Inflammation in Cardiac Surgery

This study aims to better understand 3 crucial questions: 1. Why do some patients experience more severe complications after heart surgery than others? 2. Are there markers on our genetic makeup (called epigenetic modifications) that can predict complications after major surgery? 3. How do epigenetic modifications lead to overactive inflammation that causes harm to patients after heart surgery? Over 270,000 patients undergo major surgery in Scotland each year. Major surgery is associated with increased risk of complications, particularly in older patients with multiple health conditions. Complications are a leading cause of death, delayed recovery, long-term illness and increased healthcare cost to the NHS. Significant complications occur in up to 57% of patients after heart surgery. In response to major surgery, the body stimulates an inflammatory response as part of a complex repair mechanism, however, in some cases inflammation can become exaggerated, becoming harmful and contributing to the development of complications. The investigators believe that a patient's risk of overactive inflammation, which can lead to complications after surgery, is heavily influenced by a patient-specific system of biological markers, layered upon their DNA; a scientific field known as epigenetics. Where a patient's DNA (their 'genetics') may be considered as an instruction manual for each cell's molecular processes, these 'epigenetic' markers work as if someone has highlighted sections of the manual to be read (and actioned). The pattern of these markers on immune system cells can therefore dictate the extent of the inflammatory response, especially after a major insult such as surgery. While the DNA itself cannot be modified, epigenetic markers can be modified, through strategies including diet, exercise, and medication. The aim of this study is to evaluate whether the modifiable epigenetic code of key immune-system cells dictates the extent of post-operative inflammation, contributing to organ damage and complications. With patients' permission, the investigators will: 1. Obtain blood samples before and after major heart surgery, to test for epigenetic markers and inflammation. 2. Observe patients after surgery and collect routine data from laboratory tests and patient observations which assess for organ dysfunction and inflammation. 3. Conduct patient questionnaires before and after surgery to assess physical fitness and patient-centred quality of life measures. 4. Analyse patterns between patients who have severe organ dysfunction after surgery and those patients who have minimal organ dysfunction after similar surgery, to better understand which patients are at greatest risk, according to their epigenetic makeup. This study may improve understanding of which patients are likely to suffer organ damage and complications after major surgery, and which patients may have a protective epigenetic makeup which reduces complications. With this knowledge, the investigators aim is that future patients could receive personalised treatment plans before surgery, to modify their epigenetic makeup, reduce harm from complications and improve outcomes for patients. The investigators are not testing any new treatments in this study.

This study wants to see if the medicine colchicine can help lower inflammation and reduce the chance of developing an irregular heartbeat (atrial fibrillation) after heart bypass surgery. Adults having coronary artery bypass surgery (CABG) can join. Participants will be randomly placed into one of two groups: one group will receive colchicine along with usual care, and the other will receive a placebo (a look-alike capsule with no medicine) along with usual care. Everyone will take a study capsule, and neither the patients nor the study team will know which capsule is being given. Everyone in the study will take study capsule, and neither the patients nor the study team will know who is receiving colchicine or placebo. Blood samples and health information will be collected before surgery; at 24, 48, 72, and 96 hours after surgery; and again at 10 days after surgery or at hospital discharge, whichever comes first. The investigators will look at inflammation marker levels, whether atrial fibrillation happens, and any side effects. This small study will help to generate effect size estimates and safety data that will help plan a larger study in the future.

Cardiac surgery is a high-risk surgery and is associated with a rate of postoperative adverse outcomes. Like many others major surgery, cardiac surgery procedures induce a proinflammatory phase usually counterbalanced with an immunosuppressive phase so the immune response remained balanced. In some cases, the immune response might be dysregulated with a more pronounced pro inflammatory state that compromises organ perfusion and with the occurrence of organ failure. From a mechanistic approach, the relationship between organ failure is complex and multifactorial with a high level of proinflammatory cytokines, a decrease in microcirculation, an endothelial dysfunction and an activation of coagulation and over. The clinical expression is an increase in vasopressor exposure and dose, an increase in mortality and in adverse outcomes with a predominance of acute kidney injury. Various therapies have been assessed to manage cardiac surgery related sepsis including glucocorticoid therapy. Briefly, two major randomized trials assessed glucocorticoid therapy solely in scheduled cardiac surgery with cardiopulmonary bypass. No clinical benefit was demonstrated in term of reduction in postoperative mortality or adverse outcomes. Since, data support that the selection of patients at risk is crucial to demonstrate such a strategy. Indeed, data support that surprisingly some patients will have a very light immune response reflected by a low pro inflammatory cytokine. The hypothesis is that the combination glucocorticoid and fludrocortisone could decrease adverse outcomes in selected patients.