Patient predisposition and the inflammatory response following cardiopulmonary bypass : the role of haemolysis

Cardiopulmonary bypass (CPB) is necessary for the majority of cardiac surgery however it is often associated with the development of the systemic inflammatory response syndrome (SIRS). In a proportion of patients, SIRS is complicated by acute lung injury (ALI) and the more extreme acute respiratory distress syndrome (ARDS). Despite a reduction in mortality with lung protective ventilation, there are no effective therapies for ALI consequent on snCPB. Acute neutrophilic pulmonary inflammation, dysregulated cytokine response and abnormal iron mobilisation/handling have been implicated in the pathophysiology. However, only a minority of at risk individuals develop ALI indicating a predisposing influence for disease onset. CPB induces a host of pro-inflammatory cytokines and also causing a dysregulation of iron-handling, which have also been implemented in the developed of SIRS. This thesis examines aspects of the iron handling and associated inflammatory response in patients undergoing CBP and investigates the hypothesis that genetic variation in the genes associated with these responses influences patient outcome manifest as SIRS. A cohort of patients (n=199) undergoing CPB were genotyped for biallelic single nucleotide polymorphisms (SNPs) in numerous genes including haptoglobin (HP), HAMP, LTA and IL-6 genes using sequence-specific primer polymerase chain reactions and the genotypes related to clinical outcomes. Statistically significant associations were found between polymorphisms in the homozygous carriage of HP-85AA, IL-6 -174C and IL-6 intron 4 allele G with impaired post-operative oxygenation and increased markers of systemic inflammation (i.e. CRP); and in HAMP +1960G and LTA +249A or LTA +723C with abnormal white cell count. Other associations were found with CD163, HO-1 and HO-2, Light and heavy chain ferritin and hepcidin, these results are detailed within the thesis. The findings from these investigations, suggest that genetic variation in iron handling and cytokine genes are associated with increased risk of adverse outcome following snCPB.These findings support a link between abnormal iron handling and the inflammatory response in ALI ensuing from snCPB and have important implications for future research and clinical practice.EThOS - Electronic Theses Online ServiceGBUnited Kingdo