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Lipoprotein (a) and stroke
  1. Haralampos J Milionis1,
  2. Anthony F Winder1,
  3. Dimitri P Mikhailidis1
  1. 1Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School, University College, Royal Free Campus, Pond Street, London NW3 2QG, UK
  1. Dr Mikhailidis email: tonyw{at}rfc.ucl.ac.uk

Abstract

Strokes are one of the most common causes of mortality and long term severe disability. There is evidence that lipoprotein (a) (Lp(a)) is a predictor of many forms of vascular disease, including premature coronary artery disease. Several studies have also evaluated the association between Lp(a) and ischaemic (thrombotic) stroke. Several cross sectional (and a few prospective) studies provide contradictory findings regarding Lp(a) as a predictor of ischaemic stroke. Several factors might contribute to the existing confusion—for example, small sample sizes, different ethnic groups, the influence of oestrogens in women participating in the studies, plasma storage before Lp(a) determination, statistical errors, and selection bias. This review focuses on the Lp(a) related mechanisms that might contribute to the pathogenesis of ischaemic stroke. The association between Lp(a) and other cardiovascular risk factors is discussed. Therapeutic interventions that can lower the circulating concentrations of Lp(a) and thus possibly reduce the risk of stroke are also considered.

  • atherothrombosis
  • fibrinogen
  • homocysteine
  • lipids
  • lipoprotein a
  • stroke

https://doi.org/10.1136/jcp.53.7.487

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    Strokes (cerebrovascular accidents) are considered to be one of the most common causes of mortality and long term severe disability.1 It is well documented that hyperlipidaemia is a powerful risk factor for ischaemic heart disease (IHD).2–4 However, it was not until recently that the important role of lipids in the prevention of strokes was identified.5 There is a positive correlation between serum total cholesterol (TC) concentrations and ischaemic (thrombotic) stroke, and very low TC concentrations have been associated with an increased risk of haemorrhagic stroke. Raised low density lipoprotein cholesterol (LDL) or triglyceride (TG) concentrations, reduced high density lipoprotein cholesterol (HDL) concentrations, and a high TC to HDL ratio are associated with an increased risk of non-haemorrhagic stroke.5 There is evidence that lipoprotein (a) (Lp(a)) is a predictor of many forms of vascular disease, including premature coronary artery disease.6 Studies in subjects with average lipid profiles indicate that raised serum Lp(a) concentrations are associated with myocardial infarction, coronary stenosis, re-occlusion of aortocoronary bypass vein grafts, peripheral atherosclerosis, and cerebral ischaemia.6–8

    In this review, we focus on the possible role of Lp(a) in the pathogenesis of ischaemic (thrombotic) stroke. We scanned the National Library of Medicine (USA) search service in MEDLINE and Pre-MEDLINE (with links to participating online journals) and other related databases. Our research covered all languages and the years between 1962 and October 1999. The keywords were stroke, cerebrovascular accident, and Lp(a).

    Lp(a): a link between atherogenesis and fibrinolysis

    THE STRUCTURE OF LP(a)

    Lp(a) is an LDL like molecule consisting of an apoprotein (apo) B-100 particle attached by a disulphide bridge to apo(a).6 Apo(a) is a member of a family of “kringle” containing proteins, such as plasminogen, tissue platelet activator (tPA), prothrombin, factor XII, and macrophage stimulating factor (MSF).9,10 Lp(a) shares a high degree of sequence identity with plasminogen.9,11

    The apo(a) gene is highly polymorphic; more than 34 different sized alleles have been identified.12 Corresponding isoforms with molecular weights ranging from 187 to 648 kDa were identified in human serum.13,14 The size polymorphism of apo(a) is mainly the result of the genetically determined number of kringle IV type 2 repeats.12

    MODULATION OF PLASMA LP(a) concentrations

    Plasma Lp(a) concentrations are variable and their distribution in the general population is highly skewed (approximately 90% of the population has serum values less than 300 mg/litre); occasional patients have values above 20000 mg/litre.15 Lp(a) exhibits a high degree of heritability through kringle isoform transmission.16 Nevertheless, certain metabolic abnormalities, as well as pharmacological agents, can influence the circulating concentrations of Lp(a). These values can be increased as part of the acute phase response,17 and in diabetes mellitus,18 chronic renal failure,19–21 nephrotic syndrome,22,23 cancer,24 menopause, and hypothyroidism.25 The potential rise in circulating Lp(a) concentrations as part of the acute phase response is of special interest because the atherosclerotic process is thought to have an inflammatory component.26 Therefore, serum Lp(a) concentrations could perhaps be influenced by the presence of extensive vascular disease. Lp(a) values are decreased in liver failure27 and hyperthyroidism.28 Furthermore, nicotinic acid,29 tamoxifen,30 oestrogens,31 progesterone, and anabolic steroids32 might decrease Lp(a) concentrations. Fibrates have been shown, in some studies, to reduce Lp(a) concentrations,33,34 whereas statins might increase Lp(a) concentrations.35–37

    APO(a) gene polymorphism and phenotypes

    Plasma Lp(a) concentrations are inversely correlated with the size of the apo(a) isoform.38 For example, significantly raised Lp(a) concentrations in patients with rheumatoid arthritis were caused mainly by an increase in the S3 (low molecular weight) isoform.39 However, recent evidence suggests that the contribution of the apo(a) isoform size to the control of plasma Lp(a) concentrations is considerably lower than previously thought. This is because the variability in plasma Lp(a) concentration is not uniform across the apo(a) size spectrum.16,40 It is still unclear whether further apo(a) gene polymorphism (not affecting the size of the Lp(a) molecule) influences the circulating concentrations of Lp(a).41 Small (low molecular weight) isoforms are usually associated with higher total Lp(a) values (probably because assembly is less complex and thus faster) and a higher risk of atherogenesis compared with the large (high molecular weight) isoforms.42 It is also worth considering that the risk attributed to Lp(a) might not be continuous. Thus, very high concentrations might be substantially more dangerous than values closer to the epidemiological cut off value of 300 mg/litre.26 Whether the risk of stroke associated with a moderate increase of Lp(a) is conditioned by the coexisting LDL concentrations remains to be established.

    THE PATHOPHYSIOLOGICAL LINK BETWEEN LP(a) and atherothrombosis

    The accumulation of Lp(a) molecules has been demonstrated in the arterial walls of human coronary and cerebral vessels.43 This process might be attributed to the tendency of apo(a) to bind to connective tissue elements, such as proteoglycans, glycosaminoglycans, and, especially, fibronectin.44 This binding process is promoted by lipoprotein lipase or sphingomyelinase.45

    Lp(a) particles are susceptible to oxidative modification and scavenger receptor uptake, leading to intracellular cholesterol accumulation and foam cell formation,46,47 which contributes further to atherogenesis. The raised sialic acid content of Lp(a) is thought to contribute to the oxidative resistance of the native particle.47 The prothrombotic action of Lp(a) is, however, far more well established. Because of the structural homology with plasminogen, Lp(a) might have important antithrombolytic properties, which could contribute to the pathogenesis of atherothrombotic disease. For example, Lp(a) binding to immobilised fibrinogen and fibrin results in the inhibition of plasminogen binding to these substrates.48 In addition, Lp(a) competes with plasminogen for its receptors on endothelial cells, leading to diminished plasmin formation, thereby delaying clot lysis and favouring thrombosis.48 The high affinity of Lp(a) for fibrin provides a mechanistic basis for their frequent colocalisation in atherosclerotic plaques.49,50

    In vitro studies indicate that Lp(a) enhances the synthesis of plasminogen activator inhibitor 1 (PAI-1) by endothelial cells. PAI-1 is the main inhibitor of the fibrinolytic system.51 Another potentially important action of Lp(a) is that by displacing plasminogen from the surfaces of macrophages in atherosclerotic plaques, it reduces the activation of latent transforming growth factor β (TGF-β). In the absence of activated TGF-β, cytokines might induce smooth muscle cell proliferation and the transformation of these cells to a more atherogenic cellular phenotype.52

    The relative importance of oxidation or thrombogenic mechanisms is difficult to establish at this stage.

