Are the effects of statins on HDL-cholesterol clinically relevant?

Transcription

1 European Heart Journal Supplements (2004) 6 (Supplement C), C58 C63 Are the effects of statins on HDL-cholesterol clinically relevant? M.J. Chapman National Institute for Health and Medical Research (INSERM), Unit 551, H^opital de la Pitie, Paris Cedex 13, France KEYWORDS Atheroprotection; High-density lipoprotein; Low-density lipoprotein; Statin therapy Introduction The relationship between plasma high-density lipoprotein (HDL)-cholesterol levels and the development of atherosclerosis is complex. However, it has been established that an independent, inverse relationship exists between the level of plasma HDL-cholesterol concentration and the risk of coronary heart disease (CHD). 1 Subnormal HDLcholesterol levels (<44 mg dl 1 ) constitute the most common form of familial dyslipidaemia occurring in kindreds with CHD. 2 Moreover, a meta-analysis of four prospective studies (the Framingham Heart Study, the Multiple Risk Factor Intervention Trial (MRFIT), the Lipid Research Clinics Prevalence Mortality Follow-up Study and the Coronary Primary Prevention Trial) revealed that CHD risk is elevated by 3% in women and 2% in men for each 1 mg dl 1 (0.026 mmol l 1 ) decrement in HDL-cholesterol. 3 However, the question of whether each 1 mg dl 1 increment in HDL-cholesterol may confer a 2 3% decrease in CHD risk awaits confirmation in prospective trials in which the clinical benefit of raising HDL-cholesterol can be readily identified, independently of reduction Correspondence: National Institute for Health and Medical Research, H^opital de la Pitie, 83, boulevard de l h^opital, Paris Cedex 13, France. Tel./fax: þ address: chapman@chups.jussieu.fr (M.J. Chapman). It has been established that the level of plasma high-density lipoprotein (HDL)-cholesterol is inversely proportional to the risk of coronary heart disease (CHD). HDL particles are highly heterogeneous, particularly in terms of their biological activities, many of which are atheroprotective. For example, in addition to carrying out reverse cholesterol transport, HDL protects the vascular endothelium by inhibiting monocyte adhesion and the oxidative modification of low-density lipoprotein (LDL), eliminates some of the atherogenic products of LDL oxidation, and possesses antithrombotic activity, due to the inhibition of platelet activation and aggregation. Statin therapy has been shown to increase the level of plasma HDL-cholesterol. However, the clinical benefit of statin-induced elevation of HDL-cholesterol is unclear from trial data, perhaps as a result of the concomitant overwhelming risk benefit of statin-induced reduction of LDL-cholesterol. c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. in levels of atherogenic apolipoprotein B-containing lipoproteins. Nevertheless, high levels of HDL-cholesterol (>65 mg dl 1 (1.7 mmol l 1 ) were shown to afford protection against CHD events in the Framingham Study, even when low-density lipoprotein (LDL)-cholesterol concentrations were elevated above 160 mg dl 1 (4.1 mmol l 1 ) (Fig. 1). 4 At low levels of HDL-cholesterol, however, the level of LDL-cholesterol is the more robust predictor of risk and, indeed, CHD risk is elevated at all concentrations of LDL-cholesterol (Fig. 1). 4 Despite such observations at the population level, the precise impact and value of raising HDL-cholesterol in a given individual remains uncertain, particularly as clinical benefit may be conditioned by the global risk profile of that individual, thereby reflecting risk factor interaction. 5 The guidelines of the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) recognize low levels of HDL-cholesterol as a major cardiovascular risk factor, although specific targets for HCL-C are not recommended. 6 The structure and function of HDL In order to understand the mechanistic basis of the antiatherogenic activity of circulating HDL particles, it is X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi: /j.ehjsup

