Genotypic Impact on Outcomes after CABG Surgery

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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..