(Circulation. 1997;95:1347-1348.)
© 1997 American Heart Association, Inc.
Articles |
New Views on the Relationship of Plasma Lipids to Cardiovascular Disease
the Departments of Pathology (R.P.T.), Biochemistry (R.P.T., P.B.T.), and Medicine (P.B.T.), University of Vermont, Burlington.
Correspondence to Dr R.P. Tracy, Department of Pathology, University of Vermont, 55A South Park Dr, Colchester, VT 05446. E-mail rtracy{at}moose.uvm.edu
Key Words: Editorials • thrombosis • lipoproteins • platelets • lipids
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Introduction |
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In this issue, Nofer et al1 report on a possible new mechanism that may help explain the relationship between plasma lipids and cardiovascular disease (CVD). New views on "established" relationships are always welcome and frequently important. Data supporting the general relationship of plasma lipids and CVD are extensive. The important contributions of Keys and colleagues in the Seven Countries Study2 3 as well as other multipopulation studies4 5 6 clearly established that higher saturated fat and cholesterol in the diet were associated with a greater incidence of CVD. Major epidemiological studies such as the Framingham Study7 established the risk relationship that exists between plasma lipid levels and CVD.
A large body of evidence, including work in animal models and human clinical trials, has established that plasma lipids play a causal role in atherosclerotic CVD. Our belief in causality has resulted in a national effort to document the plasma cholesterol concentrations in healthy individuals and modify them when appropriate under the guidelines prepared by the National Cholesterol Education Panel.8 These guidelines take into account the probable harmful effects of LDL particles and beneficial effects of HDL particles but do not address any possible effects of fasting or postprandial VLDL particles, because data on this topic have been difficult to obtain.
The exact mechanism by which plasma lipids exert this "causal" effect has been the subject of intense research over the past two to three decades. As is always the case when we try to establish exact mechanisms in complex biological systems, this search is far from completion. Although there are many possible ways to categorize this body of work, we might most simply consider two categories: effects on atherosclerosis and effects on thrombosis. In the first category, much recent work has focused on the modifications that occur to LDL particles during their lifetime and the effect of these modifications on the routes of elimination of these particles. In particular, oxidative modifications resulting in so-called "oxidized LDL" cause macrophages to take up LDL particles through a receptor-independent pathway and in this way appear to be important in increasing the atherogenicity of LDL particles.9 Work continues in this area, with recent emphasis on the possible roles of antioxidants such as certain vitamins10 11 and on the different subforms of the HDL and LDL particles.12
In the second category, the focus is less clear. Procoagulant enzymatic complex assembly and activity (eg, prothrombinase) require a surface,13 and there is some evidence that lipoprotein particles may be able to provide this surface.14 However, this role has not been firmly established. Also, it has been suggested that a form of LDL, Lp(a), may interfere with proper fibrinolysis,15 but again this has been difficult to establish in vivo.
With regard to possible connections between lipoprotein particles and platelets, a Medline search covering the past 5 years on blood platelets and hyperlipidemia revealed more than 50 publications, virtually all of which documented some alteration in platelet function with elevated plasma lipid levels in either humans or animal models such as the hypercholesterolemic rabbit. For this relationship to have meaning in the general population, however, there must be a firmly established connection between some aspect of platelet function and CVD risk. Investigators in the Atherosclerosis Risk in Communities (ARIC) study have demonstrated an association between plasma levels of ß-thromboglobulin, a marker of platelet activation, and carotid artery wall thickness,16 whereas investigators in the Caerphilly study have shown cross-sectional relationships between platelet aggregation and the presence of CVD.17 Platelet function is associated with other risk factors, such as smoking,18 and since the proximate cause of most myocardial infarction is thrombosis, platelet function is a good candidate for continuing studies.
The work of Nofer et al1 offers another possible mechanism to help explain the causal relationship of LDL to CVD: altered platelet metabolism resulting in increased platelet responsiveness to activating agents. Their work appears to implicate two separate mechanisms. The first is a short-term effect observed when LDL particles are added to washed platelets, which leads to a significant drop in intraplatelet pH and inhibition of the agonist-induced Na+/H+ exchange protein. This acute effect results in a relative acidification of the platelet, a state known to be associated with an augmented response to activating stimuli. The maximum effect of LDL they observed under these conditions appeared to occur at relatively low LDL concentrations (25 to 50 mg/dL), well below the minimum value observed in most people. Therefore, most people will experience the maximum LDL effect, which raises the question of whether there is significant interindividual variation in the maximum inhibition, a question that awaits further studies.
Apparently, there is also a long-term, chronic mechanism that may involve alterations in the cholesterol content of the platelet membrane. This effect was observed when washed platelets from patients with familial hypercholesterolemia were found to be relatively acidic and exhibited reduced Na+/H+ exchange activity compared with those from healthy control subjects. This effect could be reversed, and in fact normalized, after the lowering of LDL levels in these patients by apheresis methods.
Interestingly, these authors had previously identified an effect of HDL particles that opposes this LDL effect and enhances agonist-induced Na+/H+ exchange activity.19 This suggests that cholesterol transport may not be the only mechanism through which HDL interacts with the atherothrombotic process.
In summary, then, this intriguing and potentially important study should stimulate us to consider several questions: (1) Does the interindividual variation in platelet function observed in relatively healthy individuals play a role in their susceptibility to CVD? (2) What is the interindividual variability in the short-term LDL effect on platelet Na+/H+ exchange? (3) Concerning the long-term effect, what is the variation in intracellular platelet pH in healthy individuals and how does this relate to the plasma LDL concentration in these individuals? (4) How do the platelet effects of LDL and HDL balance each other in the individual?
Answers to these questions and others yet to be posed will be needed before we can come to a conclusion about the importance of the findings of Nofer et al1 for our understanding of atherothrombotic disease. However, the stimulation that accompanies a new view in this area has an importance of its own.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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