Lp(A) in Hypertensive Patients

ORIGINAL ARTICLE Lp(a) in hypertensive patients

M Catalano1, E Perilli1, G Carzaniga1, F Colombo2, M Carotta1 and S Andreoni1 1Research Center on Vascular Diseases; 2Department of Internal Medicine, University of Milan, L. Sacco Hospital, Milan, Italy

Lipoprotein(a) (Lp(a)) is considered an important risk trations of Lp(a), total cholesterol (TC), triglycerides factor for coronary disease, cerebrovascular pathology (TG) and very low density lipoprotein (VLDL-C) than and re-stenosis of coronary bypass. Few studies have controls (P Ͻ 0.01), with no differences in the plasma been conducted on this lipoprotein in essential arterial concentrations of Lp(a) between the two sexes. Only 10 hypternsive patients. The purpose of our study was to hypertension patients and seven controls had plasma measure the serum concentrations of Lp(a) and the concentrations of Lp(a) of over 30 mg/dl. Lp(a) does not main parameters of the lipid profile in a group of essen- correlate with the main parameters of the lipid profile. tial hypertensive patients not receiving pharmacological We can confirm that hypertension and dyslipidaemia, treatment and with no clinical signs of associated which are two of the main risk factors for vascular dis- pathologies or organ damage. A total of 123 Caucasian eases on an atherosclerotic basis, are often associated. essential arterial hypertensive patients (47 men and 76 However, higher plasma concentrations of Lp(a), albeit women) were studied and compared with 89 controls (36 within the normal range, could be an independent risk men and 53 women) matched in terms of age, sex, body factor for atherosclerosis, and could contribute towards mass index (BMI) and smoking habits. It was found that increasing the incidence of cardiovascular disease in the hypertensive patients had higher plasma concen- people with essential arterial hypertension.

Keywords: lipoprotein(a); total cholesterol; apolipoprotein; hypertension

Introduction only associated with an increased risk of vascular diseases such as CHD24–31 and the re-stenosis of cor- Many studies have shown clearly that high concen- onary bypass32–35 but are also considered an inde- trations of low-density lipoproteins (LDL-C), Apoli- pendent risk factor for these pathologies. poprotein B (Apo B) and total cholesterol (TC) Up to now there is very little information on Lp(a) accompanied by low concentrations of high-density in hypertensive patients available in the literature, lipoproteins (HDL-C) and Apoprotein AI (Apo AI) and any results published are contrasting.36–41 are the main risk factors for coronary heart disease Therefore, the aim of our study was to measure 1–15 (CHD), and there is considerable evidence that the serum concentrations of lipoproteins, and in all measures which are capable of lowering LDL-C particular of Lp(a) in a group of untreated hyperten- and raising HDL-C concentrations also help to lower sive patients with no clinical signs of associated 16 the incidence of acute events in these patients. In pathologies or organ damage and no family histories patients with essential hypertension there are often of coronary or cerebrovascular atherosclerotic dis- cardiovascular risk factors. Indeed, in these patients, ease. a modification of the lipid profile has been observed, with increased levels of total cholesterol, triglycerides and LDL-C and low blood concentrations of Materials and methods 17–19 HDL-C. Patients The lipoprotein(a) Lp(a) was described for the first time in 1963 by Berg.20 It consists of a set of lipopro- A total of 123 Caucasian patients (47 men and 76 teins with different molecular weights (from 350 to women) with essential arterial hypertension [sys- 900 KD),21 in which particles of LDL are bonded to tolic blood pressure (SBP) 165 ± 1.5 mm Hg and apoprotein(a) (apo(a)), which has a kringle structure diastolic blood pressure (DBP) 101 ± 0.4 mm Hg] with a high level