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Title: The role of the Toll-like receptors in systemic inflammatory response to cardiac surgery
Author: Naase, Hatam
ISNI:       0000 0004 6421 0170
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Background: Cardiac surgery with cardiopulmonary bypass (CPB) can lead to a spectrum of post-operative complications as a result of activation of systemic inflammatory responses. Cellular injury can lead to the release of damage-associated molecular patterns (DAMPs) such as mitochondria DNA (mtDNA), which act as a ligand activating leukocytes and endothelial cells via innate immunity receptors such as Toll-like receptor 9 (TLR9). However, the contributions of DAMPs to inflammatory responses to CPB are unknown. Aim: This study is to identify the DAMPs and associated receptors that drive systemic inflammatory responses to surgery, which may lead to the identification of novel anti-inflammatory interventions such as TLR antagonists with subsequent translation of our findings to the clinical field. Additionally, Post-operative atrial fibrillation (POAF) is frequent complication in cardiac surgery, which may contribute to the inflammatory response. We aimed to identify a possible predictor for POAF, which may lead to its prevention or early management. Methods: Sixty-six patients undergoing CABG were recruited, 44 with on-pump and 22 with off-pump CABG (OPCAB) to compare the effect of CPB. To identify the effect of ischemic heart disease (IHD) on the mtDNA release. We recruited a separate group of 22 patients undergoing aortic valve replacement (AVR) with normal coronary angiogram. Blood samples were taken at different time-points to CPB. Quantitative PCR was generated to quantify mtDNA concentration (Chapter 3). Pro-inflammatory biomarkers such as interleukines, interferons, MAP kinases , NF-κB and other biomarkers were assessed by PCR array (Chapter 5). Both mtDNA and the proinflmmatory biomarker were preoperatively compared to assess of the development of POAF (Chapter 6). Additionally, we used different animal models experiments, to establish the effect of surgery and CPB on TLR9 signalling and to test the effect of blocking TLR9. Specifically, we performed sternotomy in mouse and rat models respectively and performed sternotomy with CPB in the pig model (Chapter 4). Results: mtDNA was significantly higher in patients with IHD than those without (p < 0.01). CABG with CPB led to a significant elevation in serum mtDNA levels compared to OPCAB (p < 0.001 at peak of CPB time). The potential downstream activation of TLR9 also showed significant elevation in all cytokines and chemokines utilizing the TLR9 signalling pathway (p varies from < 0.001 - < 0.05) but not those using other signalling pathway (p > 0.05). Blocking the TLR9 in mice has significantly reduced the production of proinflammatory cytokine (IL-6). INF-α and mtDNA were the only independent predictors for POAF development. Conclusion: Elevation in circulating mtDNA level is related to the extent of the IHD. CPB can influence the release of circulating mtDNA and proinflammatory cytokines production via signalling the TLR9, which may contribute to the initiation of a sterile systemic inflammatory response. The mtDNA and INF- α were independent predictors for development of POAF, which are in agreement with the inflammatory theory that relates the inflammation to the POAF development.
Supervisor: Athanasiou, Thanos ; Evans, Paul ; Angelini, Gianni Sponsor: Biosensors
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral