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Most LDL-lowering trials are limited in duration while the disease process occurs over decades. It is informative, therefore, to evaluate the long-term effects of treatment by undertaking extended observation beyond the formal double-blind phase of intervention studies. The current review brings together the findings of major trials that have conducted such long-term follow-up.Extended observation of trial cohorts has reinforced the long-term safety of LDL-lowering therapy (with statins and other agents), with no evidence of late development of cancers or other adverse outcomes. Post-trial follow-up reveals also legacy benefits in terms of improved survival (due principally to decreased cardiovascular death rates), and lower hospitalization rates for cardiovascular disease. A number of trials report further risk reduction even after the formal intervention has ceased, and the appearance of delayed benefits such as reduced rate of heart failure.The perceived value of LDL lowering is enhanced significantly by the legacy benefits that persist after administration of treatment to individuals with established coronary heart disease or to those at high risk of developing disease. Safety, efficacy and the economics of intervention can be judged more fully in light of the knowledge gained from extended observation in clinical trials.

This review discusses whether the relationship of small dense low-density lipoprotein to cardiovascular risk is direct, due to the atherogenic properties of the particle, or a reflection of concomitant abnormalities in high-density lipoprotein and plasma triglyceride.Recent studies have examined whether low-density lipoprotein size distribution or concentration of small low-density lipoprotein is related more strongly to risk. It appears that the latter is a better predictor in major surveys, although in smaller cohort studies particle size shows a strong association with atherosclerosis burden. While the main causes of the formation of small dense low-density lipoprotein are relatively well understood, novel metabolic factors may also play a role, and pharmacologic interventions such as glitazones may have a direct regulatory impact.Evidence links abnormalities in low-density lipoprotein structure to cardiovascular risk. The plasma concentration of small dense low-density lipoprotein is likely to be more informative than relative low-density lipoprotein particle size, and although methods are available for quantitation of this subfraction, there is considerable room for improvement. It is not yet clear how knowledge of the small dense low-density lipoprotein concentration may add to risk prediction.

Statin therapy has been conclusively shown to offer patients clinical benefit, virtually irrespective of their baseline risk status. However, the absolute risk reductions observed in different clinical trials, which have recruited patients across a spectrum of lipid levels and vascular disease states, show that baseline global risk determines the absolute benefit gained and in turn will specify the number of patients needed to be treated in order to realize this benefit. Global risk assessment is therefore central to the clinically meaningful use of statin therapy, and a strong case is now argued in the literature for a high-risk primary prevention strategy that goes hand in hand with standard secondary prevention. The routine use of Framingham-based risk assessment tools is advocated because these are the most widely evaluated and have been repeatedly shown to predict the risk of coronary heart disease accurately in western populations. The risk threshold in primary prevention that should determine pharmacological intervention is the subject of controversy. The currently used annual risk figure of 3% would clearly capture all very high-risk individuals but would also deny treatment to many individuals who will subsequently die from their first coronary event. Although a 1.5% annual risk threshold is economically untenable in the present UK health system, a level of 2% is, we believe, both achievable and affordable.

Further understanding of the causative link between plasma lipids and coronary heart disease will come from a deeper appreciation of the impact of lipoprotein heterogeneity on the processes of atherosclerosis and thrombosis. It is now widely appreciated that remnants of triglyceride-rich lipoproteins, IDL and specific LDL subfractions may have a role in atherogenesis disproportionate to the plasma concentrations of these species. Elucidation of the factors that control the distribution of subfractions within the spectrum of apolipoprotein B-containing lipoproteins is underway but far from complete. Important influences are the rate and nature of lipoproteins secreted from the liver, the extent of remodelling by lipid exchange and lipolysis in the circulation and the affinity of the various particles for cell surface receptors.

Apolipoprotein B‐100‐containing lipoprotein assembly is dependent on the successive addition of triglyceride by microsomal transfer protein. Assembly may end at this point and the lipoprotein secreted or it may continue with the bulk addition of triglyceride by an unknown transfer process. These steps are independently regulated and result in the secretion of a spectrum of apolipoprotein B‐100‐containing particles. The production of small, dense LDL is determined by the type of VLDL secreted by the liver. Large, triglyceride‐rich VLDL1 results in the formation of small, dense LDL through triglyceride exchange and subsequent hydrolysis. Small, dense LDL are cleared from plasma relatively slowly and tend to accumulate in the circulation where they exert their atherogenic effects. Curr Opin Lipidol 9:197–202. © 1998 Lippincott–Raven Publishers

Molecular biological studies in familial hypercholesterolaemia have indicated that the severity of the disease, at least in terms of circulating LDL-cholesterol levels, varies depending on the kind of structural defect found in the LDL receptor gene. This may well influence individual risk and signal that more aggressive therapeutic intervention is required. The discovery of the statins has revolutionized therapy for the familial hypercholesterolaemia heterozygote, but the prognosis for the rare homozygote, who fails to respond adequately to therapy, remains poor unless extreme measures are taken.