of homology to plasminogen.22,23 were studied. Their average age was 53 ± 9 and their The physiological function of this lipoprotein is still average body mass index (BMI) was 25.4 ± 3.9. They unknown but the importance attributed to it has included 14 smokers (11%), but no former smokers. increased considerably in the light of the evidence The diagnosis of essential hypertension was reached that high plasma concentrations of Lp(a) are not after repeatedly measuring the patients’ arterial pressure at different times of the day using a mer- cury sphygmomanometer (Korotkoff sounds I and V) Correspondence: Professor M Catalano, Research Center on Vas- after lying in a supine position for 10 min, consider- cular Diseases, University of Milan, L. Sacco Hospital, Via G.B. Ͻ Ͻ Grassi 74, 20157 Milano, Italy ing an SBP of 140 mm Hg and a DBP of 90 42 Received 22 April 1997; revised 3 July 1997; accepted 5 August mm Hg as normal pressure values. Any patients 1997 with secondary hypertension, a positive family his- Lp(a) in hypertensive patients M Catalano et al 84 tory of cardiovascular diseases, the presence of clini- ations for TC, TG, HDL were: TC 0.8–0.7%, TG 0.7– cally evident cardiovascular (coronary, cerebral, and 0.6% and HDL 1.05–1.32%, respectively. The LDL- peripheral vascular diseases) or tumoral disease; or C and VLDL-C lipoprotein fractions were obtained with electrocardiographic signs of angina, alteration using Friedewald’s formula Apo AI, AII and B were of the S-T segment, changes in T, sugar dysmetabol- determined by means of radioimmunodiffusion ism (fasting glycemia Ͼ110 mg/dl), BMI Ͼ30 kg/m2, (RID), using plates containing polyclonal antibodies disorders of the renal (creatinine Ͼ1.2 mg/dl), liver (Daichi, Tokyo, Japan).46 Lastly, Lp(a) was assayed (AST Ͼ25 IU/L, ALT Ͼ29 IU/L, total bilirubin using two different anti-Apo(a) antibodies, the first Ͼ1.2 mg/dl, ␥-GT Ͼ38 IU/L) or thyroid functions of which was a monoclonal solid-phase antibody, (TSH Ͻ0.5 ␮U/ml or 3.5 ␮U/ml) and uricemia while the second was polyclonal, and marked with Ͼ5.7 mg/dl for the female and Ͼ7 mg/dl for the male a peroxidase (Macra Enzyme Immunoassay kit: patients, were excluded. Terumo Medical Corporation, Strategic Diagnosis Eighty-nine Caucasian subjects (36 men and 53 Division, Elkton, MD 21921, USA).47 The inter- and women) with no clinically evident pathologies and intra-assay coefficients of variations for Lp(a) were originating from the same geographical area were 3.1–1.3%, respectively. The lowest measurable used as a control group. They were matched with Lp(a) concentration was calculated to be 0.8 mg/dl. the hypertensive patients in terms of age (51 ± 3), ± sex, BMI (24.8 3.4) and smoking habits (11 smok- Statistical analysis ers = 12%) (see Table 1). For the purpose of this study, the patients did not receive any drugs capable In order to choose the most appropriate statistical of altering their lipid profiles for at least 4 weeks test, the variables were tested for skewness. Thanks before taking the blood samples. They were given to this preliminary statistical evaluation, it was no dietary restrictions. The hypertensive patients established that, with the exception of Lp(a), all the and the controls all came from Medical Angiology variables in question had a sufficiently normal dis- or Internal Medicine out-patient departments. tribution. For this reason, the statistical analysis was perfor- med using analysis of variance (ANOVA) and Blood samples Tukey’s test, and in view of the skewed distribution The blood samples for determining the apolipoprot- of blood Lp(a) concentrations in the hypertensive ein profiles were taken at 8.00 am, without stasis, and normal subjects we applied the Mann–Whit- by inserting a needle into the vein after fasting and ney test. refraining from cigarette smoking for at least 12 h. The ␹2 test was used for the non-parametric variables. Values of P Ͻ 0.05 were considered