Endothelial dysfunction in hypercholesterolemia and obesity: treatments and preventions

This thesis addresses endothelial pathologies in early cardiovascular disease. It examines risk factors such as hypercholesterolemia and obesity and explores adjunct treatment strategies and novel biomarkers. As well a comprehensive assessment of novel methodologies to assess endothelial function in man and patients with cardiovascular disease was undertaken. Patients with hypercholesterolemia are regularly treated with statins which effectively, and with minimal side effects, lower low density lipoprotein (LDL) cholesterol by 18-55% (Ballantyne, 2007). However, despite the efficacy of statin therapy, the majority of patients with hypercholesterolemia remain at higher risk of developing cardiovascular disease than healthy individuals (GISSI-HF Investigators 2008). Omega-3 fatty acids, members of the polyunsaturated fatty acids (PUFAs) family, have been demonstrated to be effective in reducing triglyceride levels and blood pressure (Lungershausen et al., 1994). Omega-6 fatty acids, on the other hand, have opposing actions (Dubnov & Berry 2004). Little, however, is known about the influence of the ratio of omega-6:omega-3 PUFAs. In Chapter 2, a dietary intervention examining the effects of altering omega-6:omega-3 PUFAs ratio on vascular health in patients on statins was conducted. We were primarily interested as to whether the introduction of a diet rich in PUFAs could improve vascular health in patients already on standard clinical care. A secondary interest was to study whether a low or high omega-6:omega-3 PUFAs ratio diet was more efficacious. We found that the diet interventions improved endothelial function and blood pressure but neither high nor low omega-6:omega-3 PUFAs ratio was better than the other. Obesity is the leading preventable cause of death worldwide, contributing to the likelihood of cardiovascular disease and type II diabetes. Cardiovascular risk factors are associated with decreased levels of circulating endothelial progenitor cells (EPCs), marked by combinations of CD133, CD34, CD117 and KDR markers in flow cytometry (Muller-Ehmsen et al., 2008) and increased intima-media thickness (IMT) (Lorenz et al., 2010). Weight reduction has been associated with reduction in cardiovascular risk factors (Karason et al., 1999; Muller-Ehmsen et al., 2008). In Muller-Ehmsen's study, the participants only underwent dietary intervention plus physical activity for six months and no study was performed to examine the function of EPCs in these subjects. In contrast, there was evidence of increased EPCs (colony forming units - a measure of EPC function) and increased IMT in the severely obese cohort in our study, which weight reduction had no impact on. Endothelial dysfunction, defined as decreased bioavailability of nitric oxide (NO), is an early manifestation in atherosclerosis (Kuvin et al., 2003). The evaluation of endothelial function in vivo is therefore commonly used to identify individuals at high risk for atherosclerosis, as well as for risk stratification of patients with established coronary artery disease (CAD) (Tousoulis et al., 2005). Several invasive and non-invasive techniques have been developed to evaluate endothelial function. Non-invasive techniques are clearly more advantageous in the clinical setting. Methodologies using flow-mediated dilation (FMD) assessed by Doppler and strain-gauge plethysmography are commonly used in human experimental research studies while the FDA approved EndoPAT-2000, a novel technique is arguably yet to be validated. In Chapter 5, we compared the assessment of endothelial function using this methodology against the other two better established methods in both healthy individuals and patients at high cardiovascular risk. We found evidence of endothelial dysfunction in the high cardiovascular risk group using all three techniques. However, while the correlation between both the established techniques were significant, neither correlated with assessment using the EndoPAT-2000. It is concluded that assessment of function using the EndoPAT-2000 requires further validation in this and other populations.