The recognition of lipoprotein heterogeneity has given new depth to our understanding of lipoprotein metabolism and the role of plasma triglyceride as a determinant of lipoprotein subclass distribution and potential atherogenicity. It has also provided insight into the relationship between exogenous and endogenous lipid transport pathways, the roles of endothelial lipases and lipid transfer proteins in the remodelling of lipoproteins, and the link between insulin resistance, lipids and coronary disease.

Purpose of review To assess recent advances in cardiovascular disease biomarkers, focusing on past failings, current promise, and areas for future work. Recent findings Despite intense interest in novel biomarkers, few have yet to show utility in improving cardiovascular disease risk scores as assessed by predictive statistical models. Indeed, there is current debate as to how to evaluate clinical utility. There is increasing interest in biomarkers from pathophysiological pathways other than inflammation (cardiac signals, renal function, metabolic measures, novel lipids, nutritional, etc), as well as interest in combining such markers in panels to increase cardiovascular disease risk discrimination, and in ‘omics’ techniques. A challenge to the biomarker concept in cardiovascular disease is the contribution of other factors – for example, socioeconomic position or family history of premature cardiovascular disease – that present cheaper and more efficient way of gaining discrimination. Some have been added already to risk score guidelines in some countries. Whether novel plasma biomarkers can add further prediction requires study. Summary The jury is still out on the ability of biomarkers to enhance risk scores in a cost-efficient way. New technologies and statistical models may optimize efforts but use of simpler lifestyle and demographic markers in recent risk scores revisions have raised the bar.

Response to statin treatment can vary widely from person to person as a result of inherited traits (genotype) and acquired characteristics such as obesity (phenotype). The aim of this review is to describe what is known about factors that determine a patient's response, and to offer a mechanism to explain how plasma triglyceride influences the nature and magnitude of lipid lowering on statin therapy.In normotriglyceridemic individuals statins have little impact on the concentration of large VLDL, but as basal plasma triglyceride rises there is an increasing tendency for large VLDL, chylomicrons, chylomicron remnants and small, dense LDL to fall on treatment. These phenotype-dependent effects are in contrast to the phenotype-independent actions on IDL and LDL. Recent studies have also revealed that the principal mechanism by which statins lower VLDL (and LDL) in hypertriglyceridemic individuals is by stimulation of lipoprotein clearance. Individuals with low HDL-cholesterol are increasingly treated with statins. The increase in this lipoprotein affects the subfraction distribution, with a specific increase in alpha1 HDL components. Polymorphism in the promoter for the ABCG8 gene has been linked to variations in response to statins; individuals with the rarer D19H genotype exhibit a greater reduction in LDL-cholesterol. Similarly, the magnitude of the statin-induced increase in HDL-cholesterol has been linked to a polymorphism in the promoter for apolipoprotein A1.Statins are administered to a wide range of individuals on an empirical basis. Investigation of the phenotype and genotype influences on treatment response will allow a more tailored use of these drugs.

Plasma lipoproteins carry a number of highly active enzymes in the circulation. One of these is lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase. This review addresses the molecular properties of Lp-PLA(2), the controversy surrounding its role in atherosclerosis and the regulation of its plasma levels in humans.Recent reports indicate that the enzyme Lp-PLA(2) found in both LDL and HDL may be independently regulated in these lipoprotein subclasses and have distinct roles in atherogenesis. Seminal findings establishing the response-to-retention hypothesis of atherosclerosis support further the potentially damaging role that in-situ release of LDL-associated oxidative products by Lp-PLA(2) may have in the formation of arterial wall lesions. In the mouse, where Lp-PLA(2) circulates mainly bound to HDL, overexpression leads to reduced atherosclerosis, raising the possibility that the enzyme in HDL may have a protective role. Further evidence for a potential protective role is seen in studies of partial or complete deficiency of the enzyme. In the more general setting of population studies, however, it is clear that Lp-PLA(2) is a positive risk factor for coronary disease and measurements of its mass may contribute to the prediction of coronary heart disease risk, especially in individuals with low LDL cholesterol levels.Lp-PLA(2) is an enzyme with potentially multiple risks in atherosclerosis. In humans the weight of evidence suggests that it is a positive risk factor for coronary heart disease - an observation commensurate with its position in the direct pathological sequence leading from formation of oxidized LDL in the artery wall to cellular dysfunction and formation of lesions.