Postoperative morbidity and mortality is an under-recognized, yet significant public health problem. In 2004. 1.4% of all inpatients died after surgery. Myocardial infarction is a major contributor to postoperative mortality. Perioperative (pharmaco-)genetics may reduce adverse outcomes by individualizing therapeutic options and drug therapy ("personalized medicine"). However, there is currently a significant paucity of Studies investigating the potential benefits of perioperative pharmacogenetics. This K23 proposal is for a career development program in perioperative pharmacogenetics. The research component centers on a randomized blinded controlled trial investigating the association between gene variants in intermediary metabolic pathways known to be altered by nitrous oxide and postoperative myocardial ischemia. Nitrous oxide is the most commonly used general anesthetic in the world. It inhibits vitamin 812 and increase homocysteine concentrations. Chronic homocysteinemia has been associated with adverse cardiac events.The MTHFR 677 C>T polymorphism is the most important genetic determinant for elevated homocysteine and is also associated with significantly higher homocysteine after nitrous oxide anesthesia. Thus, this investigation will test the hypothesis that patients with this gene variant have a higher incidence of postoperative myocardial ischemia after nitrous oxide, anesthesia than wild-type patients (aim 1). We will also determine if this risk can be ameliorated by blinded, randomized perioperative supplementation of vitamin B12 and folate (aim 2). The trial will target patients at high risk for cardiac events undergoing major noncardiac surgery. The didactic training component of the K23 proposal will be the Masters of Science program in Genetic Epidemiology. The overall long-term career objective is to become an independent investigator in perioperative pharmacogenetics.

Public Health Relevance

Postoperative myocardial ischemia is one of the most important contributors to surgical morbidity and mortality with 2-3 million Americans at risk annually. This research will answer if nitrous oxide is a risk factor for postoperative myocardial ischemia and if this risk can be ameliorated by B-vitamins. Thus, this research might serve as important evidence to assess the safety of nitrous oxide in high-risk patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23GM087534-03
Application #
8206712
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2010-01-04
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$114,572
Indirect Cost
$8,487
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Nagele, Peter; Brown, Frank; Francis, Amber et al. (2014) In reply. Anesthesiology 120:515-6
Duma, Andreas; Helsten, Daniel; Brown, Frank et al. (2014) The effect of nitrous oxide anesthesia on early postoperative opioid consumption and pain. Reg Anesth Pain Med 39:31-6
(2014) Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology 120:564-78
Nagele, Peter (2013) Exome sequencing: one small step for malignant hyperthermia, one giant step for our specialty--why exome sequencing matters to all of us, not just the experts. Anesthesiology 119:1006-8
Nagele, Peter; Brown, Frank; Francis, Amber et al. (2013) Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial. Anesthesiology 119:19-28
Johnston, Joshua; Pal, Swatilika; Nagele, Peter (2013) Perioperative torsade de pointes: a systematic review of published case reports. Anesth Analg 117:559-64
Nagele, Peter; Brown, Frank; Gage, Brian F et al. (2013) High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J 166:325-332.e1
Blake, C M; Kharasch, E D; Schwab, M et al. (2013) A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics. Clin Pharmacol Ther 94:394-9
Nagele, Peter (2011) Perioperative genomics. Best Pract Res Clin Anaesthesiol 25:549-55
Nagele, Peter; Meissner, Konrad; Francis, Amber et al. (2011) Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification. Pharmacogenet Genomics 21:426-31

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