Reconstituted HDL: A Therapy for Atherosclerosis and Beyond

Andrew J Murphy; Jaye Chin-Dusting; Dmitri Sviridov

Disclosures

Clin Lipidology. 2009;4(6):731-739. 

In This Article

Abstract and Introduction

Abstract

Cardiovascular disease is the leading cause of death in developed countries. As low levels of the cardioprotective particle HDL are associated with cardiovascular disease, raising HDL levels may lead to positive outcomes. Reconstituted HDL (rHDL) therapy in humans has resulted in regression of atheroma volume and plaque remodeling. The applications of rHDL appear vast as encouraging results in improving glucose uptake and insulin levels have also been reported in Type 2 diabetics. The potent anti-inflammatory properties of rHDL can also be exploited to reduce inflammation is diseases such as rheumatoid arthritis. Furthermore, as HDL is an inert particle, it may also have applications in drug delivery. This paper discusses the results obtained to date with rHDL therapy and provides an outlook into the future in regards to potential uses.

Introduction

Cardiovascular disease (CVD) is still the leading cause of global morbidity and mortality despite advances in clinical management; therefore, novel therapeutic alternatives remain a high priority. Thus, even though current treatments for CVD are improving, largely owing to better risk management and the use of statins, the majority of adverse vascular events are not averted. Thus there is a clear need for alternative therapeutic approaches to manage CVD.

Numerous studies have demonstrated that HDL is an inverse predictor of CVD and it has been hypothesized that HDL could be developed as a cardioprotective drug.[1] Further research has also demonstrated that HDL induces a number of cardioprotective functions. These include the ability to facilitate reverse cholesterol transport (RCT), act as an anti-inflammatory and antithrombotic particle and regulate vascular tone by stimulating nitric oxide (NO) production.[2,3] Thus, there is considerable evidence to suggest that an increase in the circulating levels of HDL in patients suffering from CVD may reduce the burden of disease. Furthermore, the complex nature of the HDL metabolic pathway opens the avenue for a number of potential strategies to raise HDL levels.

HDL is an extremely complex particle, comprising numerous lipid species and proteins/enzymes that are constantly changing through the life cycle of the particle.[4] The make-up of HDL also affects its size, structure and function. Manipulating the HDL pathway may selectively affect a particular species of HDL and select for a particular population that may not afford all of the known cardio-protective effects of HDL. Therefore, a potentially more effective approach to increasing HDL levels is to intravenously infuse a synthetically derived form of HDL termed 'reconstituted HDL' (rHDL).[5] This may remove some of the variation as a particle that is controlled for size and make-up can be delivered. Another synthetic HDL that may be considered are the apoA-I mimetic peptides, elegantly reviewed by Sethi et al.;[6] however, this article focuses on particles constructed from apoA-I proteins. This paper focuses on evidence suggesting that rHDL therapy may be a promising alternative for treating CVD. We will discuss the various rHDL particles, the currently tested applications for rHDL therapy and possible future applications, including its potential as a drug delivery device and as a diagnostic/therapeutic.

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