2 Are the effects of statins on HDL-cholesterol clinically relevant? C59 FC,PL ABCA1 ApoAI Apo AI FC+PL Pre-β-HDL LCAT Liver Intestine LCAT Discs (PL+FC+apoAI) Plasma HDL Pool Fig. 1 HDL-cholesterol versus LDL-cholesterol as a predictor of cardiovascular risk: Framingham data. This information was originally published in [4]. necessary to consider their structure and function. The HDL fraction is defined as that isolated over the density range from to 1.21 g/ml; these particles equally exhibit small size (Stokes diameter 5 17 nm). 7 HDL particles are highly heterogeneous, due to qualitative and quantitative differences in lipid, protein and enzyme content, and vary in their hydrated density, surface and core fluidity, surface charge and antigenicity. 8 Typically, ultracentrifugation separates two major HDL fractions: HDL 2 (1:063 < d < 1:125 g/ml) and HDL 3 (1:125 < d < 1:250 g/ml). HDL contains two major apolipoproteins ApoA-I and ApoA-II, and minor amounts of the low molecular weight apolipoproteins ApoE, C-I, C-II and C-III. The surface of an HDL particle is covered by apoproteins, phospholipid and free cholesterol. The core of HDL particles, which may constitute up to 20% of the total particle mass, contains both cholesteryl ester (CE) and triglycerides (TG). Most HDL particles are quasi-globular in shape and migrate on agarose gel electrophoresis in a fraction with a-electrophoretic mobility. However, newly synthesized HDL molecules lack a central nonpolar core, have a disc-like bilayer structure, and exhibit pre-a- or pre-b-electrophoretic mobility. Structurally, there are two major families of HDL particles: those that contain ApoA-I alone, and those that contain both ApoA-I and ApoA-II. The former contains two major particle subpopulations on the basis of size, whereas the latter contains three. These particle species are spread throughout the density range g/ml. In addition to their physicochemical heterogeneity, HDL particles are highly heterogeneous in their origin, formation, intra-vascular metabolism and tissue catabolism. Furthermore, it is becoming increasingly clear that HDL particles are even more heterogeneous in terms of their biological activities. HDL formation The liver and intestine are able to produce the major apoproteins of HDL and there are three major pathways of HDL formation (Fig. 2). Fig. 2 Chylomicrons VLDL Lipolysis Pathways of HDL formation. 1. ApoA-I can be secreted in lipid-poor form and, through the ATP binding cassette transporter protein AI (ABCA1), it can pick up free cholesterol on phospholipid from peripheral cells, to form pre-b- HDL particles, which are avid acceptors of cellular cholesterol. Under the influence of the lecithin:cholesterol acyltransferase (LCAT) enzyme, free cholesterol is esterified to CE and these particles are transformed into spherical, mature HDL, which contains a CE-rich hydrophobic core. 2. Nascent discoid particles containing ApoA-I, phospholipid and free cholesterol are secreted and transformed, by the action of the LCAT enzyme, into mature HDL. 3. TG-rich lipoproteins, chylomicrons and very low-density lipoprotein (VLDL) are lipolyzed by lipoprotein lipase and, as a consequence, surface fragments containing phospholipid, free cholesterol and small apoproteins are released from these particles. These surface fragments sequester to the HDL pool. Since this pathway is deficient in individuals with hypertriglyceridaemia, we can reasonably predict that HDL levels will be subnormal in these individuals. Biological properties of HDL particles LDL Surface fragments PL+FC + Apo s Since the original seminal hypothesis of Gordon et al. was proposed in 1977, 9 the atheroprotective role associated with HDL has become widely recognized. Whether HDL is implicated directly or indirectly in atherogenesis has still to be determined, but a plethora of potential mechanisms that may account for the cardioprotective effects of HDL have been documented, several of which may be mutually interactive and, indeed, synergistic. The inverse correlation between HDL levels and CHD risk might be explained by the ability of HDL to remove cholesterol from the peripheral circulation and deliver it to the liver for excretion in the bile, in the process known as reverse cholesterol transport. 10 ApoB100-containing particles deliver cholesterol to peripheral tissues and to

3 C60 M.J. Chapman the developing plaque, whereas HDL, primarily through the scavenger receptor class B type I (SR-BI/Cla-1) and LIMPII analogous 1 (CD-36) receptor on human macrophages, is able to pick up cholesterol from atherosclerotic plaque and return it to the liver for excretion in the form of bile acids. Although reverse cholesterol transport is one of the major functions of HDL particles, HDL exerts several other potentially anti-atherogenic actions. An early cellular event in atherogenesis is the adhesion of mononuclear leukocytes to the endothelium. This occurs via the expression of cell adhesion molecules on the endothelial surface, principally vascular cell adhesion molecule-1 (VCAM-1), but also intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Cytokine-induced expression of VCAM-1, ICAM-1 and E-selectin is inhibited by HDL, the most pronounced inhibition of these molecules occurring at physiological concentrations of HDL HDL, in particular HDL 2, has also been shown to abrogate the adhesion of monocytes to endothelial cells that is induced as a result of the upregulation of monocyte chemotactic protein-1 by oxidized LDL. 14 The oxidation of LDL is an integral part of the atherosclerotic process. Oxidized LDL acts as a chemoattractant for monocytes, transforms macrophages into foam cells, exerts cytotoxic effects on the endothelium, stimulates the migration and proliferation of vascular smooth muscle cells (VSMC), and exacerbates the vasodilative effect of nitric oxide. 