    THE RELATION BETWEEN LP(a) and atherosclerosis

    The question of whether Lp(a) plays a primary or synergistic role in atherosclerosis has been investigated recently.53 Almost all cross sectional and retrospective studies involving white men have shown an increased risk of coronary, peripheral, and cerebrovascular atherosclerotic disease associated with plasma Lp(a) concentrations greater than the 80th centile (> 250–300 mg/litre). Prospective studies have provided controversial data. However, cross sectional and retrospective studies could be misleading because of selection bias or the effect that the disease itself can have on the studied parameter.53 Furthermore, storage of the samples and the use of suboptimal Lp(a) assays might interfere in the interpretation of the results.53 Nevertheless, most of the more recent prospective studies revealed a modest significant association between IHD and raised plasma Lp(a) concentrations.54–56

    Another question that has been raised is whether atherosclerosis itself can cause high plasma Lp(a) concentrations. In this context, it is relevant that patients with IHD as well as children with a positive family history of IHD commonly exhibit small apo(a) phenotypes.42,57 This association of small apo(a) isoforms with higher Lp(a) concentrations suggests that raised Lp(a) concentrations antedate the atherosclerotic process.53

    Lp(a) and other thrombotic risk factors

    LP(a) and fibrinogen

    Serum Lp(a) concentrations correlate significantly with plasma fibrinogen values in some, but not all, studies.58,59 This association is of interest because platelet activity is enhanced by fibrinogen,60,61 and raised plasma fibrinogen concentrations are predictors of vascular events, both in healthy populations and in patients with IHD.62 In the Goettingen risk incidence and prevalence study (GRIPS), Lp(a) and fibrinogen concentrations proved to be of value in estimating the risk of myocardial infarction.63 Data from GRIPS and the European concerted action on thrombosis and disabilities (ECAT) studies support the hypothesis that fibrinogen is a particularly important risk factor for acute coronary events in patients with asymptomatic or overt IHD.64,65

    There is strong evidence that fibrinogen is an independent risk factor for ischaemic atherothrombotic stroke.66 Fibrinogen values remain significantly raised after stroke, and are associated with an increased risk of recurrent vascular events.67 In patients with stroke, fibrinogen is associated with a decrease in white blood cell elasticity and red blood cell deformability, and an increase in plasma erythrocyte viscosity.68 Fibrinogen also promotes platelet aggregation and consumption in the ischaemic area in patients with stroke.69

    In this context, fibric acid derivatives can reduce the circulating concentrations of Lp(a) and fibrinogen.64,70,71 Therefore, the platelet inhibitory activity of fibric acid derivatives could be mediated via their action on lipid fractions (mainly TG and HDL), Lp(a), and/or fibrinogen.72,73 The preliminary results of two recently presented fibrate trials are discussed below.

    LP(a) and homocysteine

    Even a moderate rise in the circulating concentration of homocysteine is associated with an increased risk of atherosclerosis and arterial or venous thrombosis.74,75 There is epidemiological evidence showing that the risk of vascular events is increased in those with a concomitant rise of both Lp(a) and homocysteine.76 This association is of interest because both Lp(a) and homocysteine can have unwanted effects on platelets as well as on coagulation and fibrinolysis. Experimental data showed that hyperhomocysteinaemia is associated with increased platelet aggregability and thromboxane A2 (TXA2) release.77 TXA2 is a vasoconstrictor and a promoter of platelet aggregation. Homocysteine has a low mitogenic effect on vascular smooth muscle cells, but it enhances the mitogenic properties of platelet derived growth factor BB (PDGF-BB).78 Of the PDGF stored in human platelets, 30% is in the PDGF-BB form; the remainder is in the PDGF-AB form.79

    There is epidemiological evidence that homocysteine is a strong predictor of ischaemic stroke.80 Moderate increases in homocysteine values (even within the population reference range) are associated with vascular pathology through a variety of mechanisms, including atherosclerosis and thrombosis.80 Homocysteine concentrations are influenced by renal function and vitamin B12 status in patients with stroke.81

    Homocysteine, Lp(a), and fibrinogen probably interact to promote atherosclerosis.82 Therefore, it is likely that their clustering increases the risk of vascular events. This possibility deserves further investigation. There is already evidence, from epidemiological studies, indicating that the dyslipidaemia + raised Lp(a) and dyslipidaemia + raised fibrinogen combinations increase the risk of vascular events.63,83,84

    LP(a) and other cardiovascular risk factors

    Plasma concentrations of Lp(a), TC, TG, and very low density lipoprotein (VLDL) cholesterol are higher in patients with hypertension.85,86 It has been shown recently that raised Lp(a) concentrations and the presence of low molecular weight apo(a) isoforms are strong and independent risk factors for IHD in patients with hypertension.87

    The data on Lp(a) concentrations in diabetes are largely based on small studies and are conflicting. Larger studies and those including apo(a) phenotype analysis suggest that Lp(a) concentrations are not different from those in patients without diabetes, or are at most only moderately raised in patients with insulin dependent diabetes.85 However, there is evidence that Lp(a) concentrations are raised in patients with diabetes associated renal function impairment. Furthermore, atherosclerotic complications in patients with diabetes are associated with higher Lp(a) concentrations.85

    Cigarette smoking is associated with increased values of LDL, TG, and VLDL and decreased concentrations of HDL. However, no direct effect on Lp(a) values has been reported in smokers.88

    There is some controversy about the effect of obesity on Lp(a). In one study, Lp(a) concentrations were not influenced by obesity, visceral fat content, or weight loss after a very low energy diet.89 However, there is also some evidence that obese individuals have higher Lp(a) values and that weight loss (by diet or surgical intervention) is associated with a significant reduction in these values.90,91 The mechanism(s) responsible for these changes remain(s) to be defined.

    Lipid variables and the risk of stroke

    TC AND STROKE

    Early studies did not suggest that raised serum TC values consistently predict stroke related mortality.92,93 Indeed, in some studies, TC values were inversely related to death as a result of stroke.94 In a meta-analysis of 13 000 strokes in a total of 450 000 people, no significant association between serum TC concentrations and stroke was found.95 In the Framingham heart study,96 TC concentrations were positively related to stroke mortality in women aged less than 55 years, whereas a U-shaped association was seen in women older than 55, and an inverse relation between TC and short term (within five years) mortality in women older than 70 years of age. In Israel, Korn-Lubetzki et al found that patients with stroke had low serum TC and LDL cholesterol values.97 These early results might have been inconclusive in demonstrating an association between lipid concentrations and stroke because ischaemic and haemorrhagic strokes were not differentiated.

    Epidemiological surveys showed an inverse association between TC values and the risk of intracerebral haemorrhage, independently of age and sex.98–107 Specifically, 54 385 Swedish men and women participated in a health survey with serum cholesterol and diastolic blood pressure determinations.101 The follow up period was 20.5 years (1964 to 1985). The relative risk for subarachnoid haemorrhage in men, but not in women, increased with decreasing TC values.101 In women, the relative risk for intracerebral haemorrhage was inversely related to TC values. For cerebral haemorrhage in men, the risk function was U-shaped.101 Adjustment for diastolic blood pressure did not significantly change the relation between the risk for any of the different stroke types and the cholesterol values.101 Furthermore, a large cohort (61 756 subjects aged 40 to 89 years) study was performed in the San Francisco-Oakland metropolitan area from 1977 to 1985.100 The average follow up period was 10.7 years. In this study, an association between low TC values and increased risk for intracerebral haemorrhage was confined to elderly men (aged 65 years or older).100 In more recent studies, such as the multiple risk factor interventional trial (MRFIT), a positive relation between serum TC values and non-haemorrhagic strokes was shown, whereas serum TC values were inversely related to intracranial haemorrhage.102,103 In a case control study, conducted from 1990 to 1992 in Italy, Di Mascio and colleagues107 showed a strong linear relation between TC concentrations and the risk for myocardial infarction (p < 0.0001). However, a significant linear trend in risk was also found between TC values and ischaemic stroke (p < 0.01).107

    Although it has been shown that serum TC is an independent factor for stroke104 and transient ischaemic attacks (TIA),105 the relation between TC and ischaemic stroke does not seem to be as strong as it is with IHD,106,107 perhaps because different pressure gradients and vessels are involved. When considering large studies (for example, the Honolulu heart study in migrants from Japan and the MRFIT screening study), an increase in non-haemorrhagic stroke was seen at the highest, but not intermediate, concentrations of TC.106

    TG CONCENTRATIONS AND STROKE

    Interestingly, it has been shown that postprandial hypertriglyceridaemia is associated with carotid artery atherosclerosis.108 However, there is controversy regarding the association between serum TG values and the risk of stroke.5 Nevertheless, in the Copenhagen City heart study,109 a log linear association between serum TG concentrations and non-haemorrhagic stroke was found (relative risk, 1.12/1 mmol/litre increase in serum TG; 95% confidence interval, 1.07 to 1.16); this association was independent of age and sex.

    HDL CHOLESTEROL AND STROKE

    In general, most case control studies reported an inverse association between HDL cholesterol and stroke risk.5 Although no association was found in the Framingham study,110 in the Copenhagen City heart study109 a negative relation was evident (relative risk, 0.53; 95% confidence interval, 0.34 to 0.83).

