Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection?

BACKGROUND Two preconditioning stimuli should induce a more consistent overall cell protection. We hypothesized that remote ischemic preconditioning (RIPC, second preconditioning stimulus) applied during isoflurane inhalation (first preconditioning stimulus) would provide more protection to the myocardium of patients undergoing on-pump coronary artery bypass grafting. METHODS In this placebo-controlled randomized controlled study, patients in the RIPC group received four 5-min cycles of 300 mmHg cuff inflation/deflation of the leg before aortic cross-clamping. Anesthesia consisted of opioids and propofol for induction and isoflurane for maintenance. The primary outcome was high-sensitivity cardiac troponin T release. Secondary endpoints were plasma levels of N-terminal pro-brain natriuretic peptide, high-sensitivity C-reactive protein, S100 protein, and short- and long-term clinical outcomes. Gene expression profiles were obtained from atrial tissue using microarrays. RESULTS RIPC (n = 27) did not reduce high-sensitivity cardiac troponin T release when compared with placebo (n = 28). Likewise, N-terminal pro-brain natriuretic peptide, a marker of myocardial dysfunction; high-sensitivity C-reactive protein, a marker of perioperative inflammatory response; and S100, a marker of cerebral injury, were not different between the groups. The incidence for the perioperative composite endpoint combining new arrhythmias and myocardial infarctions was higher in the RIPC group than the placebo group (14/27 vs. 6/28, P = 0.036). However, there was no difference in the 6-month cardiovascular outcome. N-terminal pro-brain natriuretic peptide release correlated with isoflurane-induced transcriptional changes in fatty-acid metabolism (P = 0.001) and DNA-damage signaling (P < 0.001), but not with RIPC-induced changes in gene expression. CONCLUSIONS RIPC applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass grafting.