15;16 HDL has been shown to inhibit the oxidative modification of LDL. 17;18 This antioxidant activity is due in part to the fact that HDL particles contain the enzyme paraoxonase, which hydrolyzes lipid peroxides. 10;19 HDL can also eliminate some of the products of LDL oxidation, such as cytotoxic lipoperoxides and lysophosphatidylcholine The formation of atherosclerotic plaques is generally preceded by functional changes in the vessel wall, which include reduced local availability of nitric oxide, enhanced surface expression of cell adhesion molecules, changes in inflammatory markers, production of cytokines, and the oxidative modification of lipoproteins Vessel function is controlled predominantly by the endothelium, and endothelial dysfunction may promote intra-vascular coagulation and macrophage infiltration into the vessel wall, decrease fibrinolysis and impair vasorelaxation. 26 By inhibiting the oxidation of LDL, HDL protects the endothelium from acetylcholine-mediated vasodilatation, and antagonizes the inhibition of vasodilatation caused by lysophosphatidylcholine. 27;28 HDL has also been shown to inhibit the infiltration of oxidized LDL into the vessel wall. 28 HDL can protect endothelial cells from complementmediated lysis 29;30 and has been shown to be a carrier of the glycoprotein protectin, which inhibits complement cytolysis. 31 In addition, HDL can stimulate endothelial synthesis of prostacyclin and prolong its plasma half-life, which enhances vasorelaxation. 32;33 Similarly, HDL can stimulate the production of endothelin-1 by endothelial cells, 34 and modulate the production of naturietic peptide C. 35 HDL also possesses antithrombotic activity, due to the inhibition of platelet activation. 36;37 Platelet aggregation is antagonized due to the presence of HDL receptors on their surface. 38;39 Statins and HDL In the atherogenic dyslipidaemias, statins act to decrease levels of atherogenic lipoproteins and to re-establish equilibrium between cardioprotective HDL and atherogenic ApoB-containing lipoproteins. 40 As a consequence, cholesterol efflux from the plaque is enhanced, whereas cholesterol influx from atherogenic lipoproteins is considerably diminished. A decrease in plaque cholesterol and macrophage content decreases inflammation and enhances plaque stability, resulting in a decrease in cardiovascular events (Fig. 3). 40 Such features of statin action have been demonstrated in a recent study, in which the effect of atorvastatin on the progression of atherosclerosis was quantified using postmortem Raman spectroscopic plaque imaging in APOE*3 Leiden transgenic mice, who were fed a high-fat/high-cholesterol diet for 28 weeks. 41 In the control group, Raman spectroscopy revealed large areas of cholesterol-loaded foam cells and a minimal area of VSMC. By contrast, in the group treated with atorvastatin, there was a greatly reduced surface area of macrophage foam cells and a dramatic increase in the area of extra-cellular matrix and VSMC. 41 At their most frequently used doses, treatment with atorvastatin, fluvastatin, pravastatin and simvastatin results in an elevation in HDL-cholesterol that varies between 3% and 12% in type IIA and type IIB hyperlipidaemia. However, there are indications from recent literature that these effects may be, to some degree, phenotype-specific. 42 The Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study was a randomized, doubleblind trial that compared the effects of 2 years of treatment with either high-dose atorvastatin (80 mg/ day) or moderate-dose simvastatin (40 mg/day) in 325 patients with familial hypercholesterolaemia. 42 The Fig. 3 Statins, HDL and plaque stability. From Sposito and Chapman. 40