    APOLIPOPROTEIN E PHENOTYPES AND STROKE

    Apolipoprotein E (apoE) phenotypes have been associated with strokes.111 Pedro-Bodet et al, in a case control study,111 showed that the frequency of the apoE4 gene is high in patients with ischaemic stroke. In addition, it has been shown that the apoE3/E3 phenotype has a “protective” association with stroke, because it was present more frequently in stroke free controls than in patients with ischaemic stroke.111 In contrast, the apoE2 genotype is a risk factor possibly expressed through any concurrent obesity, diabetes, or hypertension.112

    GEOGRAPHICAL VARIATION IN THE INCIDENCE OF STROKE

    It has been reported that in Japan and China, the age standardised annual death rate from stroke is greater than that of IHD, whereas in Northern Europe and the USA the IHD associated mortality is three to four times greater than the stroke related deaths.5,113 The increased stroke mortality in Japan might be related to a higher proportion of haemorrhagic strokes.113 In contrast, in Mediterranean countries, deaths as a result of both IHD and stroke display an approximate 1 : 1 ratio.113 Serum TC values, smoking, alcohol intake, and traditional diets account for these differences.5,114 Unfortunately, we are not aware of extensive epidemiological studies that compared Lp(a) values in these nations. However, there is some evidence that median serum Lp(a) values are very similar in American white and Chinese individuals (90 and 80 mg/litre, respectively).16 There also appeared to be a shift towards apo(a) alleles of larger sizes in the Chinese.16

    Lp(a) and stroke

    Apart from the well established risk factors for strokes (such as increasing age, hypertension, diabetes, smoking, or the presence of vascular disease),1,5 the possibility that Lp(a) is a risk factor for ischaemic stroke has been assessed in several (mainly retrospective) studies (table 1).

    View this table:
    Table 1

    Studies evaluating the role of lipoprotein (a) as a risk factor for ischaemic stroke

    STUDIES SUPPORTING LP(a) as a risk factor for stroke

    In a case control study, serum Lp(a) values were significantly (p < 0.001) higher in patients with ischaemic stroke compared with healthy individuals (median, 95 v 50 mg/litre).115 This difference was also evident in a subgroup of subjects aged 30 to 69 years (p < 0.001).115

    Lindgren et al determined lipid variables in 131 patients six months after their stroke.116 These patients had higher TG and Lp(a) values and lower TC, LDL, and HDL concentrations compared with controls.

    Vavernova et al investigated Lp(a) values in 45 patients with stroke (younger than 55 years of age) and their first degree relatives.117 They reported that Lp(a) values were genetically conditioned in patients with ischaemic strokes.

    With regard to the genetic control of plasma Lp(a) concentrations, Jurgens et al determined Lp(a) values and apo(a) phenotypes in a consecutive series of 265 patients with ischaemic stroke in comparison with 288 controls.118 They suggested that raised Lp(a) concentrations comprise a primary risk factor associated with the presence of this disease. In addition, they demonstrated that low molecular weight (≤ 580 kDa) apo(a) isoforms were more frequent in the patients with stroke (42.65% v 16.73%; p < 0.001). Peynet et al evaluated the Lp(a) concentration and apo(a) isoform size in 90 young patients (mean age: 37.4 years) with acute cerebral ischaemia compared with those of age and sex matched controls.119 They showed that serum Lp(a) concentrations were significantly increased in the patients with stroke (p = 0.009). However, there was no difference in the apo(a) isoform distribution between patients and controls.119

    Van Kooten and colleagues120 assessed Lp(a) concentrations in 151 consecutive patients admitted because of acute cerebral ischaemia. They found that in about one third of patients Lp(a) values were significantly raised, but this increase was not associated with the cardiovascular risk profile, stroke characteristics, or the prognosis.

    In a recent cross sectional study, Lp(a), PAI-1, and tPA were determined in patients with and without a history of stroke.121 After studying a total of 210 patients (half with a history of ischaemic stroke), a relation between Lp(a) and cerebral ischaemia was found. This was limited to individuals below 70 years with raised (> 500 mg/litre) plasma Lp(a) values.121

    Nagayama et al, in a case control study, investigated Lp(a) values in patients after a mean period of 27 months since their stroke.122 Lp(a) was a crucial and independent risk factor for ischaemic stroke, but not for lacunar stroke (< 1 cm2 in size), especially in young adults.122

    Peng et al investigated the relation between serum lipids, apoE genotypes, and the risk of ischaemic stroke.123 They studied 90 patients who experienced an acute ischaemic stroke versus 90 healthy individuals. Serum Lp(a) concentrations and the apoE4 genotype were the prominent lipid predictors for ischaemic stroke in addition to the more established risk factors such as hypertension, family history of stroke, and cigarette smoking.123

    asymptomatic, “silent”, cerebral infarction has also attracted interest. A silent stroke is usually detected on incidental imaging (computed tomography scan, magnetic resonance imaging) in patients with no localised neurological signs.124 These findings are a predisposing factor for subsequent overt stroke.124 In most cases of silent infarction, lacunar strokes of less than 1 cm2 in size are detected in the basal ganglia in apparently healthy elderly people.125 These lesions are associated, in most reports, with advanced age and hypertension, and constitute a major cause of dementia.124,125 Kario and colleagues126 reported that silent multiple lacunar strokes in 178 asymptomatic, high risk, elderly Japanese patients (aged 44 to 93 years) were associated with a hypercoagulable state, endothelial damage, and significantly raised Lp(a) concentrations. The authors further subdivided the silent lacunar group into subgroups based on the number of lacunes (few lacunes, 1–2; moderate number, 3–4; numerous lacunes, ≥ 5). Raised Lp(a) values (and particularly those > 300 mg/litre) were more common in the “numerous lacune” than the “few lacune” subgroups.126

    In the atherosclerosis risk in communities (ARIC) study, the association of Lp(a) with stroke was investigated in 15 160 participants (4160 blacks and 11 000 whites).127 In this study, Lp(a) was an independent risk factor for strokes and TIA, in both blacks and whites. The relative risk of Lp(a) associated stroke morbidity was not influenced by race.127

    This evidence might indicate that the mean Lp(a) concentration is higher in patients with atherothrombotic brain infarction than in those with brain haemorrhage or lacunar infarction.128

    Patients with IHD are at an increased risk of having a stroke.5 Thus, a selection bias might influence the relation between Lp(a) and risk of stroke because of an association between IHD and Lp(a) values.

    STUDIES NOT SUPPORTING LP(a) as a risk factor for stroke

    The link between Lp(a) and stroke has been disputed by some investigators. Hachinski et al,129 in a case control study, determined lipid variables, including Lp(a), in 90 patients with stroke or TIA of atherothrombotic origin. Increased LDL and TG concentrations correlated with atherothrombotic stroke risk, whereas there was no significant difference in the Lp(a) concentrations or the distribution of apoE phenotypes among patients and controls.129

    The possibility of predicting ischaemic stroke by the determination of plasma Lp(a) concentrations and antibodies to Chlamydia pneumoniae was investigated by Glader et al.130 They studied 101 subjects who had suffered an ischaemic cerebral infarction and 201 controls. No association between baseline plasma Lp(a) values, the presence of anti-C pneumoniae antibodies, and future ischaemic cerebral infarctions was found. There was no evidence of an interactive effect between high Lp(a) values and anti-C pneumoniae antibody titres.130

    In a prospective study in Finland, no association was found between Lp(a) or homocysteine values and atherosclerotic disease (myocardial infarction or stroke) in logistic regression analyses among 7424 men and women aged 40–60 years without atherosclerotic disease at baseline.131 There were 134 events (myocardial infarction or stroke) in men and 131 in women.131 However, the lack of association between homocysteine values and the myocardial infarction/stroke end point might have been the result of the exceptionally low gene frequency predisposing to homocysteinaemia in Finland.131

    A cohort of 14 916 predominantly white, healthy, middle aged male physicians (physicians' health study) was followed prospectively for a period of 7.5 years.132 These subjects had no previous history of stroke, TIA, or myocardial infarction. During follow up, 198 physicians developed a stroke (155 thromboembolic, 35 haemorrhagic, and eight indeterminate).132 Their samples were analysed for Lp(a) together with paired controls, matched for age and smoking habit. Among the subjects participating in the study, no association between baseline plasma concentration of Lp(a) and future risk of total (all types of stroke) or thromboembolic stroke was found.132

    Atherosclerotic lesions in intracranial vessels

    LIPIDS AND ATHEROSCLEROSIS OF THE CEREBRAL ARTERIES

    Evidence from experimental data suggested that the intracranial arteries are relatively resistant to cholesterol related endothelial damage.133–135 Thus, studies in primates failed to show an association between the hyperlipidaemic state and the development of atherosclerosis in intracranial arteries.133 Studies with cynomolgus and rhesus monkeys fed a hyperlipidaemic diet for eight to 12 months showed that the atherosclerotic lesions in their carotid arteries were more extensive than those in the basilar, vertebral, and middle cerebral arteries.134 However, the coexistence of hypertension and hypercholesterolaemia resulted in accelerated atherosclerosis of intracranial arteries in rat models.135

    Studies based on human necropsies have shown that atherosclerotic changes in cerebral arteries make their appearance 20 years later than in the coronary arteries.136 Differences in the prevalence and extent of atherosclerotic lesions in the aorta and coronary or cerebral arteries were observed between different age and race groups. Black individuals and older people tend to have more extensive cerebral atherosclerosis.136 Interestingly, Postiglione and colleagues137 reported that no atherosclerotic lesions were found in the cerebral arteries of young patients with homozygous familial hypercholesterolaemia, despite a severe involvement of all the other vascular beds.

