microRNA signatures of perioperative myocardial injury after elective non-cardiac surgery: prospective observational cohort study

Abstract

BackgroundElevated plasma/serum troponin, indicating perioperative myocardial injury (PMI), is common after non-cardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident.MethodsNested case-control study of samples obtained before and after non-cardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with/without PMI, matched for age, gender and comorbidity. Real-time polymerase chain reaction quantified relative microRNA expression (cycle quantification threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO).ResultsMicroRNA were detectable in all 59 patients (median age:67yrs (61-75); 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, PMI was not associated with increased serum microRNA expression levels after surgery (hsa-miR-1-3p mean fold-change (FC):3.99 (95%CI:1.95-8.19); hsa-miR-133-3p FC:5.67(95%CI:2.94-10.91); p<0.001). hsa-miR-208b-3p was more commonly detected after PMI (odd ratio (OR):10.0 (95%CI:1.9-52.6); p<0.01). Bioinformatic analysis of differentially expressed microRNAs from cohorts one and two identified pathways associated with adrenergic stress involving calcium dysregulation, rather than ischaemia.ConclusionsCirculating microRNAs synonymous with cardiac ischaemia were universally elevated in patients after surgery, independent of developing myocardial injury.