4 Are the effects of statins on HDL-cholesterol clinically relevant? C61 study showed that both statins induced a significant (P < 0:0001) increase in HDL-cholesterol levels of approximately 13%. 42 The mechanistic basis of statin-mediated HDL-cholesterol elevation Animal studies have demonstrated that the CLA-1/SR-B1 receptor pathway accounts for approximately 50% of the cholesterol that is returned to the liver by HDL particles. 42 The remaining 50% of reverse cholesterol transport is carried out via the cholesterol-ester-transfer-protein-mediated mechanism. The CE formed in HDL by LCAT is transferred to both VLDL and LDL, and so this mechanism is potentially atherogenic, since the cholesterol content and mass of these particles is increased (Fig. 4). Statins induce an increase in ApoA-I production of approximately 15%, primarily in the liver. 43 In addition, as a result of an increase in the expression of LDL receptors, there is a dramatic reduction (up to approximately 50%) in the numbers of potentially atherogenic acceptors of CE via the CE transfer protein (CETP) mechanism from HDL. Guerin et al. 44;45 have shown that low-dose atorvastatin induces a 30% reduction in the ability of CETP to transfer CE from HDL to these particles, as a result of a marked reduction in the numbers of ApoB-100-containing particle acceptors. Moreover, treatment with atorvastatin significantly increased plasma ApoA-I levels (þ24%; P < 0:05), suggesting that this statin enhances ApoA-I production and the formation of nascent pre-b HDL particles. 43 Statin-induced HDL-cholesterol elevation and HDL particle function Guerin et al. 44 recently investigated the ability of plasma from patients with type IIB dyslipidaemia to enhance free cholesterol efflux from cultured Fu5AH hepatoma cells. These cells release cholesterol via the SR-B1 mechanism. The study showed that plasma from patients treated with 10 mg/day atorvastatin increased cholesterol efflux by 15% (P ¼ 0:0003), and plasma from patients treated with Fig. 4 The mechanism of statin action on HDL-cholesterol. Fig. 5 Prospective Pravastatin Pooling Project: baseline HDL and CHD events. From Sacks et al mg/day increased cholesterol efflux by a further 35% (P < 0:0001), compared with baseline levels. Clinical relevance of statin-induced elevation in HDL-cholesterol In the Prospective Pravastatin Pooling Project, data from three large randomized trials with pravastatin 40 mg/day (the West Of Scotland COronary Prevention Study (WOSCOPS), the Cholesterol And Recurrent Events study (CARE), and the Long-term Intervention with Pravastatin in Ischemic Disease study (LIPID)) were analyzed using a prospectively defined protocol. 46 When CHD event rates were plotted against HDL quintile ranges, it was shown that, in patients treated with placebo, an increasing level of HDL-cholesterol was associated with a reduction in event rate (Fig. 5). In patients treated with pravastatin, there was no apparent additional effect due to HDL-cholesterol in terms of reduction of events, and cardiovascular risk remained very high in patients with low levels of HDL-cholesterol (Fig. 5). 46 A meta-analysis of four prospective studies (the Framingham Heart Study, the Multiple Risk Factor Intervention Trial [MRFIT], the Lipid Research Clinics Prevalence Mortality Follow-up Study and the Coronary Primary Prevention Trial) showed that every 1 mg dl 1 (0.026 mmol l 1 ) increase in HDL-cholesterol is associated with a significant CHD risk reduction of 2% in men and 3% in women. 3 However, in both primary and secondary prevention trials with statins, only small, insignificant increases in HDL-cholesterol were achieved: in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), treatment with lovastatin resulted in a 6% mean increase in HDL-cholesterol; 47 in the West Of Scotland COronary Prevention Study (WOSCOPS), treatment with pravastatin resulted in a 5% increase; 48 in the Cholesterol And Recurrent Events trial (CARE), pravastatin also increased HDL-cholesterol by 5%; 49 and in the Scandinavian Simvastatin Survival Study (4S), simvastatin increased HDL-cholesterol by 8% (nonsignificant when corrected for the placebo group). 50 Therefore, at the present time, there is no clear indication that HDL-cholesterol elevation by statins translates into clinical benefit.

5 C62 Conclusion The anti-atherogenic actions of HDL particles are now well established, and epidemiological data from several cohort studies suggest that HDL-cholesterol elevation is associated with a reduction in CHD risk. At commonly used doses, treatment with statins is associated with minor elevations in HDL-cholesterol. Recent data suggest that statin therapy may be associated with enhanced cholesterol efflux and enhanced reverse cholesterol transport. However, definitive proof for the clinical relevance of statin-mediated elevation of HDL-cholesterol is presently lacking. This may be a consequence of the difficulty in disassociating this effect from the overwhelming risk benefit associated with the major reduction in LDL-cholesterol achieved with statin therapy. References 1. Maron DJ. The epidemiology of low levels of high-density lipoprotein cholesterol in patients with and without coronary artery disease. Am J Cardiol 2000;86:11L 4L. 2. 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