗死、冠状动脉移植失败和CABG术后心源性死亡，我们知之甚少。这项建议的总体目的是调查特定的凝血和纤溶基因和表型是否与接受需要体外循环的冠脉搭桥术的人的特定不良、围手术期出血和ATC结局的发生率增加有关。为了实现这一总目标，提出了三个具体目标。具体目标#1：为需要体外循环的冠状动脉旁路手术患者建立一个强大的围手术期血液样本库和不良临床结果数据库。具体目标#2：确定特定的凝血和纤溶表型是否可以预测需要体外循环的冠脉搭桥术患者的不良反应、围手术期出血和ATC结果。具体目标#3：在接受冠脉搭桥术的患者中，建立凝血和纤溶同种异型与不良反应、围手术期出血和ATC结局的关系。应聘者是一名心胸麻醉师，在心脏患者的临床管理方面有12年的经验，具有统计学和临床试验设计和执行方面的背景。为了为未来的独立研究奠定基础，除了在基本分子技术方面的直接经验和培训外，申请者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，以评估遗传对不良结果的影响，并利用这些技能进行以患者为导向的创新临床研究。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提供的独特的统计、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。在接受需要体外循环的冠状动脉搭桥术的患者中，识别与特定不良反应、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和表型，可能会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..