Coronary vascular disease can lead to myocardial infarction. While increased standards of care have greatly improved morbidity and mortality following infarction, it is now widely accepted that ischemia/reperfusion (I/R) injury occurs following successful thrombolytic therapy, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Although I/R, inflammation and coagulation disturbances are known to contribute to perioperative adverse outcomes (e.g., the phenotypes), the observed severity of these outcomes differs significantly amongst individuals One possible explanation is genetic variability in the biologic pathways that mediate adverse perioperative outcomes. Recent basic science studies from several groups, including our own, have shown that complement plays an important role in I/R injury. We have shown that inhibition of the mannose-binding lectin (MBL)-dependent portion of the lectin complement pathway plays an important role in the inflammation, dysfunction and injury following reperfusion in animal models of myocardial ischemia. In order to evaluate the role of the lectin complement pathway (LCP) in human diseases, we developed and validated a novel fluorochrome-linked immunoassay (FLISA) to measure the functional aspects of the lectin complement pathway to the level of C3 cleavage in human sera. Preliminary haplotype data from the CABG Genomics Program demonstrate that the high expressor MBL2 """"""""LYQA secretor"""""""" haplotype is an independent predictor of postoperative myocardial infarction following CABG surgery. In the present application, we will extend our basic and clinical science findings by combining genomic (MBL2) and phenotypic (MBL concentration) data in the setting of CABG using the CABG Genomic Program database and sample repository. We hypothesize that genetic variation within the MBL2 gene and perioperative serum MBL levels will be predictive indicators of myocardial injury after CABG surgery with CPB. Data generated from this proposal will not only further define the role of MBL and the LCP in myocardial injury, but will also provide insight into genetic and molecular mechanisms that predispose individuals to perioperative morbidity following cardiac surgery. Furthermore, successful completion of these specific aims may subsequently lead to improved perioperative risk stratification, resource utilization and the development of novel anti-complement therapies to be used in a funded clinical trial.

Public Health Relevance

Death from cardiovascular disease remains the number one killer of Americans. Recent scientific findings from human and animal studies have demonstrated that genetic variability of a known innate immune molecule (e.g., mannose binding lectin, MBL2) and the serum concentration of this protein are independent predictors of myocardial injury following coronary artery bypass grafting (CABG) and myocardial ischemia/reperfusion, respectively. Using a novel and validated immunoassay that was recently developed in our laboratory, we will investigate the genetic variation within the MBL2 gene and perioperative MBL2 serum concentration (as well as its downstream activation products, C4b and C3b) in predicting the myocardial injury that occurs following CABG using the CABG Genomics Program database and sample repository.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL092469-02
Application #
7743036
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2008-12-01
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$222,500
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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