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.

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Methods: Patients were randomised to off-pump coronary artery bypass grafting (OPCAB) or conventional coronary artery bypass grafting with cardiopulmonary bypass (CABG-CPB). Small intestine function was assessed by differential four sugars (0=methyl-D-glucose, D-xylose, L-rhamnose, and Lactulose) permeability and absorption tests before surgery, at day 1 and day 5 post-surgery. Liver function was assessed before and at the end of surgery by monoethylglycinexyhdide (MEGX)/Iidocaine ratios after injection of 1 mg/kg bolus of lidocaine and by serial measurements of transaminases (AST and ALT), bilirubin, and alkaline phosphatase (ALP).

Purpose: To assess the prognostic effect of coronary collaterals on early and long-term clinical outcomes in patients undergoing first time isolated off-pump coronary artery bypass (OPCAB) surgery.

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Coronary stents are tubular type scaffolds that are deployed, using an inflatable balloon on a catheter, most commonly to recover the lumen size of narrowed (diseased) arterial segments. Even though numerous stent designs, of varying geometrical and material complexity, are used in clinical practice today, the adverse biological responses post-stenting are not completely eliminated. In-stent restenosis (IR), reduction in lumen size due to neointima formation within 12 months of procedure, and stent thrombosis (ST), formation of a blood clot inside a stented vessel, are the two most common adverse responses to stents. Such adverse responses are multifactorial and their causes are not completely understood. However, the geometric design of a stent, which is a common differentiating factor between the numerous commercially available stents, is known to be a key factor influencing adverse responses. In light of the above, this thesis exploits stent geometry parameterisation in both constrained and multiobjective optimisation. Gaussian process surrogate modelling is used to cost effectively (a) understand the influence of stent geometry parameters on metrics indicating adverse response, and (b) obtain families of stent designs which are potentially more resistant to such responses. Various computational models are developed to evaluate the efficacy of a stent in terms of the factors influencing the adverse responses. In particular, two finite element analysis (FEA) models and two computational fluid dynamics (CFD) models are developed. The FEA models are used to simulate the balloon-expansion of stents in a representative coronary artery and bending of stents on application of bending moments. On the other hand, the CFD models simulate haemodynamic flow in the stented artery and the associated drug-release into the tissue. The expansion FEA models are validated against manufacturer provided pressure-diameter relationship and the flexibility FEA models are validated against the numerical studies found in literature. The numerical models are then used to extract metrics which are related to the adverse responses. Six metrics are formulated: (i) acute recoil, which measures the radial strength of the stent; (ii) volume average stress, which measures potential arterial injury caused by the stenting procedure; (iii) haemodynamic low and reverse index, which measures the haemodynamic alteration relevant to IR; (iv) volume average drug, which measures the amount of anti-proliferative drug delivered into the tissue; (v) drug deviation, which measures the uniformity of drug-distribution in the tissue; and (vi) flexibility metric, which measures the deliverability of the stent. These metrics are then used to compare the performance of different geometric stent designs. Two parameterisation techniques – one for a generic ring and link topology of stents, and one for the commercial CYPHER (Cordis corporation, Johnson & Johnson company) – are proposed to study the effect of geometrical variation in stent design on the formulated metrics of efficacy. These techniques are then combined with surrogate modelling to perform stent design optimisation studies and study the effect of stent geometry on the evaluation metrics. Finally, three paradigms to choose optimal stent designs from a set of non-dominated solutions, in terms of the evaluation metrics, are proposed, and optimal designs under such paradigms are identified. The last part of this thesis concerns surrogate assisted optimisation, and is not specific to the problem of stent design. Here, the use of analytically available gradient information in widely used Kriging predictors is explored. A search algorithm to locate all stationary points of a Krig, using a combination of an iterative sequence of the Krig derivative and a low-discrepancy sequence is proposed.

