• Myocardial ischemia assessed by peak serum troponin I concentration [ Time Frame: first 3 postoperative days ] [ Designated as safety issue: No ]
  

• Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI) [ Time Frame: 30 day postoperative ] [ Designated as safety issue: No ]
  

Background and significance: Recent studies have shown that nitrous oxide (N2O) anesthesia may be associated with an increased risk of adverse cardiovascular outcomes. It is well-known that N2O inhibits vitamin B12-dependent enzymes and as a result increases plasma homocysteine concentrations. Homocysteine has been identified as risk factor for cardiovascular disease. Therefore elevations in homocysteine after N2O may be a causative factor in N2O toxicity. In a previous investigation, we found that patients who carry a homozygous mutation in the MTHFR gene develop higher homocysteine levels after N2O anesthesia than non-carriers. These patients might be at higher risk for adverse cardiac outcomes from N2O. Thus, there may be a pharmacogenetic mechanism to account for the adverse cardiac outcomes from N2O. Moreover, prevention of N2O-increased homocysteine concentrations in these high risk patients by perioperative vitamin B12 and folate supplementation might decrease the incidence of adverse cardiac outcomes.

Hypothesis: Patients carrying a homozygous MTHFR 677C>T or 1298 A>C variant allele will have a higher incidence rate of postoperative myocardial ischemia after N2O anesthesia [detected by serial TnI measurements] due to elevated homocysteine levels than normal "wild-type" non-carriers, and that the incidence rate will be reduced if they receive perioperative vitamin B12/folate supplementation.

Primary outcome: Myocardial ischemia in the first 72 hours after surgery

Outcome definition: Peak serum troponin I concentration during the first 3 postoperative days

Secondary outcome: Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI)

Design: Randomized controlled trial. Patients will be randomized to receive vitamin supplementation or placebo before surgery. All patients will receive N2O during surgery. Mendelian randomization of MTHFR genotype.

Intervention: IV vitamin B12 (1 mg) and folate (5 mg) preoperatively

Study setting: Barnes-Jewish-Hospital, St. Louis, MO

Patients: Patients scheduled for major surgery with previously diagnosed coronary artery disease or at risk for coronary artery disease

Statistical Approach: Comparison of two groups: MTHFR homozygous vs. heterozygous/wild-type patients. General linear model will be fit to the data after normalizing transformation (e.g. log troponin).

Anticipated result: Patients carrying a homozygous MTHFR 677C>T or 1298 A>C variant allele will have a 50% increased peak TnI due to elevated homocysteine compared to non-carriers. Secondly, treatment with vitamin B12/folate will prevent the homocysteine increase as well as the increase in peak troponin and myocardial ischemia.