    It has been proposed that the paucity of pinocytic vesicles in the endothelium of cerebral arteries, their rich innervation, and the lower distending pressures make these vessels more resistant to hyperlipidaemia compared with coronary or peripheral arteries.136

    LIPIDS AND ATHEROSCLEROTIC CHANGES IN CAROTID ARTERIES

    In a recent study of 79 patients, Landray et al showed that age and smoking history predicted carotid atherosclerosis, whereas the LDL score was of a borderline significance.138 Furthermore, there was evidence that small, dense LDL subfractions were associated with carotid atherosclerosis and might be a modifiable risk factor for strokes and IHD.138

    In an experimental model of occlusive arterial thrombus formation in cynomolgus monkeys, high Lp(a) values were associated with permanent cessation of flow and occlusive arterial thrombosis.139 Analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima.139

    Jurgens and Koltringer140 studied 808 randomly selected patients (with positive stroke history as well as asymptomatic subjects). Plasma Lp(a) values correlated with carotid atherosclerosis in subjects younger than 60 years of age.140

    It has been suggested that apo(a) can cause endothelial dysfunction by enhancing lipid deposition in vessel walls, inhibiting fibrinolysis, and modulating smooth muscle cell proliferation.26 Moreover, Watts and colleagues141 measured lipid variables (including Lp(a)) in 49 white patients with TIA undergoing carotid angiography. Raised Lp(a) concentrations were a significant determinant of the extent of carotid atherosclerosis. Therefore, the measurement of serum Lp(a) concentrations might help identify patients with an increased risk of stroke.141

    Lipid associations with stroke might result from emboli originating in the aortic arch.142,143 However, it is still not clear whether lipid lowering treatment greatly reduces the risk of this complication of atherosclerotic disease. Endothelial dependent vasomotor tone is also related to lipoprotein values but the implications for cerebral events are not yet determined.144

    Can serum Lp(a) values be reduced?

    DIETARY MODIFICATION

    Diet is not thought to influence Lp(a) values to any great extent. However, saturated and n-3 polyunsaturated fatty acids may slightly reduce Lp(a) values. Thus, a diet rich in palm oil has been reported to reduce Lp(a) concentrations by approximately 10%.145 In one study, a short term diet with n-3 polyunsaturated fatty acids had no significant effect on Lp(a) concentrations, but long term administration reduced these values by as much as 20%.146

    NICOTINIC ACID

    Nicotinic acid has a favourable, although inconsistent, effect on Lp(a) concentrations.5,29 However, this drug is difficult to tolerate at the high doses required.

    STATINS

    Interestingly, a recently published overview of all randomised trials of statin treatment demonstrated that large reductions in TC values are associated with significant benefit on stroke and total mortality.5 All the patients had atherosclerotic vascular disease, itself a major risk factor for stroke.5 In the Scandinavian simvastatin survival study (4S), simvastatin treatment (20 to 40 mg daily) reduced the combined incidence of TIA and stroke by 29%.4 Similarly, in the cholesterol and recurrent events (CARE) trial, pravastatin (40 mg daily) reduced the relative risk of stroke by as much as 32%, over a median follow up period of five years.147 In the long term intervention with pravastatin in ischaemic disease (LIPID) study, pravastatin (40 mg daily) reduced the relative risk of stroke by 19%.148 These beneficial effects on stroke and myocardial infarction occur against a background of statins causing a slight increase in circulating Lp(a) values.35–37 The fact that statins do not reduce Lp(a) concentrations supports the concept that the LDL receptor does not play an important part in the catabolism of Lp(a).26

    FIBRATES

    Fibric acid derivatives exert as favourable an effect on HDL and TG concentrations as on LDL quantity and quality. These drugs also reduce fibrinogen and possibly Lp(a) values.33,34 It is tempting to speculate that the favourable clinical end points observed in two recently presented fibrate based clinical trials might be attributable, at least in part, to these beneficial actions. Thus, in the bezafibrate infarction prevention study (BIP), a reduction in the highest fibrinogen concentrations was associated with a decrease in the incidence of the primary end points: cardiac death and ischaemic stroke.149 Unfortunately, serum Lp(a) values were not monitored. In BIP, there was a very small reduction (6.5 %) in serum LDL values. This reduction in LDL would not be expected to account for the results of this trial. However, because the clinical benefit was limited to patients with raised TG (with or without reduced concentrations of HDL) it is possible that this effect is related to a pronounced rise in HDL and fall in TG values. Another possibility is a fibrate induced reduction in oxidised LDL production because this form of LDL is highly atherogenic. The results of BIP are supported by those of the veterans affairs HDL intervention trial (VA-HIT). In this trial150, gemfibrozil (1200 mg daily) reduced total reported stroke from 6.9% in the placebo group to 5.1% (p = 0.05) in the treated group. TIA in the same trial were reduced from 4.2% to 1.7% (p = 0.001), and carotid endarterectomy was significantly (p = 0.001) reduced (gemfibrozil, 1.3%; placebo, 3.5%); LDL values were essentially unchanged.

    DIABETES, ANTIHYPERTENSIVE DRUGS, AND HORMONAL TREATMENT

    Optimising body weight and tight glycaemic control may beneficially influence Lp(a) values in patients with type 1 and type 2 diabetes.151 This effect is in part linked to TG metabolism, which is impaired in type 2 diabetes, as well as the glycosylation of Lp(a), which interferes with its catabolism.151 In this setting, it has been shown that treating dyslipidaemia in patients with diabetes (for example, by using a fibrate) improves the lipid profile and lowers the incidence of IHD.152

    Antihypertensive agents can affect plasma fibrinogen and Lp(a) values as well as the lipid profile.153 These additional properties might influence the choice of medication, especially in patients where these predictors of vascular events (including stroke) are raised.153

    Hormonal replacement therapy (HRT) in postmenopausal women is probably associated with a reduction in the risk of developing coronary artery disease.154. HRT favourably affects cholesterol, Lp(a), and homocysteine concentrations, especially in those women with the highest concentrations of these risk factors.155 Several, but not all, studies showed that thyroid replacement treatment decreases Lp(a) concentrations, probably because of an effect upon apo(a) production, or possibly Lp(a) assembly.28

    FUTURE “THERAPEUTIC” DIRECTIONS

    Lp(a) undergoes further modifications after entry into the arterial wall. Whether these changes influence cardiovascular risk or are mere epiphenomena is yet to be determined. However, post-translational events (such as oxidation and proteolysis) could become potential targets for therapeutic intervention.26

    Any reliable evaluation of a therapeutic intervention to reduce Lp(a) values must rely on a reproducible and standardised assay with appropriate calibration and data analysis appropriate to a highly skewed variable. At present, this objective has not been completely achieved.26 Initial studies involving Lp(a) measurement may have used even less reliable assays.53 Clearly, this assay problem is relevant to epidemiological studies. It might also be appropriate to convert data for LDL for the quantity incorporated into Lp(a) molecules. This amount might not be trivial in patients with high Lp(a) concentrations.

    Studies assessing the risk attributed to Lp(a) must consider the contribution of other predictors of vascular events (such as hypertension, dyslipidaemia, fibrinogen, and homocysteine).63,76,83,84,87,156

    Concluding remarks

    The evidence that Lp(a) is a strong predictor for ischaemic stroke is contradictory. Apart from the lack of universally accepted, standardised methods for determination, Hobbs and White proposed several factors that might contribute to the existing confusion in attributing risk to Lp(a).53 These include: (1) small sample sizes unable to determine the relation between apo(a) phenotypes and Lp(a) concentrations, (2) different ethnic groups, (3) the influence of oestrogens in women participating in studies, (4) plasma storage before Lp(a) determination, (5) inappropriate methods of data analysis, and (6) selection bias.53 However, on balance, there is evidence that raised circulating Lp(a) concentrations are associated with an increased risk of vascular events. Furthermore, other risk factors (such as dyslipidaemia or raised homocysteine values) enhance the risk attributed to Lp(a). Therefore, the association between high Lp(a) values and atherosclerotic complications might be weaker in prospective studies than in cross sectional studies. In the latter, the presence of the disease is a prerequisite and, thus, other risk factors could significantly contribute to the atherosclerotic burden.53

    The determination of apo(a) isoforms in epidemiological surveys (especially prospective studies), although expensive, might be necessary to define the risk load attributable to Lp(a). Consideration of other risk factors that might be related to plasma Lp(a) values (for example, fibrinogen), or act synergistically with Lp(a) (for example, LDL), will be mandatory in these studies. The genetic and environmental factors controlling the circulating concentrations of Lp(a) also need further definition. Our understanding of the vascular pathology of Lp(a) remains relatively poor.

