Atherosclerotic Plaques - current knowledge and future clinical needs

Myocardial infarction and stroke, resulting rupture of unstable atherosclerotic plaques account for a huge cost in human tragedy in addition to a health bill in excess of £1.7 billion per annum.Stabilisation of the unstable plaque remains an unmet clinical challenge, despite current therapeutic regimens.

Complex fundamental biological processes, such as, inflammation, thrombogenesis, changes in cell phenotype, which lead to the unstable plaque, are shown to be ameliorated by high-density lipoproteins (HDLs).HDLs can also reduce the production of factors, such as cytokines and oxidised lipoproteins, known to induce inflammation and thrombogenesis. These data support the hypothesis that HDLs could maintain atherosclerotic plaque stability and ultimately reduce the devastating clinical sequelae of plaque rupture.

We propose investigating the ability of HDLs to stabilise atherosclerotic plaques by infusing reconstituted HDL into patients 24 hours before they have atherosclerotic plaque removed from their carotid artery.Using quantitative molecular techniques we will compare the expression of thrombomodulatory genes in atherosclerotic plaque material between treatment and placebo groups.

This work represents the first clinical analysis of the effects of rHDL on gene expression in the atherosclerotic plaque and will provide a foundation for further studies aimed at understanding the atheroprotective mechanism of action of HDLs.With an enhanced interest in raising plasma HDLs it is becoming imperative that we learn the precise mechanism of action of these lipoproteins.