Background: Sick sinus syndrome (SSS) is common and may require electronic pacemaker implantation, gene therapy (biopacemaking) may be an alternative. For SSS, repair may be better than the generation of a de novo biopacemaker, due to the complex nature of the sinoatrial node (SAN). We hypothesised that an ex vivo model of SSS could be created by the identification of a subsidiary pacemaker in the SAN region, and that expression of a pacemaker channel (HCN4 or HCN212) in this region would accelerate the pacing rate. Methods: A bradycardic SSS model was generated by the removal of the upper two thirds of a rat SAN and a system to record the intrinsic activity during tissue culture was developed. The leading pacemaker site of the SSS preparations were identified by activation mapping then characterised by If blockade, β-adrenergic stimulation, histology and immunohistochemistry. Further SSS preparations were injected in this region with recombinant adenovirus (RAd) expressing no functional ion channel (Ad5-GFP or Ad5-GFP-HCN4Δ); or RAd expressing a functional If channel (Ad5-HCN212 or Ad5-PREK-HCN4). During tissue culture electrical activity was monitored using bipolar electrodes. Results: Tissue culture and monitoring of the rat SAN is feasible and does not induce significant changes in HCN4 or connexin-43 expression. The uninjected SSS preparations displayed a slower rate than the control SAN (p<0.001). In 5/6 cases the subsidiary pacemaker was HCN4 -ve and Connexin-43 +ve (in contrast to the SAN) and was close to the superior aspect of the inferior vena cava. The cell size of the subsidiary pacemaker was comparable to that of the SAN and smaller than working myocardium (p<0.001). Pacing was responsive to β-adrenergic stimulation and was partially dependent on If current. The pacing rate of the AdHCN212-injected SSS preparations was significantly faster than the uninjected SSS preparations (p<0.001). The remaining RAd did not significantly affect the pacing rate of the SSS model. Conclusions: There is subsidiary pacemaker tissue close to the superior aspect of the IVC that shares some characteristics of the SAN. These results suggest that adenovirus-mediated expression of HCN channels in subsidiary pacemaker tissue of the right atrium may be a useful strategy in biopacemaking for SSS.

The prediction of adverse outcomes following major non-cardiac surgery is complex. Clinical variables and risk factors, functional status, electrocardiography and non-invasive cardiac investigations can all be used to assess and stratify the risk of post-operative cardiac morbidity or mortality. Multiple factors can be combined into bed-side scoring systems. Increasingly, cardiac biomarkers such as b-type natriuretic peptide (BNP) have been shown to predict heart failure and mortality in non-surgical populations. In the studies in this thesis, I have investigated the incidence of peri-operative cardiac morbidity and mortality in patients undergoing major non-cardiac surgery and identified clinical variables that predicted adverse outcomes. I have tested the utility of BNP for prediction of cardiac complications. I have investigated the long-term survival of the patients in the cohort to identify predictors of reduced survival. I have examined the predictive value of the pre-operative 12-lead ECG for adverse outcomes. I have also studied the utility of a commonly used risk scoring system, the revised cardiac risk index (RCRI), for prediction of cardiac events. The study was a prospectively performed observational study of consecutive patients undergoing major surgery. The cohort consisted of patients undergoing aortic surgery (25.8%), lower limb bypass surgery (29.8%), amputation (25.2%) and laparotomy (20.0%). The patients underwent post-operative screening for myocardial infarction; consisting of serial ECG and troponin measurement. The end-points were major adverse cardiac event (MACE), defined as myocardial infarction or cardiac death and all-cause mortality. Long term follow-up was performed following discharge. Three hundred and forty-five patients were recruited to the trial. Forty-six patients (13.3%) suffered a peri-operative MACE and twenty-seven patients (7.8%) died in the post-operative period (six weeks). Independent predictors of peri-operative MACE were pre-operative anaemia, urgent surgery, a history of hypertension and age > 70 years. Pre-operative BNP was significantly higher in patients who subsequently went on to have a peri-operative MACE, compared with those who did not. An elevated BNP was an independent predictor of both MACE and peri-operative mortality on multivariate analysis. A low BNP was highly indicative of an uneventful post-operative period, with a negative predictive value of 96% for MACE and 95% for all-cause mortality. Traditional clinical markers of heart disease, such as past history of ischaemic heart disease, prior myocardial infarction, cerebro-vascular disease or history of cardiac failure provided no predictive utility for either MACE or mortality. The mortality rate at 1 year was 19.1%. The median follow-up period was 953 days (IQR 661-1216 days). Age > 70 years, diabetes, hypertension, renal impairment, a history of left ventricular failure, anaemia and urgent surgery were associated with reduced long-term survival. A BNP concentration of 87.5 pg/ml provided the best combined sensitivity and specificity for prediction of long-term mortality. Patients with an elevated BNP (>87.5 pg/ml) had a significantly reduced survival and BNP >87.5 pg/ml independently predicted reduced survival on Cox regression analysis. Urgent surgery and anaemia were also independent predictors of reduced long-term survival. An abnormal ECG was observed in 41% of patients recruited. An abnormal ECG was associated with an increased peri-operative MACE and mortality rate. Ventricular strain and prolonged QTc (>440ms) were ECG abnormalities that predicted MACE on multivariate analysis. Patients with an abnormal ECG, but no prior cardiac history, represent a high risk group that may benefit from optimisation. The studies in this thesis have identified that BNP, a simple pre-operative blood test, provides valuable information regarding the risk of both peri-operative morbidity and mortality, and long-term survival after major non-cardiac surgery. Improved risk stratification could allow targeted intervention and medical optimisation prior to surgery with the aim of modifying the risk of adverse outcomes.