    Reducing the circulating values of Lp(a) might prove difficult. One approach is to deal aggressively with all the other modifiable risk factors.

    References

    1. ↵
      American Heart Association. Heart and stroke facts: 1994 statistical supplement. Dallas: American Heart Association, 1993.
    2. ↵
      West of Scotland Coronary Prevention Study Group. West of Scotland coronary prevention study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996;348:1339–2.
      OpenUrlCrossRefPubMedWeb of Science
    3. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/l (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 1993;72:1031–7.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994;344:1383–9.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      Papadakis JA, Mikhailidis DP, Winder AF. Lipids and stroke: neglect of a useful preventive measure? Cardiovasc Res 1998;40:265–71.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      Dahlen G. Lp(a) lipoprotein in cardiovascular disease. Atherosclerosis 1994;108:111–26.
      OpenUrlCrossRefPubMedWeb of Science
    7. Cheng SW, Ting AC, Wong J. Lipoprotein (a) and its relationship to risk factors and severity of atherosclerotic peripheral vascular disease. Eur J Vasc Endovasc Surg 1997;14:17–23.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      Konemari G. Lipoprotein(a) and other risk factors for cerebral infarction. Hiroshima J Med Sci 1995;44:65–77.
      OpenUrlPubMed
    9. ↵
      Huby T, Chapman J, Thillet J. Pathophysiological implication of the structural domains of lipoprotein(a). Atherosclerosis 1997;133:1–6.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      Ikeo K, Takahashi K, Gojobori T. Different evolutionary histories of kringle and protease domains in serine proteases: a typical example of domain evolution. J Mol Evol 1995;40:331–6.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      McLean JW, Tomlinson JE, Kuang WJ, et al. cDNA sequence of human lipoprotein(a) is homologous to plasminogen. Nature 1987;330:132–7.
      OpenUrlCrossRefPubMed
    12. ↵
      Byrne C, Lawn R. Studies on the structure and function of the apolipoprotein(a) gene. Clin Genet 1994;46:34–41.
      OpenUrlPubMedWeb of Science
    13. ↵
      Van der Hoek YY, Wittekoek ME, Beisiegel U, et al. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms. Hum Mol Genet 1993;2:361–6.
      OpenUrlAbstract/FREE Full Text
    14. ↵
      Marcovina SM, Hobbs HH, Albers JJ. Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature. Clin Chem 1996;42:436–9.
      OpenUrlAbstract/FREE Full Text
    15. ↵
      Boerwinkle E, Leffert C, Lin J, et al. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992;90:52–60.
    16. ↵
      Gaw A, Boerwinkle E, Cohen JC, et al. Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common “null” allele at the apo(a) locus. J Clin Invest 1994;93:2526–34.
    17. ↵
      Craig W, Ledue T. Lipoprotein(a) and the acute phase response. Clin Chim Acta 1992;210:231–2.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      Bruckert E, Davidoff P, Grimaldi A, et al. Increased serum levels of lipoprotein(a) in diabetes mellitus and their reduction with glycemic control. JAMA 1990;263:35–6.
    19. ↵
      Kronenberg F, Koenig P, Neyer U, et al. Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 1995;6:110–20.
      OpenUrlAbstract
    20. Siamopoulos KC, Elisaf MS, Bairaktari HT, et al. Lipid parameters including lipoprotein(a) in patients undergoing CAPD and hemodialysis. Perit Dial Int 1995;15:342–7.
      OpenUrlAbstract/FREE Full Text
    21. ↵
      Milionis H, Elisaf M, Tselepis A, et al. Apolipoprotein (a) phenotypes and lipoprotein (a) concentrations in patients with renal failure. Am J Kidney Dis 1999;33:1100–6.
      OpenUrlPubMedWeb of Science
    22. ↵
      Stevingel P, Berglund L, Heimbuerger O, et al. Lipoprotein(a) in nephrotic syndrome. Kidney Int 1993;44:1116–23.
      OpenUrlPubMedWeb of Science
    23. ↵
      Elisaf MS, Bairaktari HT, Tzallas CS, et al. Increased lipoprotein(a) levels in patients with proteinuria. Cardiovascular Risk Factors 1996;6:289–93.
      OpenUrl
    24. ↵
      Wright LC, Sullivan DR, Muller M, et al. Elevated apolipoprotein(a) levels in cancer patients. Int J Cancer 1989;43:241–4.
      OpenUrlPubMedWeb of Science
    25. ↵
      Engler H, Riesen W. Effect of thyroid function on concentration of lipoprotein(a). Clin Chem 1993;39:2466–9.
      OpenUrlAbstract
    26. ↵
      Scanu AM. Atherothrombogenicity of lipoprotein (a): the debate. Am J Cardiol 1998;82:26Q–33Q.
      OpenUrlPubMedWeb of Science
    27. ↵
      Feely J, Barry M, Keeling PWN, et al. Lipoprotein(a) in cirrhosis. BMJ 1992;304:545–6.
    28. ↵
      Kung AWC, Pang RWC, Lauder I, et al. Changes in serum lipoprotein(a) and lipids during treatment of hyperthyroidism. Clin Chem 1995;41;226–231.
      OpenUrlAbstract/FREE Full Text
    29. ↵
      Carlson L, Hamsten A, Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidemic subjects treated with nicotinic acid. J Intern Med 1989;226:271–6.
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      Elisaf M, Bairaktari H, Tzallas Ch, et al. The beneficial effect of tamoxifen on the serum lipoprotein Lp(a) levels: an additional anti-atherogenic property. Anticancer Res 1996;16:2725–8.
      OpenUrlPubMedWeb of Science
    31. ↵
      Farish E, Spowart K, Barnes JF, et al. Effects of postmenopausal hormone replacement therapy on lipoproteins including lipoprotein(a) and LDL subfractions. Atherosclerosis 1996;126:77–84.
      OpenUrlPubMedWeb of Science
    32. ↵
      Crook D, Sidhu M, Seed M, et al. Lipoprotein Lp(a) levels are reduced by danazol, an anabolic steroid. Atherosclerosis 1992;92:41–7.
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      Maggi FM, Poglionica MR, De Michele L, et al. Bezafibrate lowers elevated plasma levels of fibrinogen and lipoprotein (a) in patients with type IIa and IIb dyslpoproteinaemia. Nutr Metab Cardiovasc Dis 1994;4:215–20.
    34. ↵
      Mikhailidis DP, Ganotakis ES, Spyropoulos KA, et al. Prothrombotic and lipoprotein variables in patients attending a cardiovascular risk management clinic: response to ciprofibrate of lifestyle advice. Int Angiol 1998;17:225–33.
      OpenUrlPubMedWeb of Science
    35. ↵
      Kostner GM, Gavish D, Leopold B, et al. HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 1989;80:1313–19.
      OpenUrlAbstract/FREE Full Text
    36. Hunninghake DB, Stein EA, Mellies MJ. Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein(a). J Clin Pharmacol 1993;33:574–80.
      OpenUrlPubMedWeb of Science
    37. ↵
      Nair DR, Papadakis JA, Jagroop IA, et al. Statins and fibrinogen. Lancet 1998;351:1430.
      OpenUrlCrossRef
    38. ↵
      Marcovina SM, Albers JJ, Jacobs DR, et al. Lipoprotein(a) concentrations and apolipoprotein(a) phenotypes in Caucasians and African Americans. Arterioscler Thromb 1993;13:1037–45.
      OpenUrlAbstract/FREE Full Text
    39. ↵
      Asanuma Y, Kawai S, Aoshima H, et al. Serum lipoprotein (a) and apolipoprotein (a) phenotypes in patients with rheumatoid arthritis. Arthritis Rheum 1999;42:443–47.
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      Gaw A, Brown EA, Ford I for the West of Scotland Coronary Prevention Study Group. Impact of apo(a) length polymorphism and the control of plasma Lp(a) concentrations. Evidence for a threshold effect. Arterioscler Thromb Vasc Biol 1998;18:1870–6.
      OpenUrlAbstract/FREE Full Text
    41. ↵
      Suzuki K, Kuriyama M, Saito T, et al. Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphism in its 5`-flanking region. J Clin Invest 1997;99:1361–6.
      OpenUrlCrossRefPubMedWeb of Science
