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The role of free radicals and antioxidants in human disease, particularly cardiovascular disease is an area of intensive research. Diabetes mellitus is the most common condition associated with increased oxidative stress and accelerated a therosclerosis.Increased levels of lipid peroxides and diminished antioxidant vitamin status have been reported in diabetic patients and are also implicated in the chronic complications of diabetes. The autoxidation and glycoxidation reactions of glucose are sources of free radicals in vitro and a preliminary investigation that these reactions may be a source of free radicals in vivo was undertaken in patients admitted to hospital with severe hyperglycaemia or diabetic ketoacidosis. Plasma lipid peroxides were elevated 2-7 fold above the reference range, but decreased during the recovery period in these patients. Plasma urate and ascorbate levels decreased rapidly, whilst interestingly, a-tocopherol levels / lipid ratios were preserved. The study indicated the resilient nature of the antioxidant defences in plasma, although further studies are required in order to elucidate fully the role of autoxidation and glycoxidation reactions in vivo. Insulin resistance and hyperinsulinaemia are also tightly linked with atherogenesisin type II diabetes and weight loss in obese subjects plays an important part in the reversal of insulin resistance. The safety and efficacy of two weight loss interventions - very low calorie diet (VLCD) and intensive conventional dietetic (ICD) therapy - on cardiovascular risk factors and indices of oxidative stress were investigated in obese diabetic and non-diabetic subjects. The ICD therapy produced modest weight loss in patients with established diabetes with transient improvements in diastolic blood pressure and plasma ascorbate, but with a reduction in vitamin E/ serum lipid ratios. The VLCD produced large and rapid weight loss in diabetic and non-diabetic patients with improvements in cardiovascular risk factors, lipid peroxides and vitamin E/ serum lipid ratios, which were maintained after 12 months. Plasma ascorbate concentrations were significantly lower in diabetic patients than nondiabetic patients on the VLCD, indicating that formulated diets may require higher concentrations of vitamin C for diabetic patients and this requires further investigation. The VLCD successfully reversed type II diabetes and normalized plasma lipid peroxide levels in two newly diagnosed patients.

Catheter ablation complex or fractionated atrial electrograms (CFAE) may improve outcomes for persistent AF. However, it is unclear whether CFAE are important in maintaining AF or whether targeting of CFAE can be refined based on electrogram morphology or knowledge of the remodelling process. A detailed classification of CFAE was described. Assessment of 100 CFAE by visual inspection in real time correlated well with detailed offline measurement. Targeting of different CFAE morphologies in 20 patients with persistent AF caused cycle length prolongation only with ablation of certain CFAE morphologies. Therefore, targeting CFAE is not simply atrial de-bulking, certain CFAE morphologies are more important for maintaining AF. A computer model was established to simulate LA wall stress using a 3D reconstruction of the chamber from CT imaging. Electrophysiologic data was acquired in 19 patients in persistent AF and compared to simulated wall stress data. Peaks in wall stress were associated with areas of low voltage suggestive of focal remodelling. CFAE were not associated with peaks in wall stress or areas of remodelling. Wall stress did not determine whether ablation of CFAE caused cycle length prolongation. Long term outcome of catheter ablation for AF was good with little late recurrence. Outcome for persistent AF was improved by targeting CFAE in addition to pulmonary vein isolation and may reduce late recurrence.

Thesis (M.S.)--Boston University