significant. Determination of the apolipoprotein profile The correlations between Lp(a) and all the The samples for determining the plasma concen- remaining parameters studied were checked using trations of total cholesterol, triglyceride, VLDL-C, the Spearman Correlation Test, taking Lp(a) as an LDL-C, HDL-C, Apoproteins AI, AII and B and Lp(a) independent variable. were placed in pre-cooled test tubes containing EDTA (1 mg/ml) and centrifuged immediately at Results 1500 g for 15 min at a temperature of 4°C. The plasma obtained in this way was then frozen and Table 1 describes the main clinical characteristics of stored at −85°C, and assayed within 2 weeks after the essential hypertensive patients and of the nor- sampling. TC and TG were assayed using enzyme mal controls. The two groups were similar in terms methods, with kits supplied by Boehringer of age, sex, smoking habits and BMI, while the aver- (Mannheim, Germany).43,44 The HDL-C concen- age systolic and diastolic BP values were higher in tration was measured after precipitation of the lipo- the patients with essential hypertension. proteins containing Apo B with phosphotungstic Table 2, on the other hand, shows the plasma con- acid and subsequent enzymatic assaying of choles- 45 Table 2 Apolipoprotein profile of normotensives and hyperten- terol. The inter- and intra-assay coefficients of vari- sives

Parameters Normotensives Hypertensives P Table 1 Demographic data TC (mg/dl) 204.8 ± 33.1 220.0 ± 38.5 Ͻ0.01b Normotensives Hypertensives TG (mg/dl) 92.6 ± 40.5 128.3 ± 61.9 Ͻ0.01b HDL-C (mg/dl) 46.2 ± 10.7 47.5 ± 10.8 n.s. Subjects 89 123 LDL-C (mg/dl) 144.5 ± 31.3 146.7 ± 36.7 n.s. Female 53 (59.5%) 76 (61.8%) VLDL-C (mg/dl) 18.2 ± 8 25.3 ± 12.3 Ͻ0.01b Male 36 (40.5%) 47 (38.2%) TC/HDL (mg/dl) 5.0 ± 1.4 4.8 ± 1.4 n.s. Age (years ± s.d.) 51 ± 353± 9 Apo AI (mg/dl) 137.1 ± 19.5 135.5 ± 27.9 n.s. Smokers 11 (12%) 14 (11%) Apo AII (mg/dl) 36.0 ± 6.2 34.1 ± 6.4 n.s. BMI (kg/m2 ± s.d.) 24.8 ± 3.4 25.4 ± 3.9 Apo B (mg/dl) 104.4 ± 28.9 102.3 ± 24.9 n.s. SBP (mm Hg ± s.d.) 128 ± 1.8 165 ± 1.5 Lp(a) values (mg/dl)c 0.8–82.8 (4.1) 0.8–95.7 (7.5) Ͻ0.01a DBP (mm Hg ± s.d.) 86 ± 2.1 101 ± 0.4 aMann–Whitney. In the individuals studied, sex, smoking habits and BMI were bANOVA and Tukey test. not significant. cRange and median. Lp(a) in hypertensive patients M Catalano et al 85 centrations of Lp(a) and the lipid profiles in the two Table 3 Correlations between Lp(a) levels and other parameters groups. The plasma concentrations of total choles- in hypertensive subjects terol, triglyceride, VLDL-C and Lp(a) were higher in Parameters Hypertensive subjects P the hypertensive patients than in the controls (r value) (P Ͻ 0.01). No significant differences were found between the two groups as far as the plasma concen- Age 0.086 n.s. trations of HDL-C, Apo AI, Apo AII, Apo B and LDL- TC (mg/dl) −0.047 n.s. C were concerned. TG (mg/dl) −0.073 n.s. In order to examine the difference in the plasma HDL-C (mg/dl) −0.149 n.s. LDL-C (mg/dl) 0.002 n.s. concentrations of Lp(a) between the two sexes, the VLDL-C (mg/dl) −0.069 n.s. hypertensive subjects were split up into two sub- TC/HDL (mg/dl) 0.065 n.s. groups, one male and one female. No significant dif- Apo AI (mg/dl) −0.016 n.s. ferences were found in the plasma concentrations Apo AII (mg/dl) −0.083 n.s. of Lp(a), although the female essential hypertensive Apo B (mg/dl) 0.010 n.s. patients did have slightly higher values than the male patients (female Lp(a) range 0.8–95.7 mg/dl, Spearman Correlation test. median value 7.6 mg/dl; male Lp(a) range 0.8–43.2 mg/dl, median value 7.5 mg/dl). Only 10 of the hypertensive patients (8.1%) and seven of the normal controls (7.8%) had plasma concentrations of Lp(a) higher than 30 mg/dl (Figure 1). Table 3 shows the coefficients of correlation between Lp(a) and all the other parameters studied. No correlation was noted between Lp(a) and the main parameters of the lipid profile.

