Current Medical Research and Opinion (1996), 13, No. 7, 379-390
LDL subfractions and atherogenicity:|
an hypothesis from the
University of Glasgow
C. J. Packard, MRCPath, DSc
Professor of Pathological Biochemistry, Department
of Pathological Biochemistry, Glasgow University,
Accepted: 8th April 1996
The small dense LDL III particles are more atherogenic than the lighter fractions. Poor recognition by the LDL receptor-mediated clearance mechanism allows them to stay in the plasma compartment for longer, thereby penetrating the arterial intima more readily. In addition, they are more readily oxidised and may contain less antioxidant, and are more easily taken up by macrophages to create foam cells. The overall effect is highly atherogenic.
The evidence in the medical literature for an association
between LDL density and increased cardiovascular risk is as follows:
The lipid shuttle is the essential process by which the triglyceride-rich lipoproteins exert their atherogenic effect. The speed of the lipid shuttle is determined not by the activity of the enzyme but by the concentration of the triglyceride-rich lipoproteins. High plasma triglyceride levels promote a more rapid cholesterol ester transfer to the LDL subfractions, thereby increasing the atherogenicity of the lipoprotein profile. Conversely, lower plasma triglyceride levels slow the lipid exchange, reducing the atherogenicity of the LDL subfractions.
The atherogenic lipoprotein phenotype carries a very
high risk of premature cardiovascular disease. Roughly speaking,
normal total cholesterol, together with a triglyceride level above
2.0 mmol/l and an HDL cholesterol below 1.0 mmol/l
(the hallmarks of ALP) carries the same risk as a total cholesterol
of 6.5 mmol/l in a patient whose triglycerides
and HDL are within the normal range. If that cholesterol level
is accompanied by a triglyceride level of 2.5 mmol/l
and an HDL cholesterol of less than 1 mmol/l the
risk is more than doubled (Figure 2).
Everyone now accepts that a cholesterol of 6.5 mmol/l demands intervention and, because of the 4S study, 7 cardiologists are starting to treat patients whose total cholesterol exceeds 5.5 mmol/l. The atherogenic lipoprotein phenotype deserves the same attention.
The treatment strategy must aim at lowering the triglyceride level in order to slow the CETP lipid shift and drive the dynamic exchange in the reverse direction. The result would be a shift towards larger LDL and HDL subfractions, and a loss of cholesterol ester from the triglyceride-rich lipoproteins. Consequently, the overall atherogenic potential would fall (Figure 3).
One of the most useful effects of the fibrates is their effect on the size distribution and metabolic fate of the LDL subfractions, a direct consequence of their powerful hypotriglyceridaemic effect. The size of the lipoprotein particles seems to be reflected in the length of time that they stay in the circulation. The large light fractions that bind tightly to the LDL receptors are removed quite quickly. The small dense ones, that bind much more weakly to the receptors, are much more persistent, and this persistence is one of the factors that makes them so atherogenic.
|LDL III (mg/dl)|
Adapted from Reference 8.
*The ratio of the risk of CAD or MI between the high and low LDL III groups. Equal risk gives a ratio of 1.0, a higher risk in the low LDL III group gives a ratio less than 1.0, a higher risk in the high LDL III group gives a ratio greater than 1.0
Our results suggest that the risk of coronary artery disease or myocardial infarction is considerably greater in those groups with higher concentrations of plasma LDL III (> 100 mg/dl).8 The relative risk for coronary artery disease associated with LDL III > 100 mg/dl was 4.5 (p < 0.01), and that for myocardial infarction 6.9 (p < 0.001).
We took 8 patients with hypercholesterolaemia (cholesterol > 7.0 mmol/l, triglycerides < 2.3 mmol/l)
and treated them with fenofibrate (100 mg tid) for eight weeks. Radioisotope tracers were used to follow the paths of the fast- and slow-moving LDL
fractions. The method involved treating LDL with cyclohexanedione to modify its structure so that it no
longer binds to the LDL receptor (although in all other respects it behaves like normal LDL). Each patient's
LDL was divided it into two portions, one labelled with 125I and the other with131I. The 131I fraction was
treated with cyclohexanedione and the 125I fraction was left unchanged. In this way, we obtained two
markers that followed the fast- and slow-moving LDL fractions, respectively (Figure 4).
The total mass of cholesterol in each of the LDL pools was calculated, as was the amount of cholesterol that passed into and out of each pool per day (Figure 5).
Unpublished results also showed that fenofibrate shifts distribution of LDL subfractions from the small dense particles derived from pool B to the larger, lighter ones that bind to the receptor. The results suggest that the effect is due to some fundamental influence on the synthesis of LDL particles that increases both their average size and their affinity for the LDL receptor. In these patients, fenofibrate, because of its effect on plasma triglyceride levels, was able to correct the underlying abnormality in LDL metabolism.
The modes of action of the two main classes of agents in this area differ in significant ways. We have discussed the fibrates and their selective activity in reducing triglyceride levels and LDL III concentration. By contrast, the statins have a less selective effect. They work by depleting the liver cell of cholesterol, forcing the cell to take more cholesterol from the plasma. As a result, plasma LDL levels fall. The effect is non-selective: the statins reduce the concentration of all the LDL subfractions equally, although they may have a mildly preferential effect on the larger lighter fractions that bind more tightly to the LDL receptor.15 In patients with raised LDL who have normal triglyceride levels, this is relatively unimportant because most of the LDL will be in the larger, less dense fractions. But, if the plasma triglyceride concentration is high, the proportion of LDL in the small dense atherogenic fraction is greater, and maximum lipid reduction (and clinical benefit) may not be achieved.
A second effect of the triglycerides on the vascular endothelium is their ability to stimulate the synthesis of thrombogenic mediators such as plasminogen activator inhibitor or PAI-1. There is a great deal of evidence that PAI-1 activity is enhanced (and fibrinolysis impaired) in patients with hypertriglyceridaemia.16, 17 It appears that arterial endothelial cells secrete PAI-1, suggesting that enhanced production could suppress local plasmin synthesis and accelerate intra-arterial fibrin deposition. Evidence for this comes from studies in which human arterial endothelial cells that have been incubated with VLDL from hypertriglyceridaemic patients speed up their production of PAI-1.18 VLDL from normolipaemic individuals, on the other hand, has no such effect.19 This strongly suggests a direct link between hypertriglyceridaemia and impaired fibrinolysis.
The prevention of coronary heart disease has focused
exclusively on hypercholesterolaemia. These insights into the
role of triglycerides suggest that clinicians should extend their
vigilance to another group of patients, those with raised triglyceride,
low HDL cholesterol and moderately raised cholesterol that characterise
the atherogenic phenotype. The Glasgow experience suggests that
treatment with a third generation fibrate may bring a reduction
in risk of the same order as that seen in the simvastatin trial.7
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