BACKGROUND: Anesthetic gases modulate gene expression and provide organ protection. This study aimed at identifying myocardial transcriptional phenotypes to predict cardiovascular biomarkers and function in patients undergoing off-pump coronary artery bypass graft surgery. METHODS: In a prospective randomized trial, patients undergoing elective off-pump coronary artery bypass graft surgery were allocated to receive either the anesthetic gas sevoflurane (n = 10) or the intravenous anesthetic propofol (n = 10). Blood samples were collected perioperatively to determine cardiac troponin T, N-terminal pro-brain natriuretic peptide, and pregnancy-associated plasma protein A. Cardiac function was measured with transesophageal echocardiography and pulmonary artery thermodilution. Atrial biopsies were collected at the beginning and end of bypass surgery to determine gene expression profiles. RESULTS: N-terminal pro-brain natriuretic peptide and pregnancy-associated plasma protein A blood levels were decreased with sevoflurane treatment. Echocardiography showed preserved postoperative cardiac function in sevoflurane patients, which paralleled higher cardiac index measurements. N-terminal pro-brain natriuretic peptide release was predicted by sevoflurane-induced transcriptional reduction in fatty acid oxidation, whereas changes in cardiac index were predicted by preoperative gene activity of the peroxisome proliferator-activated receptor gamma coactivator-1alpha pathway. Sevoflurane-mediated attenuation of transcripts involved in DNA-damage signaling and activation of the granulocyte colony-stimulating factor survival pathway predicted improved postoperative cardiac index and diastolic heart function, respectively. CONCLUSIONS: Anesthetic-induced and constitutive gene regulatory control of myocardial substrate metabolism predicts postoperative cardiac function in patients undergoing off-pump coronary artery bypass graft surgery. The authors' analysis further points to novel cardiac survival pathways as potential therapeutic targets in perioperative cardioprotection.