Conclusions This study shows the plasma concentrations of Lp(a) and of the main parameters of the lipid profiles of patients with essential hypertension with no other clinically evident pathologies. The first result emerging from this investigation consists of signifi- cantly higher plasma concentrations of Lp(a) in the hypertensive patients than in the healthy controls. Although they found no differences in the concen-

Figure 2 Distribution of the total cholesterol values in hypertensive (HT) patients and normal controls.

trations of Lp(a) and in the apo(a) phenotypes between hypertensive patients and controls, some authors pointed out a positive correlation between high Lp(a) concentrations (characterised by isoforms of apo(a) with a low molecular weight) and a positive family history of CHD in the hypertensive 36 Figure 1 Distribution of the Lp(a) values in hypertensive (HT) patients. patients and normal controls. In the past, it has also been observed that the Lp(a) in hypertensive patients M Catalano et al 86 had Lp(a) concentrations falling with what are defined as normal values for this lipoprotein, and only a very minor portion of them (8.1%) had Lp(a) values exceeding 30 mg/dl (these were considered high risk patients for aterothrombotic diseases). These higher values could not be explained by the presence of a family history of CHD. In fact, our study called for patients with essential arterial hypertension with no clinical signs of pathologies or organ damage and with no family histories of CHD. Thus, the higher concentrations of Lp(a) in the hypertensive patients than in the controls, could constitute a first pathological sign, in the absence of noticeable organ damages. CHD and stroke are the main causes of morbidity and mortality in patients with arterial hyperten- sion50 and in many studies Lp(a) has been found to be an important risk factor for cardiovascular disease.51–53 The mechanisms by means of which Lp(a) increases the risk of thrombosis is not completely clear. Some observations that Lp(a) concentrates in the atherosclerotic plaques by means of mechanisms similar to those described for oxidised or modified LDLs. Indeed, in its protein fraction, in addition to Figure 3 Distribution of the triglyceride values in hypertensive apo(a), Lp(a) also contains a certain quantity of Apo (HT) patients and normal controls. B 100. Similarly to LDL, this can be modified by oxi- dation, and can also undergo phagocytosis by the monocytic and macrophagous cells through specific receptors, with the formation of ‘foam cells’.54 In addition, through apo(a), Lp(a) is capable of bonding with the fibronectin55 present in early atheromatous lesions and also with the glycosaminoglycans present in the arterial walls.56–58 It seems that this lipoprotein can be retained in the sub-intimal space of the arteries longer than LDL, with consequent greater atherogenicity.58,59 It has also been shown that there is a close correlation between high serum concentrations of Lp(a) and the concentrations of apo(a) in the arterial wall.60 Lp(a) can also modulate operation of the fibrinolytic mechanism.61 Indeed, it may even be capable of sti- mulating the synthesis of PAI-1.62 Although in vivo studies have given rise to contrasting results, it has been possible to observe in vitro that Lp(a) inhibits activation of the plasminogen to plasmin,63,64 and is capable, thanks to apo(a), of bonding with the tissue activator of plasminogen (t-PA), reducing its capacity to activate plasminogen to a significant extent.65 These observations indicate that Lp(a) could also have a considerable atherogenic and thrombogenic potential, and the fact that we found higher