Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial

Peter Nagele, Frank Brown, Amber Francis, Mitchell G Scott, Brian F Gage, J Philip Miller, VINO Study Team, Peter Nagele, Frank Brown, Amber Francis, Joshua Johnston, Lesley K Rao, Jane Blood, Konrad Meissner, Anson Liu, Olumuyiwa Idowu, Samantha Morley, Kenji Kobayashi, Mitchell Scott, Brian F Gage, Lisa de las Fuentes, J Philip Miller, Peter Nagele, Frank Brown, Amber Francis, Mitchell G Scott, Brian F Gage, J Philip Miller, VINO Study Team, Peter Nagele, Frank Brown, Amber Francis, Joshua Johnston, Lesley K Rao, Jane Blood, Konrad Meissner, Anson Liu, Olumuyiwa Idowu, Samantha Morley, Kenji Kobayashi, Mitchell Scott, Brian F Gage, Lisa de las Fuentes, J Philip Miller

Abstract

Background: Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C gene variant. In this randomized controlled trial, the authors sought to determine whether patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and whether this risk could be mitigated by B-vitamins.

Methods: The authors randomized adult patients with cardiac risk factors undergoing noncardiac surgery, to receive nitrous oxide plus intravenous B-vitamins before and after surgery, or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I increase within the first 72 h after surgery.

Results: A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n=98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild-type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85-1.07; P=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78 to 1.32; P=0.91).

Conclusions: Neither MTHFR C677T and A1298C gene variant, nor acute homocysteine increase are associated with perioperative cardiac troponin increase after nitrous oxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin I increase.

Conflict of interest statement

Conflicts of Interest:

Nagele: Roche Diagnostics US (Indianapolis, IN) provided us with free troponin assays and funds to cover the costs running these assays. No other conflicts of interest.

Brown and Francis: No conflicts of interest.

Scott: Research Support - Siemens Healthcare Diagnostic (Tarrytown, NY); Consulting - Roche Diabetes Care (Indianapolis, IN)

Gage and Miller: No conflicts of interest.