    42. ↵
      Sandholzer C, Saha N, Kark JD, et al. Apo(a) isoforms predict risk for coronary heart disease. A study in six populations. Arterioscler Thromb 1992;12:1214–26.
      OpenUrlAbstract
    43. ↵
      Rath M, Niedorf A, Rablin T, et al. Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients. Arteriosclerosis 1989;9:579–92.
      OpenUrlAbstract/FREE Full Text
    44. ↵
      Kostner GM, Bihara Varga M. Is atherogenicity of Lp(a) caused by its reactivity with proteoglycans? Eur Heart J 1990;11(suppl E):184–9.
    45. ↵
      Tabas I, Li Y, Brocia RW, Xu SW, et al. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogeneic lipoproteins with smooth muscle cell and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein (a) retention and macrophage foam cell formation. J Biol Chem 1993;268:20419–32.
      OpenUrlAbstract/FREE Full Text
    46. ↵
      De Rijke YB, Jurgens G, Hessels EM, et al. In-vivo fate and scavenger receptor recognition of oxidised lipoprotein (a) isoforms in rats. J Lipid Res 1992;33:1315–25.
      OpenUrlAbstract
    47. ↵
      Chapman MJ, Huby T, Nigon F, et al. Lipoprotein (a): implication in atherothrombosis. Atherosclerosis 1994;110(suppl):S69–75.
    48. ↵
      Aznar J, Estelles A, Breto M, et al. Euglobulin clot lysis induced by tissue type plasminogen activator in subjects with increased levels and different isoforms of lipoprotein(a). Thromb Res 1993;72:459–65.
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      Smith EB, Cochran S. Factors influencing the accumulation in fibrous plaques of lipid derived from LDL. II. Preferential immobilisation of Lp(a). Atherosclerosis 1990;84:173–81.
      OpenUrlCrossRefPubMedWeb of Science
    50. ↵
      Beisiegel U, Niendorf A, Wolf K, et al. Lipoprotein (a) in the arterial wall. Eur Heart J 1990;11(suppl):174–83.
    51. ↵
      Edelberg J, Reilly C, Pizzo S. The inhibition of tissue type plasminogen activator by plasminogen activator inhibitor-1. The effects of fibrinogen, heparin, vitronectin and lipoprotein(a). J Biol Chem 1991;4:2459–65.
      OpenUrl
    52. ↵
      Graigner DJ, Kirschenlhor HL, Metcalf JC, et al. Proliferation of human smooth muscle cells promoted by lipoprotein (a). Science 1993;260:1555–8.
      OpenUrl
    53. ↵
      Hobbs HH, White AL. Lipoprotein(a): intrigues and insights. Curr Opin Lipidol 1999;10:225–36.
      OpenUrlCrossRefPubMedWeb of Science
    54. ↵
      Kronenberg F, Steinmetz A, Kostner GM, et al. Lipoprotein(a) in health and disease. Crit Rev Clin Lab Sci 1996;33:495–543.
      OpenUrlPubMedWeb of Science
    55. Djurovic S, Berg K. Epidemiology of Lp(a) lipoprotein: its role in atherosclerotic/thrombotic disease. Clin Genet 1997;52:291–2.
      OpenUrl
    56. ↵
      Stein JH, Rosennson RS. Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997;157:1170–6.
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      Islam S, Gutin B, Smith C, et al. Association of apolipoprotein(a) phenotypes in children with family history of premature coronary artery disease. Arterioscler Thromb 1994;14:1609–16.
      OpenUrlAbstract/FREE Full Text
    58. ↵
      Slunga L, Asplund K, Johnson O, et al. Lipoprotein (a) in randomly selected 25–64 year old population: the northern Sweden MONICA study. J Clin Epidemiol 1993;46:617–24.
      OpenUrlCrossRefPubMedWeb of Science
    59. ↵
      Heinrich J, Sandkamp M, Kokott R, et al. Relationship of lipoprotein (a) to variables of coagulation and fibrinolysis in a healthy population. Clin Chem 1991;37:1950–4.
      OpenUrlAbstract/FREE Full Text
    60. ↵
      Mikhailidis DP, Spyropoulos KA, Ganotakis ES, et al. Fibrinogen and lipoprotein (a): associations in a population attending a cardiovascular risk clinic and effect of treatment with ciprofibrate. Fibrinolysis 1996;10(suppl):17.
    61. ↵
      Meade TW, Vickers MV, Thompson SG, et al. Epidemiological characteristics of platelet aggregability. BMJ 1985;290:428–32.
    62. ↵
      Mikhailidis DP, Barradas MA, Maris A, et al. Fibrinogen mediated activation of platelet aggregation and thromboxane A2 release: implications in vascular disease. J Clin Pathol 1985;38:1166–71.
      OpenUrlAbstract/FREE Full Text
    63. ↵
      Cremer P, Nagel D, Labrot B, et al. Lipoprotein(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Goettingen risk incidence and prevalence study (GRIPS). Eur J Clin Invest 1994;24:444–53.
      OpenUrlCrossRefPubMedWeb of Science
    64. ↵
      Thompson SG, Kienast J, Pyke SD, et al. Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European concerted action on thrombosis and disabilities angina pectoris study group. N Engl J Med 1995;332:635–41.
      OpenUrlCrossRefPubMedWeb of Science
    65. ↵
      Cremer P, Nagel D, Seidel D, et al. Considerations about plasma fibrinogen concentration and the cardiovascular risk: combined evidence from the GRIPS and ECAT studies. Am J Cardiol 1996;78:380–1.
      OpenUrl
    66. ↵
      Fukujim MM, Martinez TL, Pinto LE, et al. Fibrinogen as independent risk factor for ischemic stroke. Arq Neuropsiquiatr 1997;55:737–40.
      OpenUrlPubMed
    67. ↵
      Beamer NB, Coull BM, Clark WM, et al. Persistent inflammatory response in stroke survivors. Neurology 1998;50:1722–8.
      OpenUrlAbstract/FREE Full Text
    68. ↵
      Cortinovis A, Crippa A, Crippa M. Blood rheology and fibrinogenemia: two independent parameters in the assessment of cerebral vascular damage. Minerva Med 1995;86:511–18.
      OpenUrlPubMed
    69. ↵
      D'Erasmo E, Acca M, Celi FS, et al. Plasma fibrinogen and platelet count in stroke. J Med 1993;24:185–91.
      OpenUrlPubMed
    70. ↵
      Spinler SA, Cziraky M. Lipoprotein (a): physiologic function, association with atherosclerosis, and effects of lipid-lowering therapy. Ann Pharmacother 1994;28:343–51.
      OpenUrlPubMedWeb of Science
    71. ↵
      Ganotakis ES, Mikhailidis DP. Bezafibrate: treating hyperlipidemias as well as other cardiovascular risk factors. Today's Therapeutic Trends 1996;13:231–49.
      OpenUrl
    72. ↵
      Koenig W. Recent progress in the clinical aspects of fibrinogen. Eur Heart J 1995;16(suppl A):54–9.
    73. ↵
      Mathur S, Barradas MA, Mikhailidis DP, et al. The effects of a slow release formulation of bezafibrate on lipids, glucose homeostasis, platelets and fibrinogen in type II diabetics: a pilot study. Diabetes Res 1990;14:133–8.
      OpenUrlPubMedWeb of Science
    74. ↵
      Genest J, Jr, Malinow MR. Homocyst(e)ine and coronary artery disease. Curr Opin Lipidol 1992;3:295–9.
      OpenUrl
    75. ↵
      Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149–55.
      OpenUrlPubMedWeb of Science
    76. ↵
      Hopkins PN, Wu LL, Hunt SC, et al. Lipoprotein(a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease. Arterioscler Thromb Vasc Biol 1997;17:2783–92.
      OpenUrlAbstract/FREE Full Text
    77. ↵
      Durand P, Lussier-Cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 1997;11:1157–68.
      OpenUrlAbstract
    78. ↵
      Nishio E, Watanabe Y. Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: a possible role for hydrogen peroxide. Br J Pharmacol 1997;122:269–74.
      OpenUrlCrossRefPubMedWeb of Science
    79. ↵
      Khachigian LM, Chesterman CN. Platelet-derived growth factor and its receptor: structure and roles in normal growth and pathology. Platelets 1993;4:304–15.
      OpenUrlCrossRefPubMedWeb of Science
    80. ↵
      Sacco RL, Roberts JK, Jacobs BS. Homocysteine as a risk factor for ischemic stroke: an epidemiological story in evolution. Neuroepidemiology 1998;17:167–73.
      OpenUrlCrossRefPubMedWeb of Science
    81. ↵
      Vila N, Deulofeu R, Chamorro A, et al. Plasma homocysteine levels in patients with ischemic cerebral infarction. Med Clin (Barc) 1998;110:605–8.