serum concentrations of this lipoprotein in the hypertensive patients studied could be considered a negative Figure 4 Distribution of the VLDL-C values in hypertensive (HT) factor of prognosis. Furthermore, most drugs, patients and normal controls. including hypocholesterolaemic drugs, are incapable of influencing its concentrations in the plasma concentrations of Lp(a) are inversely corre- plasma. Therefore Lp(a) is a risk factor which cannot lated with the size of the apo(a) isoforms. High be controlled. plasma concentrations of Lp(a) are therefore associa- In addition, the suggestion that this lipoprotein is ted with low molecular weight apo(a) isoforms and an independent risk factor is confirmed by the fact with a higher cardiovascular risk.48–49 that Lp(a) is not correlated either with age or with On the other hand, most of the patients studied the main parameters of the lipid profile (Table 3). Lp(a) in hypertensive patients M Catalano et al 87 Another interesting datum arising out of this a prospective case-control study in middle-aged men study is that we found higher serum concentrations of the Oslo Study. Artery 1979; 5: 170–181. of total cholesterol, triglyceride and VLDL-C in 5 Keys A. Alpha lipoprotein (HDL) cholesterol in the those hypertensive patients with a lipid profile feat- serum and the risk of coronary heart disease and death. uring slight hypercholesterolaemia and normal tri- Lancet 1980; 2: 603–606. glyceridaemia (Figures 2, 3 and 4). In our opinion, 6 Faker, Rosseneu M, Deslypere JP. Discrimative value of lipids and apoproteins in coronary artery disease. it is difficult to explain the relationship which may Atherosclerosis 1982; 42: 197–203. exist between arterial hypertension and these 7 Maciejko JJ et al. Apoprotein AI as a marker of angio- changes in the lipid profile; however, we feel that it graphically assessed coronary artery disease. N Engl J could indicate a greater risk of acute cardiovascular Med 1983; 309: 385–389. and cerebrovascular events. Moreover, this result is 8 Keys A et al. HDL serum cholesterol and 24-year mor- confirmed by the data found in literature. Indeed, tality of men in Finland. Int J Epidemiol 1984; 13: patients with arterial hypertension tend, generally 428–435. speaking, to have a dislipidaemia characterised by 9 Goldbourt U, Holtzman E, Neufeld HN. Total and high increased total cholesterol, triglyceride and VLDL-C density lipoprotein cholesterol in the serum and risk concentrations and low HDL-C concentrations.18,19,66 of mortality: evidence of threshold effect. Br Med J Some authors have explained these changes in the 1985; 290: 1239–1243. lipid profile by the simultaneous presence of insu- 10 Watkins LO, Neaton JD, Kuller LH (for the MRFIT lin-resistance accompanied by compensating hyper- Research Group). Racial differences in high-density lipoprotein cholesterol and coronary heart disease insulinaemia and increased plasma concentrations 67,68 incidence in the Usual Care Group of the Multiple Risk of glucose in hypertensive patients. Studies car- Factor Intervention Trial. Am J Cardiol 1986; 57: ried out on animals have indicated that fat-rich diets 538–545. can induce insulin resistance and subsequent hyper- 11 Castelli VP et al. Incidence of coronary heart disease tension. It has been suggested that in people with and lipoprotein levels: the Framingham Study. JAMA insulin resistance, the higher plasma concentrations 1986; 256: 2835–2838. of insulin may stimulate uptake of glucose and its 12 Gordon DJ et al (for the Lipid Research Clinics metabolism in the ventromedial nuclei of the hypo- Program). High-density lipoprotein chole sterol and talamus, with activation of the