MicroRNA signatures of perioperative myocardial injury after elective noncardiac surgery: a prospective observational mechanistic cohort study

• Published in: British journal of anaesthesia : BJA Vol. 125; no. 5; pp. 661 - 671
• Main Authors: May, Shaun M., Abbott, Tom E.F., Del Arroyo, Ana G., Reyes, Anna, Martir, Gladys, Stephens, Robert C.M., Brealey, David, Cuthbertson, Brian H., Wijeysundera, Duminda N., Pearse, Rupert M., Ackland, Gareth L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2020; Elsevier
• Subjects: Acute Coronary Syndrome - blood; Acute Coronary Syndrome - etiology; Acute Coronary Syndrome - genetics; Aged; Cardiovascular; Case-Control Studies; Chromosome Mapping; Elective Surgical Procedures - adverse effects; Extracellular Matrix - chemistry; Female; Heart Injuries - blood; Heart Injuries - genetics; Humans; Male; Metabolic Networks and Pathways; microRNA; MicroRNAs - blood; MicroRNAs - genetics; Middle Aged; Myocardial Ischemia - blood; Myocardial Ischemia - genetics; noncardiac surgery; perioperative myocardial injury; perioperative period; postoperative complications; Postoperative Complications - blood; Postoperative Complications - genetics; Prospective Studies; postoperative complications; microRNA; perioperative period; perioperative myocardial injury; noncardiac surgery
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1016/j.bja.2020.05.066

Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac 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. We performed a nested case control study of samples obtained before and after noncardiac 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 or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT–PCR) relative microRNA expression (cycle quantification [Cq] 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 HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO). MicroRNAs were detectable in all 59 patients (median age 67 yr [61–75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95–8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94–10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia. Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury.