Dynamics of microRNA Expression and Systemic Inflammatory Response in POCD After Cardiac Surgery

Association of MicroRNA-151-5p Expression With Systemic Inflammatory Response and Cognitive Status in Patients After Coronary Artery Bypass Surgery (MiRNACOG)

Postoperative cognitive decline (POCD) is one of the most common complications after cardiac surgery. It is characterized by impaired memory, attention, and executive functions and can have long-term consequences. The goal of this observational study was to investigate the mechanisms of cognitive decline after cardiac surgery and potential biomarkers that could aid in the diagnosis, prevention, and treatment of POCD. The investigators focused on the role of microRNAs (miRNAs) and systemic inflammatory response to surgery, extracorporeal circulation, and anesthesia as potential factors involved in the development of the neuroinflammatory response and subsequent POCD. The main question this study aims to answer is whether perioperative miRNA 151-5p expression is associated with POCD after surgery. The second aim is to examine the association between miRNA-151-5p and systemic inflammation. The investigators measured circulating miRNA-151-5p levels and plasma levels of inflammatory biomarkers in patients undergoing surgical myocardial revascularization. To assess cognitive function, participants completed the Montreal Cognitive Assessment (MoCA Test). Changes in the measured values of miRNA-151-5p expression and inflammatory markers, as well as changes in cognitive status after surgery, were assessed in relation to the preoperative state.

Surgical myocardial revascularization is a procedure used in patients with ischemic heart disease to bypass atherosclerotic narrowings or blockages of the coronary arteries using an arterial or venous graft (Coronary Artery Bypass Grafting - CABG). One of the most common complications after cardiac surgery is postoperative cognitive decline (POCD). It is characterized by impaired memory, attention, and executive functions and can have long-term consequences, such as delayed physical therapy and mobilization, prolonged stay in the intensive care unit and hospital, more frequent discharge to nursing homes, reduced quality of life, and increased mortality.

The causes of POCD are multifactorial. The systemic inflammatory response to surgery, extracorporeal circulation, and anesthesia is considered a factor in the development of the neuroinflammatory response and subsequent POCD. Neuroinflammation can cause dysfunction or death of brain cells and damage to the blood-brain barrier, leading to an increase in the level of biochemical markers of brain injury in the blood. Studies indicate that numerous microRNAs (miRNAs) play a role in controlling the inflammatory response. MiRNAs are small, endogenous, non-coding RNA molecules, typically 18-25 nucleotides long, that regulate gene expression at the post-transcriptional level. They are central mediators of cellular proliferation, differentiation, and apoptosis. MiRNA levels in tissues and peripheral blood are similar, and circulating miRNAs are stable and suitable for measurement. Specific miRNAs (miRNA 151-5p, 505, 499, 625, and others) may be potential early biomarkers of brain damage after a mild traumatic brain injury. Anesthesia and surgery also, through complex mechanisms, can cause changes in brain cells that can lead to the release of specific miRNAs, and these miRNAs can be detected in blood and various biological fluids.

Hypothesis: Higher levels of perioperative miRNA-151-5p expression are associated with the systemic inflammatory response and with the development of POCD.

Aim of this study is:

1. To investigate the association between miRNA-151-5p expression levels and biochemical parameters of systemic inflammation, as well as the association of both with cognitive status in patient undergoing CABG surgery.
2. To investigate the association between patients' demographic and clinical characteristics and miRNA-151-5p expression levels, the level of biochemical parameters of systemic inflammation, and patients' cognitive status.

Research plan:

The research was carried out at the Clinical Hospital Centre Osijek. Respecting the inclusion and exclusion criteria for participation in the study, the research included patients aged 65 to 80 years who, according to the American Society of Anesthesiologists (ASA) classification, are classified into groups III and IV, and who are undergoing CABG surgery with the use of extracorporeal circulation. Surgeries were performed according to the standard protocol for balanced anesthesia, cardiac surgery, and extracorporeal circulation. All participants underwent the same anesthetic procedure and anesthesia based on midazolam, propofol, sufentanyl, rocuronium and sevoflurane. The depth of anesthesia was monitored using Patient State Index (PSI). All surgeries were performed using extracorporeal circulation with the maintenance of normothermia (36 °C).

Blood samples for determination of levels of cholinesterase, interleukin-6, protein S100B, miRNA-151-5p expression and routine laboratory parameters (complete blood count, levels of troponin I, C-reactive protein, procalcitonin, glucose, urea, creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, total bilirubin, albumin, electrolytes, lactate, coagulation tests, and arterial blood gas analysis) were taken at three time points: before surgery prior to induction of anesthesia, immediately after the procedure upon admission to the intensive care unit, and 48 hours after the surgical procedure.

Cognitive function testing was performed the day before surgery and postoperatively, once daily every day until the 6th postoperative day. The investigators used a validated scoring scale for assessing cognitive functions, the Montreal Cognitive Assessment - MoCA Test. Demographic and clinical data were recorded for all subjects. Subjects were followed up 7 days.

Inclusion Criteria:

• patients undergoing coronary artery bypass graft surgery to treat coronary artery disease
• two or more coronary bypass surgery with the use of extracorporeal circulation
• patients between the ages of 65 and 80
• patients according to the classification of the American Society of Anesthesiologists (ASA) classified in groups III and IV
• patients who agreed to participate in the research and signed an informed consent

Exclusion Criteria:

• patients with communication difficulties (severe visual, hearing and speech impairment)
• illiterate patients
• patients with a history of dementia, schizophrenia, Parkinson's disease, Alzheimer's disease, alcoholism
• patients with previously known liver failure of any grade according to the Child-Pough classification
• patients with previously known renal failure greater than grade 2
• patients taking immunosuppressive, corticosteroid and anticholinergic therapy
• intraoperatively used cell-saver and/or hemofilter
• patients in whom the planned procedure is not performed
• patients in whom it is not possible to assess cognitive functions postoperatively (patients sedated due to intra- or postoperative surgical complications)