The concept of HDL-c as a beneficial lipid was first proposed in the Framingham Heart Study in the latter half of the twentieth century, where low levels of HDL-c were found to be an independent risk factor for future incidence of coronary heart disease (CHD) in 2815 men and women over 12 years of follow-up. This review will summarise previous research attempting to reduce CVD risk through the modification of HDL-c levels, explore recent evidence characterising changes in the composition and function of HDL that may occur in chronic inflammatory diseases, and discuss the potential for future HDL-modifying therapeutic interventions. Recent insights into the complex structural and functional properties of HDL particles-and their vulnerability to modification when exposed to a range of CV risk factors, particularly inflammation-have shed light on the potential reasons for these negative findings, and have posed the question as to whether focusing on the ‘quality’ rather than quantity of HDL may be a more relevant target for drug development. Recent research, however, has called the causal nature of this relationship into question, with genetic studies finding little evidence of an association between elevated HDL-c levels and reduced CVD risk, and a series of major clinical trials failing to demonstrate any clinical benefit when HDL-c levels were pharmacologically raised. Over the past half-century, HDL-c has repeatedly been shown to be inversely associated with risk of future cardiovascular events, and has therefore become one of the most well-known and widely studied risk factors for cardiovascular disease (CVD). High-density lipoproteins (HDL) participate in the transfer of excess cholesterol from peripheral sites to the liver, and the cholesterol carried within these lipoproteins (HDL-c) is therefore often referred to as ‘good cholesterol’. This review will summarise evidence relating HDL to CVD risk, explore recent evidence characterising changes in the composition and function of HDL that may occur in chronic inflammatory diseases, and discuss the potential for future HDL-modifying therapeutic interventions. Evidence suggests that both the composition and function of HDL may be significantly altered in the context of an inflammatory milieu, transforming the particle from a vasoprotective anti-atherogenic particle to a noxious pro-atherogenic equivalent. Instead, focus has switched to the functional properties of the HDL particle. More recent research has questioned a causal role for HDL-c in this relationship, however, as both genetic studies and numerous large-scale randomised controlled trials have found no evidence of a cardiovascular protective effect when HDL-c levels are raised. High-density lipoprotein cholesterol (HDL-c) has long been referred to as ‘good cholesterol’ due to its apparent inverse relationship with future CVD risk.
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