sympathetic nervous coronary heart disease in hypercholesterolemic men: system and consequent hypertension.69–71 the Lipid Research Clinics Coronary Primary Preven- In spite of these studies, the relationship between tion Trial. Circulation 1986; 74: 1217–1225. insulin resistance, compensating hyperinsulinae- 13 Steinberg D. Lipoproteins and the pathogenesis of atherosclerosis. Circulation 1987; 76: 508–514. mia, lipidic parameters and arterial hypertension in 14 Scott Grundy M. Multifactorial etiology of hyperchole- man is not completely clear, also because not all sterolemia. Implications for the prevention of coronary hypertensive patients are insulin-resistant or hyper- heart disease. Arterioscler Thromb 1991; 11: 1619– 67 insulinaemic. What seems to be more certain is 1635. that patients with hypertriglyceridaemia tend to 15 Stokes J et al. The relative importance of selected risk have smaller and more dense LDL particles than factor for various manifestations of cardiovascular dis- normotriglyceridaemic people, and have a more ease among men and women from 35 to 64 years old: noticeable post-prandial hyperlipidaemia than nor- 30 years of follow-up in the Framingham Study. Circu- motriglyceridaemic patients.72 lation 1987; 75 (Suppl V): 65–73. To conclude, we can confirm that hypertension 16 LaRosa JC, Cleeman JI. Cholesterol lowering as a treat- and dislipidaemia, which are two of the main risk ment for established coronary heart disease. Circu- factors for vascular disease having an atherosclerotic lation 1992; 85: 1229–1235. basis, are often associated. In addition, high plasma 17 MacMahon SW, MacDonald GJ, Blacket RB. Plasma lipoprotein levels in treated and untreated hyperten- concentrations of Lp(a), albeit comprised within the sive men and women. Arteriosclerosis 1985; 5: 391– normal range, could constitute an independent risk 396. factor for atherosclerosis, and could contribute 18 Fuh MM-T et al. Abnormalities of carbohydrate and towards increasing the incidence of cardiovascular lipid metabolism in patients with hypertension. Arch disease in patients with essential arterial hyperten- Intern Med 1987; 147: 1035–1038. sion. 19 Catalano M et al. Serum lipids and apolipoproteins in patients with essential hypertension. Atherosclerosis 1991; 87: 17–22. References 20 Berg K. A new serum type system in man: the Lp-sys- 1 Gordon T et al. High density lipoprotein as a protec- tem. Acta Path Microbiol Scand 1963; 59: 369–382. tive factor against coronary heart disease. The Fram- 21 Gaubatz JW et al. Polymorphic forms of human ingham Study. Am J Med 1977; 62: 707–714. apolipoprotein(a): inheritance and relationship of their 2 Miller NE, Forde OH, Thelle DS, Mjos OD. The Tromso molecular weights to plasma levels of lipoprotein(a). J Heart Study: high density lipoprotein and coronary Lipid Res 1990; 31: 603–613. heart disease: a prospective case-control study. Lancet 22 Utermann G. The mysteries of lipoprotein(a). Science 1977; 1: 965–970. 1989; 246: 904–910. 3 Goldbourt U, Medalie JH. High density lipoprotein 23 McLean JW et al. cDNA sequence of human cholesterol and incidence of coronary heart disease: apolipoprotein(a) is homologous to plasminogen. Nat- the Israeli Ischaemic Heart Disease Study. Am J Epide- ure 1987; 330: 132–137. miol 1979; 109: 269–308. 24 Durrington PN et al. Apolipoproteins(a), AI, and B and 4 Enger SC et al. High density lipoprotein cholesterol parental history in men with early onset ischemic and myocardial infarction and sudden coronary death: heart disease. Lancet 1988; 1: 1070–1073. Lp(a) in hypertensive patients M Catalano et al 88 25 Hoefler G et al. Lipoprotein(a): a risk factor for myocar- immunodiffusion. Immunochemistry 1965; 2: 235– dial infarction. Arteriosclerosis 1988; 8: 398–401. 