      OpenUrlPubMed
    82. ↵
      Harpel PC, Chang VT, Borth W. Homocysteine and other sulfydryl compounds enhance the binding of lipoprotein (a) to fibrin: a potential link between thrombosis, atherogenesis, and sulfydryl compound metabolism. Proc Natl Acad Sci U S A 1992;89:10193–7.
      OpenUrlAbstract/FREE Full Text
    83. ↵
      Bartens W, Rader DJ, Talley G, et al. Lipoprotein (a) in patients with hyperlipidaemia. Eur J Clin Invest 1995;25:647–53.
      OpenUrlPubMedWeb of Science
    84. ↵
      Wild SH, Fortmann SP, Marcovina SM. A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford five-city project participants. Arterioscler Thromb Vasc Biol 1997;17:239–45.
      OpenUrlAbstract/FREE Full Text
    85. ↵
      Kronenberg F, Steinmetz A, Kostner GM, et al. Lipoprotein(a) in health and disease. Crit Rev Clin Lab Sci 1996;33:495–543.
    86. ↵
      Catalano M, Perilli E, Carsaniga G, et al. Lp(a) in hypertensive patients. J Hum Hypertens 1998;12:83–9.
      OpenUrlCrossRefPubMedWeb of Science
    87. ↵
      Gazzaruso C, Buscaglia P, Garzaniti A, et al. Association of lipoprotein (a) levels and apolipoprotein(a) phenotypes with coronary heart disease in patients with essential hypertension. J Hypertens 1997;15:227–35.
      OpenUrlCrossRefPubMedWeb of Science
    88. ↵
      Freeman DJ, Griffin BA, Murray E, et al. Smoking and plasma lipoproteins in man: effects on low density lipoprotein cholesterol levels and high density lipoprotein subfraction distribution. Eur J Clin Invest 1993;23:630–40.
      OpenUrlPubMedWeb of Science
    89. ↵
      Pandolfi C, Pellegrini L, Dede A, et al. Lipoprotein (a), parameters of lipid metabolism and hemostasis in obese patients. Minerva Endocrinol 1997;22:13–17.
      OpenUrlPubMed
    90. ↵
      Boman L, Ericson M. Lipoprotein (a) levels after intestinal bypass operation for morbid obesity. Obesity Surgery 1997;7:125–7.
      OpenUrlCrossRefPubMedWeb of Science
    91. ↵
      Zamboni M, Facchinetti R, Armellini F, et al. Effects of visceral fat and weight loss on lipoprotein (a) concentration in subjects with obesity. Obes Res 1997;5:332–7.
      OpenUrlPubMedWeb of Science
    92. ↵
      Rastenyte D, Tuomilehto J, Domarkiene S, et al. Risk factors for death from stroke in middle-aged Lithuanian men: results from a 20-year prospective study. Stroke 1996;27:672–6.
      OpenUrlAbstract/FREE Full Text
    93. ↵
      Palmer A, Bulpitt C, Beevers G, et al. Risk factors for ischaemic heart disease and stroke mortality in young and old hypertensive patients. J Hum Hypertens 1995;9:695–7.
      OpenUrlPubMedWeb of Science
    94. ↵
      Menotti A, Blackburn H, Kromhout D, et al. The inverse relation of average population blood pressure and stroke mortality rates in the seven countries study: a paradox. Eur J Epidemiol 1997;13:379–86.
      OpenUrlCrossRefPubMedWeb of Science
    95. ↵
      Prospective Studies Collaboration Group. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;346:1647–53.
      OpenUrlCrossRefPubMedWeb of Science
    96. ↵
      Emond MJ, Zareba W. Prognostic value of cholesterol in women of different ages. Journal of Women's Health 1997;6:295–307.
      OpenUrlPubMedWeb of Science
    97. ↵
      Korn-Lubetzki I, Kleinman Y, Eliashiv S, et al. Correlation between serum lipids and stroke in an Israeli population. Neurol Res 1992;14(suppl 2):78–80.
      OpenUrlPubMed
    98. ↵
      Ozawa H, Aono H, Saito I, et al. Atherosclerosis and clinical examination: epidemiology of stroke and ischemic heart disease. Rinsho Byori—Japan. J Clin Pathol 1996;44:1015–26.
      OpenUrl
    99. Puddey IB. Low serum cholesterol and the risk of cerebral haemorrhage. Atherosclerosis 1996;119:1–6.
      OpenUrlCrossRefPubMedWeb of Science
    100. ↵
      Iribarren C, Jacobs DR, Sadler M, et al. Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men? The Kaiser permanente medical care program. Stroke 1996;27:1993–8.
      OpenUrlAbstract/FREE Full Text
    101. ↵
      Gatchev O, Rastam L, Lindberg G, et al. Subarachnoid haemorrhage, cerebral haemorrhage and serum cholesterol concentration in men and women. Ann Epidemiol 1993;3:403–9.
      OpenUrlPubMed
    102. ↵
      Iso H, Jacobs DR, Jr, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–10.
      OpenUrlCrossRefPubMedWeb of Science
    103. ↵
      Neaton JD, Blackburn H, Jacobs D, et al. Serum cholesterol level and mortality findings for men screened in the multiple risk factor intervention trial. Multiple risk factor intervention trial research group. Arch Intern Med 1992;152:1490–500.
      OpenUrlCrossRefPubMedWeb of Science
    104. ↵
      Palomaki H, Kaste M, Raininko R, et al. Risk factors for cervical atherosclerosis in patients with transient ischaemic attack or minor ischaemic stroke. Stroke 1993;24:970–5.
      OpenUrlAbstract/FREE Full Text
    105. ↵
      Fonte G, Bo M, Poli L, et al. Ischemic stroke and transient ischaemic attacks: a case-control study of the risk factors in elderly hospitalized patients. Recenti Prog Med 1993;84:254–62.
      OpenUrlPubMed
    106. ↵
      Jacobs DR. The relationship between cholesterol and stroke. Health Rep 1994;6:87–93.
      OpenUrlPubMed
    107. ↵
      Di Mascio R, Marchioli R, Vitullo F, et al. Serum cholesterol and risk of ischaemic stroke: results of a case-control study. On behalf of PROGETTO 3A investigators. Prev Med 1995;24:128–33.
      OpenUrlCrossRefPubMedWeb of Science
    108. ↵
      Ryu JE, Howard G, Craven TE, et al. Postprandial triglyceridemia and carotid atherosclerosis in middle-aged subjects. Stroke 1992;23:823–8.
      OpenUrlAbstract/FREE Full Text
    109. ↵
      Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high-density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen city heart study. BMJ 1994;309:11–15.
      OpenUrlAbstract/FREE Full Text
    110. ↵
      Gordon T, Kannel WB, Castelli WP, et al. Lipoproteins, cardiovascular disease and death: the Framingham study. Arch Intern Med 1981;141:1128–31.
      OpenUrlCrossRefPubMedWeb of Science
    111. ↵
      Pedro-Bodet J, Senti M, Nogues X, et al. Lipoprotein and apoprotein profile in men with ischemic stroke: role of lipoprotein (a), triglyceride-rich lipoproteins and apolipoprotein E polymorphism. Stroke 1992;23:1557–662.
      OpenUrl
    112. ↵
      Coudec R, Mahieux F, Bailleul S, et al. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study. Stroke 1993;24:661–4.
      OpenUrlAbstract/FREE Full Text
    113. ↵
      World Health Organisation. Tobacco or health: a global status report. Geneva: World Health Organisation, 1997.
    114. ↵
      Reed DM. The paradox of high risk of stroke in population with low risk of coronary heart disease. Am J Epidemiol 1990;131:579–88.
      OpenUrlAbstract/FREE Full Text
    115. ↵
      Jurgens G, Koltringer P. Lipoprotein (a) in ischemic cerebrovascular disease: a new approach to the assessment of risk for stroke. Neurology 1987;37:513–15.
      OpenUrlAbstract/FREE Full Text
    116. ↵
      Lindgren A, Nilsson-Ehle P, Norrving B, et al. Plasma lipids and lipoproteins in subtypes of stroke. Acta Neurol Scand 1992;86:572–8.
      OpenUrlPubMedWeb of Science
    117. ↵
      Vavernova H, Novotny D, Ficker L, et al. Lipoprotein (a): a genetic risk factor for early ischemic cerebrovascular stroke. Vnitr Lek 1993;39:979–87.
      OpenUrlPubMed
    118. ↵
      Jurgens G, Taddei-Peters WC, Koltringer P, et al. Lipoprotein (a) serum concentration and apolipoprotein (a) phenotype correlate with severity and presence of ischemic cerebrovascular disease. Stroke 1995;26:1841–8.
      OpenUrlAbstract/FREE Full Text
    119. ↵
