HDL-structure and function in relation to cardiovascular disease

Coronary heart disease (CHD) is the most common cause of death in Western societies. This disease affects both men and women and accounts for approximately 500,000 deaths annually in the U.S.A. alone. For a number of years, plasma concentration of HDL cholesterol (HDL-C) was found to correlate inversely with the incidence of coronary heart disease and atherosclerosis. In addition, other studies in humans showed that higher plasma HDL-C levels correlates with slower progression of atherosclerotic lesions and possible stabilization of unstable atherosclerotic plaque. These findings have led to the suggestion that raising HDL-C will protect from the disease. One of the first trials demonstrating the potential benefit of raising HDL-C levels was the Helsinki Heart Study. In this randomized trial, 4081 men with dyslipidemia received gemfibrozil or placebo and five years later it was seen that the drug reduced CHD risk. Gemfibrozil treatment increased HDL-C levels by 11% but also reduced total plasma cholesterol levels by 10%, LDL-C cholesterol levels by 11% and triglyceride levels by 35%. Although all fibrates have been revealed to raise HDL-C significantly, their overall effect on all-cause mortality and cardiac mortality remains debatable. More recent studies have suggested that the relationship between HDL and cardiovascular risk is more complex than first thought and extends beyond consideration of levels of total HDL-C in plasma. In particular, Mendelian randomization studies challenged the existing view on HDL-C and cardiovascular risk and prompted a discussion as to whether low HDL-C is a causal risk factor for the development of heart disease. In parallel, research interest has intensified in studies aimed at better understanding the many biological functions of HDL and the partner proteins and receptors with which it interacts. There have been a number of studies over recent years indicating that HDL can fail to function effectively in subjects at risk for coronary diseases. It is important therefore to attempt to understand if abnormalities in HDL function are associated with variation in CVD risk. This is especially true in light of the failure of recent trials that raise total HDL to reduce risk of myocardial infarction and CVD. A feature that appears to be related to the atheroprotective functions of HDL is the relative level and distribution of HDL subpopulations in different individuals. Although HDL is unusually regarded as a single entity in clinical settings, studies using non- denaturing two-dimensional electrophoresis have revealed a number of HDL particles with distinct shape, size and composition. Along the same lines, administration of statins - a medication proven to reduce CHD risk - to patients increases specific subpopulation of HDL suggesting that some of the atheroprotective properties of statins may be mediated by increasing selected HDL subpopulations. The overall objective of the present work was to examine in details the relationship of HDL oxidation potential, the ability of HDL to protect LDL from oxidation, and the abundance of the major antioxidant enzyme, PON1, to atherosclerosis in a cross section of subjects recruited from across the social economic spectrum in the West of Scotland (the pSoBid study). PSoBid is valuable as a means of testing these properties of HDL because of its mix of males and females, wide age range, and the fact that it focused in recruiting people at extremes of social deprivation with widely varying lifestyles. The population has been well characterized in terms of classical risk factors and this thesis takes the investigation to a new level of detail with respect to HDL. The major questions addressed were: 1. Is HDL oxidation (measured by three factors; time at half maximum (T1/2max), maximum velocity of oxidation (Vmax), or maximum amount of oxidized HDL measured by optical density) related to a commonly used index of atherosclerosis? 2. Is HDL antioxidant potency to protect LDL from oxidation related to its protective effect in atherosclerosis risk? 3. Is HDL PON1 activity related to atherosclerotic marker? 4. If some HDL subclasses, rather than HDL-C, are particularly related to atherosclerosis? Our major findings revealed that: 1. HDL is more readily oxidized in those subgroups associated with less atherosclerosis. 2. The susceptibility of HDL to oxidation was also related to lifestyle factors associated with less atherosclerotic disease such as moderate alcohol intake, not smoking, active exercise habit and high intake of fruits and vegetables. 3. For HDL structure, %HDL2b was inversely associated with atherosclerosis while %HDL3b was directly associated with atherosclerosis. 4. Comparing the two factors which were inversely associated with atherosclerosis, HDL oxidation and the distribution of HDL subpopulations, our results revealed that HDL oxidation potential was more important than the percentage HDL subfraction distribution in relation to atherosclerosis. 5. HDL mediated inhibition of LDL oxidation was not found to be associated with carotid atherosclerosis nor did it appear to be related to major risk factors. Our interpretation for atherosclerosis is that HDL particles, which are very abundant in the circulation, might play a sacrificial role in that they are oxidized first and therefore have the capacity to prevent LDL oxidation in vivo