254. 26 Rhoads GG et al. Lp(a) lipoprotein as a risk factor for 47 Giacherio D, Matz K. Evaluation of an enzyme immu- myocardial infarction. JAMA 1986; 256: 2540–2544. noassay kit for the determination of lipoprotein(a). 27 Kostner GM et al. Lipoprotein(a) and the risk for myo- Clin Chem 1990; 36: 955a (abstract). cardial infarction. Atherosclerosis 1981; 38: 51–61. 48 Wade DP. Lipoprotein(a). Curr Opin Lipidol 1993; 4: ¨ ¨ 28 Jurgens G, Koltringer P. Lipoprotein(a) in ischemic cer- 244–249. ebrovascular disease: a new approach to the assess- 49 Utermann G. The Mysteries of Lipoprotein(a). Science ment of risk for stroke. Neurology 1987; 37: 513–515. 1989; 246: 904–910. 29 Murai A et al. Lp(a) lipoprotein as a risk for coronary 50 Reaven GM, Litheli H, Landsberg L. Hypertension and heart disease and cerebral infarction. Atherosclerosis associated metabolic abnormalities. The role of insulin 1986; 59: 199–204. resistance and the sympathoadrenal system. N Engl J 30 Zenker G et al. Lipoprotein(a) as a strong indicator for Med 1996; 334: 374–381. cerebrovascular disease. Stroke 1986; 17: 942–945. 51 Dahlen GH et al. Association of levels of lipoprotein ¨ ¨ 31 Koltringer P, Jurgens G. A dominant role of Lp(a), plasma lipids, and other lipoproteins with cor- lipoprotein(a) in the investigation and evaluation of onary artery disease documented by angiography. Cir- parameters indicating the development of cervical culation 1986; 74: 758–765. atherosclerosis. Atherosclerosis 1985; 58: 187–198. 52 Rhoads GG et al. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA 1986; 256: 2540–2544. 32 Niendorf A et al. Morphological detection and quali- ¨ ¨ fication of lipoprotein(a) deposition in atheromatous 53 Koltringer P, Jurgens G. A dominant role of lesions of human aorta and coronary arteries. Vir- lipoprotein(a) in the investigation and evaluation of chows Arch A Pathol Anat 1990; 417: 105–111. parameters indicating the development of cervical 33 Cushing GL et al. Quantitation and localization of atherosclerosis. Atherosclerosis 1985; 58: 187–198. apolipoprotein(a) and B in coronary artery bypass vein 54 Bewu ADM, Durrington PN. Lipoprotein(a): structure, grafts resected at re-operation. Arteriosclerosis 1989; 9: properties and possible involvement in thrombogen- 593–603. esis and atherogenesis. Atherogenesis 1990; 85: 1–14. 55 Salonen EM et al. Lipoprotein(a) binds to fibrinectin 34 Rath M et al. Detection and quantification of and has serin proteinase activity capable of cleaving lipoprotein(a) in the arterial wall of 107 coronary it. EMBO J 1989; 8: 4035–4040. bypass patients. Arteriosclerosis 1989; 9: 579–592. 56 Dahlen GH, Ericson C, Berg K. In vitro studies of the 35 Hoff HF et al. Serum Lp(a) level as a predictor of vein interaction of isolated Lp(a) lipoprotein and other graft stenosis after coronary artery bypass surgery in serum lipoproteins with glycosaminoglycans. Clin patients. Circulation 1988; 77: 1238–1244. Genet 1978; 14: 36–42. 36 Gazzaruso C et al. Lipoprotein(a) plasma concen- 57 Bihari-Varga M et al. Interaction of lipoprotein Lp(a) trations, apolipoprotein(a) polymorphism and family and low density lipoprotein with glycosaminoglycans history of coronary heart disease in patients with from human aorta. Arteriosclerosis 1988; 8: 851–857. essential hypertension. J Cardiovasc Risk 1996; 3: 58 Walton KW, Hitchens J, Magnani HN, Khan M. A 191–197. study of methods of identification and estimation of 37 Costans J et al. Lipoprotein(a) in 505 hospitalized Lp(a) lipoprotein and of its significance in health, hyp- patients with various pathological states: correlations erlipidaemia and atherosclerosis. Atherosclerosis with cardiovascular diseases and therapies. Int Angiol 1974; 20: 323–346. 