      Peynet J, Beaudeux JL, Woimant F, et al. Apolipoprotein (a) size polymorphism in young adults with ischemic stroke. Atherosclerosis 1999;142:233–9.
      OpenUrlCrossRefPubMedWeb of Science
    120. ↵
      Van Kooten F, van Krimpen J, Dippel DW, et al. Lipoprotein (a) in patients with acute cerebral ischemia. Stroke 1996;27:1231–5.
      OpenUrlAbstract/FREE Full Text
    121. ↵
      Margaglione M, DiMinno G, Grandone E, et al. Plasma lipoprotein (a) in subjects attending a metabolic ward. Discriminations between individuals with and without a history of ischemic stroke. Arterioscl Thromb Vasc Biol 1996;16:120–8.
      OpenUrlAbstract/FREE Full Text
    122. ↵
      Nagayama M, Shinohara Y, Nagayama T. Lipoprotein (a) and ischemic cerebrovascular disease in young adults. Stroke 1994;25:74–8.
      OpenUrlAbstract/FREE Full Text
    123. ↵
      Peng D-Q, Zhao SP, Wang JL. Lipoprotein (a) and apolipoprotein E e4 as independent risk factors in ischemic stroke. J Cardiovasc Risk 1999;6:1–6.
      OpenUrlPubMedWeb of Science
    124. ↵
      National Institute of Neurological Disorders and Stroke Ad Hoc Committee (Whisnant JP, Basford JR, Bernstein EF, et al). Classification of cerebrovascular disorders III. Stroke 1990;21:637–76.
      OpenUrlFREE Full Text
    125. ↵
      Kawamoto, A, Shimada K, Matsubayashi K, et al. Factors associated with silent multiple lacunar lesions on magnetic resonance imaging in asymptomatic elderly hypertensive patients. Clin Exp Pharmacol Physiol 1991;18:605–10.
      OpenUrlPubMedWeb of Science
    126. ↵
      Kario K, Matsuo T, Kobayashi H, et al. “Silent” cerebral infarction is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels in elderly Japanese. Arterioscler Thromb Vasc Biol 1996;16:734–41.
      OpenUrlAbstract/FREE Full Text
    127. ↵
      Schreiner PJ, Chambless LE, Brown SA, et al. Lipoprotein (a) as a correlate of stroke and transient ischemic attack prevalence in a biracial cohort: the ARIC study. Atherosclerosis risk in communities. Ann Epidemiol 1994;4:351–9.
      OpenUrlPubMed
    128. ↵
      Ichinose A, Suzuki K, Saito T. Apolipoprotein (a) and thrombosis: molecular and genetic bases of hyper-lipoprotein (a)-emia. Semin Thromb Hemost 1998;24:237–43.
      OpenUrlPubMedWeb of Science
    129. ↵
      Hachinski V, Graffagnino C, Beaudry M, et al. Lipids and stroke: a paradox resolved. Arch Neurol 1996;53:303–8.
      OpenUrlCrossRefPubMedWeb of Science
    130. ↵
      Glader CA, Stegmayr B, Boman J, et al. Chlamydia pneumoniae antibodies and high lipoprotein(a) levels do not predict ischemic cerebral infarctions: results from a nested case-control study in northern Sweden. Stroke 1999;30:2013–18.
      OpenUrlAbstract/FREE Full Text
    131. ↵
      Alfthan G, Pekkanen J, Jauhianen M, et al. Relation of serum homocysteine and lipoprotein (a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106:9–19.
      OpenUrlCrossRefPubMedWeb of Science
    132. ↵
      Ridker PM, Stampfer MJ, Hennekens CH. Plasma concentration of lipoprotein (a) and the risk of future stroke. JAMA 1995;273:1269–73.
      OpenUrlCrossRefPubMedWeb of Science
    133. ↵
      Wissler RW, Vesslinovitch D. Atherosclerosis in nonhuman primates. Adv Vet Sci Comp Med 1977;21:351–420.
      OpenUrlPubMed
    134. ↵
      Weber G, Fabbrini P, Resi L, et al. An ultrastructural comparison of diet-induced atherosclerosis of arteries supplying the central nervous system in cynomolgus and rhesus monkeys. Appl Pathol 1983;1:121–38.
      OpenUrlPubMed
    135. ↵
      Weber G, Alessandrini C, Centi L, et al. Delayed development of intimal lesions in cerebral arteries of spontaneous hypertensive rats subjected to a short term atherogenic diet (TEM observations). Appl Pathol 1986;4:233–7.
      OpenUrlPubMed
    136. ↵
      Postiglione A, Napoli C. Hyperlipidemia and atherosclerotic cerebrovascular disease. Curr Opin Lipidol 1995;6:236–42.
      OpenUrlPubMedWeb of Science
    137. ↵
      Postiglione A, Rubba P, de Simone B, et al. Carotid atherosclerosis in familial hypercholesterolemia. Stroke 1985;16:658–61.
      OpenUrlAbstract/FREE Full Text
    138. ↵
      Landray MJ, Sagar G, Muskin J, et al. Association of atherogenic low-density lipoprotein subfractions with carotid atherosclerosis. Q J Med 1998;91:345–51.
      OpenUrlAbstract/FREE Full Text
    139. ↵
      Williams JK, Bellinger DA, Nichols TC, et al. Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein (a). Arterioscler Thromb 1993;13:548–54.
      OpenUrlAbstract/FREE Full Text
    140. ↵
      Jurgens G, Koltringer P. Cerebrovascular disease and Lp(a): its role in atherosclerotic plaque formation and vessel wall elasticity of the carotid arteries. Chem Phys Lipids 1994;67–68:429–34.
      OpenUrl
    141. ↵
      Watts GF, Mazurkiewicz JC, Tonge K, et al. Lipoprotein (a) as a determinant of the severity of angiographically defined carotid atherosclerosis. Q J Med 1995;88:321–6.
    142. ↵
      Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS investigators. French study of aortic plaques in stroke. Circulation 1997;96:3838–41.
      OpenUrlAbstract/FREE Full Text
    143. ↵
      Heinzlef O, Cohen A, Amarenco P. An update on aortic causes of ischemic stroke. Curr Opin Neurol 1997;10:64–72.
      OpenUrlCrossRefPubMedWeb of Science
    144. ↵
      Delanty N, Vaughan C. Vascular effects of statins in stroke. Stroke 1997;28:2315–20.
      OpenUrlAbstract/FREE Full Text
    145. ↵
      Hornstra G, Houwelingen AC, Kester ADM, et al. A palm oil-enriched diet lowers serum Lp(a) in normocholesterolemic volunteers. Atherosclerosis 1991;90:91–3.
      OpenUrlCrossRefPubMedWeb of Science
    146. ↵
      Berg-Schmith E, Klausen IC, Kristensen SD, et al. The effect of n-3 polyunsaturated fatty acids on Lp(a). Clin Chim Acta 1991;198:271–8.
      OpenUrlCrossRefPubMedWeb of Science
    147. ↵
      Sacks FM, Pfeffer MA, Moye LA, et al for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9.
      OpenUrlCrossRefPubMedWeb of Science
    148. ↵
      The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349–57.
      OpenUrlCrossRefPubMedWeb of Science
    149. ↵
      Behar S for the BIP Study Group. Lowering fibrinogen levels: clinical update. Blood Coagul Fibrinolysis 1999;10(suppl 1):S41–3.
    150. ↵
      Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med 1999;341:410–18.
      OpenUrlCrossRefPubMedWeb of Science
    151. ↵
      Kostner GM, Krempler F. Lipoprotein (a). Curr Opin Lipidol 1992;3:279–84.
    152. ↵
      Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St Mary's, Ealing, Northwick Park diabetes cardiovascular disease prevention (SENDCAP) study. Diabetes Care 1998;21:641–8.
      OpenUrlAbstract/FREE Full Text
    153. ↵
      Papadakis JA, Ganotakis ES, Jagroop IA, et al. Effect of hypertension and its treatment on lipid, lipoprotein (a), fibrinogen, and bilirubin levels in patients referred for dyslipidemia. Am J Hypertens 1999;12:673–81.
      OpenUrlAbstract/FREE Full Text
    154. ↵
      Taskinen MR, Puolakka J, Pyorala T, et al. Hormone replacement therapy lowers plasma Lp(a) concentrations. Comparison of cyclic transdermal and continuous estrogen-progestin regimens. Arterioscler Thromb Vasc Biol 1996;16:1215–21.
      OpenUrlAbstract/FREE Full Text
    155. ↵
      van der Mooren MJ, Mijatovic V, van Baal WM, et al. Hormone replacement therapy in postmenopausal women with specific risk factors for coronary artery disease. Maturitas 1998;30:27–36.
      OpenUrlCrossRefPubMedWeb of Science
    156. ↵
      Maher V, Marcovina S, Hilga L, et al. Effects of lowering elevated low-density lipoprotein cholesterol on the cardiovascular risk of lipoprotein (a). JAMA 1995;274:1771–4.
      OpenUrlCrossRefPubMedWeb of Science