The pathogenesis of atherosclerosis and new opportunities for treatment and prevention

Summary

Atherosclerosis is the most common disease in the industrialised world and by 2020 is predicted to be the number 1 cause of death worldwide. It is a disease of the intima and media of small to medium sized arteries that develop slowly over many years. A number of risk factors for atherosclerosis have been identified, some of these are reversible and some are not. Most prominent amongst these is an elevated level of plasma cholesterol. The lowering of cholesterol reduces the risk of heart attacks, strokes and all forms of atherosclerotic vascular disease. Nonetheless, 70% of patients go on to get symptomatic disease.

The disease process sets off an inflammatory response involving the vascular endothelium and both T and B cells of the immune system. Adhesion molecules are induced and proinflammatory cytokines and growth factors are produced by cells that orchestrate the atherosclerotic process. Narrowing the lumen of the artery leads to ischaemic symptoms. Within lesions under the influence of proteolytic enzymes released from activated macrophages (or foam cells — the hallmark of atherosclerosis) the centre of the plaque becomes liquefied to take on it’s characteristic “gruel” like appearance. The shoulders of such plaque weaken and it becomes prone to rupture. Plaque rupture may lead to catastrophic thrombosis of coronary or cerebral arteries. The large amounts of tissue factor produced by macrophages make this a particularly likely event. On ulcerated plaques adherent platelets and thrombus create showers of emboli leading to ischaemic attacks.

Like the effective treatment of LDL and it’s role in the prevention of ischaemic attacks there has been a move to develop new drugs that raise HDL. The discovery of the role of a new class of ABC transporter, defective in Tangiers disease, responsible for cholesterol efflux from peripheral cells including the macrophage has created great excitement around ABC1 as a drug target. New areas, new possible targets and new genetic and genomic approaches will be discussed.