1996; 15(1): 1–5. 59 Miles LA et al. A potential basis for the thrombotic 38 Saku K et al. Effects of lisinopril and bisoprolol on risks associated with lipoprotein(a). Nature 1989; 339: lipoprotein metabolism in patients with mild-to-mod- 301–303. erate essential hypertension. Clin Therapeut 1995; 60 Rath M et al. Detection and quantification of 17(6): 1136–1146. Lipoprotein(a) in the arterial wall of 107 coronary 39 Van Wersch JW. The behaviour of lipoprotein(a) in bypass patients. Arteriosclerosis 1989; 9: 579–592. patients with various diseases. Scan J Clin Lab Invest 61 Hajjar KA, Gavish D, Breslow JL, Nachman RL. 1994; 54(7): 559–62. Lipoprotein(a) modulation of endothelial cell surface 40 Glueck CJ et al. Beta blockers, Lp(a), hypertension, and fibrinolysis and its potential role in atherosclerosis. reduced basal fibrinolytic activity. Am J Med Sci 1994; Nature 1989; 339: 303–305. 307(5): 317–324. 62 Etingin OR et al. Lipoprotein(a) regulates plasminogen 41 Zhuang YY, Wang JJ, Xu P. Increased lipoprotein(a) activator inhibitor-1 expression in endothelial cells. J as an independent risk factor for cardiovascular and Biol Chem 1991; 266: 2459–2465. cerebrovascular diseases. Chin Med J 1993; 106: 597– 63 Edelberg JM, Pizzo SV. Lp(a) inhibits plasminogen 600. activation in a template-dependent manner. Blood 42 The fifth Report of the Joint National Committee on Coagul Fibrinolysis 1991; 2: 759–764. Detection, Evaluation and Treatment of high blood 64 Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes pressure. Arch Intern Med 1993; 153: 154–183. binding of Lipoprotein(a) to immobilized fibrinogen 43 Roschlau P, Bernt E, Cruber W. Enzyatische bestim- and fibrin. Proc Natl Acad Sci USA 1989; 86: 3847– mung der gesamtecholesterins in serum. Chem Klin 3851. Biochem 1974; 12: 226–227. 65 Simon DI, Fless GM, Scanu AM, Loscalzo J. Tissue 44 Wahlefeld AW, Bergmeyer HU. Methoden der enzyma- type plasminogen activator binds and is inhibited by tischen. Analyse, 3rd Ed., Vol II Weinheim: Verlag surface-boud Lp(a) and LDL. Biochemistry USA 1991; Chemie, 1974–1978. 30: 6671–6677. 45 Lopez-Virella MF, Stone J, Ellis Golwell JA. Choles- 66 MacMahon SW, MacDonald GJ, Blacket RB. Plasma terol determination in high density lipoproteins separ- lipoprotein levels in treated and untreated hyperten- ated by three different methods. Clin Chem 1977; 23: sive men and women. Arteriosclerosis 1985; 5: 391– 882–884. 396. 46 Mancini G, Carbonara OA, Heremans JF. Immunoch- 67 Reaven GM. Insulin resistance, hyperinsulinemia, emical quantitation of antigens by single radial hypertriglyceridemia, and hypertension: parallels Lp(a) in hypertensive patients M Catalano et al 89 between human disease and rodent models. Diabetes etic nervous system activity. Hypertension 1991; 17: Care 1991; 14: 195–202. 669–677. 68 Shieh SM et al. Plasma lipid and lipoprotein concen- 71 Landsberg L, Young JB. Sympathoadrenal activity and trations in Chinese males with coronary artery disease, obesity: physiological rationale for the use of adre- with and without hypertension. Atherosclerosis 1987; nergic thermogenic drugs. Int J Obes Relat Metab Dis- 67: 49–55. ord 1993; 17 (Suppl 1): S29–S34. 69 Ward KD et al. The realtionship of epinephrine 72 Patsch JR et al. Relation of triglyceride metabolism and excretion to serum lipid levels: the Normative Aging coronary artery disease: studies in the post-prandial Study. Metabolism 1994; 43: 509–513. state. Arterioscler Thromb 1992; 12: 1336–1345. 70 Troisi RJ et al. Relation of obesity and diet to sympath-