apolipoprotein to - heartthat determine the distribution of atheroma throughout the circulation...

Br Heart J 1993;69:26-30

Apolipoprotein (a) concentrations andsusceptibility to coronary artery disease inpatients with peripheral vascular disease

P Groves, A Rees, A Bishop, R Morgan, M Ruttley, N Lewis, I Lane, R Hall

AbstractObjective-To investigate the relation

between apolipoprotein(a) concentra-tions and angiographically defined coron-ary artery disease in patients with ath-eromatous peripheral vascular disease.Design-40 consecutive patients were

recruited at the time of admission forperipheral vascular surgery. All under-went clinical assessment and coronaryarteriography. Apolipoprotein(a) con-centrations were measured by animmunoradiometric assay.Setting-Tertiary referral centre.Subjects-Patients requiring surgical

intervention for large vessel peripheralvascular disease.Main outcome measures-Presence or

absence and severity and distribution ofangiographically defined coronary arterydisease. Measurement of circulating con-trations of apolipoprotein(a) and otherlipid indices.Results-Coronary artery disease was

absent in 11 patients (group 1), mild tomoderate in 12 (group 2), and severe in 17(group 3). The distribution of peripheralvascular disease and of standard lipidindices was similar in these three groupsof patients. There was a significantdifference in apolipoprotein(a) concen-trations between the three groups, withconcentrations progressively increasingwith the severity of coronary artery dis-ease (mean (95% confidence interval):group 1, 112 U/I (52 to 242); group 2,214 U/I (129 to 355); group 3, 537 U/I (271 to1064) (analysis ofvariance p < 0 005). Theprevalence ofcoronary artery disease wasincreased 7A4 fold in patients withapolipoprotein(a) concentrations thatwere greater than the cohort median (206U/1) (p < 0 01).Conclusions-The results show an

association between apolipoprotein(a)concentrations and angiographicallydefined coronary artery disease inpatients with large vessel peripheralvascular disease. The findings implydifferences in the pathogenesis of coron-ary and peripheral atheroma and suggestthat the measurement of apolipo-protein(a) may prove a useful additionaltool in the risk factor assessment ofpatients undergoing peripheral vascularsurgery.

(Br Heart J 1993;69:26-30)

There is a high prevalence of coronary arterydisease among patients with peripheral vas-cular disease, which reflects the diffuse natureof atheroma.' Patients with intermittentclaudication are up to four times more likelythan controls to have coronary artery disease23and approximately half the deaths that com-plicate peripheral vascular surgery are due toacute myocardial infarction.4 While the wide-spread nature of atheroma implied a commonpathogenesis throughout the circulation, theabsence of angiographically significant coron-ary artery disease in more than 30% of patientswith advanced peripheral vascular disease56suggested that this may not be the case. Indeed,differences have emerged from epidemiologicalstudies regarding the relative risk factors thatare important in the development of coronaryand peripheral artery disease,7 and the factorsthat determine the distribution of atheromathroughout the circulation remain poorlyunderstood.

Apolipoprotein(a) (apo (a)) is a modifiedglycoprotein that is bound by disulphide bondsto low density lipoprotein to form thelipoprotein(a) (Lp(a)) complex.8 Circulatingconcentrations of apo(a), and therefore Lp(a),are largely genetically determined9 and thoughthe function of this lipoprotein remains poorlyunderstood considerable interest has centredaround the likelihood that concentrations ofLp(a) may explain a substantial part of theassociation between genetic predisposition andcoronary risk.'0 Prospective analysis has iden-tified high concentrations of Lp(a) as anindependent risk factor for subsequentmyocardial infarction or death from coronaryheart disease." Several case-control andangiographic studies have also shown anassociation between increased concentrationsof Lp(a) and the presence of coronary arterydisease'2-4 and cerebrovascular disease. 1%17Such an association, however, has not beensought in the presence of advanced atheromaelsewhere and in this study we investigated therelation between apo(a) concentrations andangiographically defined coronary artery dis-ease in patients with advanced peripheral vas-cular disease.

Patients and methodsWe studied 40 consecutive patients admittedfor peripheral vascular surgery. Informed con-sent was obtained from each patient and thestudy was approved by the hospital ethicscommittee. All patients underwent clinicalassessment with particular attention paid to thepresence or absence of clinical features

Department ofCardiology,University Hospital ofWales, CardiffP GrovesN LewisR HallDepartment ofMedicine, UniversityHospital of Wales,CardiffA ReesA BishopR MorganDepartment ofRadiology, UniversityHospital of Wales,CardiffM RuttleyDepartment ofSurgery, UniversityHospital of Wales,CardiffI LaneCorrespondence to:Dr P H Groves, Departmentof Cardiology, University ofWales College of Medicine,Heath Park, Cardiff CF44XN.Accepted for publication29 June 1992

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Apolipoprotein (a) concentrations and susceptibility to coronary artery disease in patients with peripheral vascular disease

indicative of underlying coronary artery dis-ease. Current medication was reviewed and thepresence of risk factors for coronary and peri-pheral vascular disease was documented. Ven-ous blood was sampled for liver function testsin view of the recognised influence that hepaticdisease may exert on circulating concentrationsof apo(a)."8 All patients had the followinginvestigations.

CORONARY AND PERIPHERAL ARTERIOGRAPHYCoronary arteriography was performed via theright brachial or femoral approach. Theangiograms were reported by an experiencedcardiac radiologist (MR) who was unaware ofthe results of the other investigations. A Brandtscoring system"9 was used which was-modifiedto include an assessment of the coronary cir-culation supplying both right and left ventri-cles. This scoring system gives an index of theseverity and distribution of coronary arterydisease by providing a total myocardial scorethat depends on the number, degree, and site ofcoronary stenoses. With this method a min-imum score of zero denotes the absence ofangiographically demonstrable coronary dis-ease. On the basis of the total myocardial score,patients were divided into three groups: thosewith absent (0), mild to moderate (0-9), orsevere ( > 9) coronary artery disease.The distribution of peripheral vascular dis-

ease was assessed by arterial or venous cath-eterisation with conventional or digital sub-traction angiography. The pattern of diseasewas defined anatomically according to thepresence or absence of aneurysmal dilatation ofthe descending aorta or significant (>50%)narrowing within the iliac, femoral, or poplitealvessels, or both.

LIPID, LIPOPROTEIN, AND APOLIPOPROTEINANALYSISVenous blood was taken after a 12 hour over-night fast. The sample was allowed to coagulateand the serum was separated within six hoursand divided into smaller volumes for futurelipid and lipoprotein analysis. These sampleswere stored at - 20'C except for those thatwere later assayed for HDL cholesterol, whichwere stored at - 70°C. Total cholesterol andtriglyceride were measured by standardenzymatic procedures.20 2' HDL cholesterolwas measured after phosphotungstate/mag-nesium precipitation22 and LDL cholesterolwas calculated by the Friedewald formula.23Apolipoprotein Al and apolipoprotein B were

Table 1 Clinical characteristics of the three groups ofpatients

Group I Group 2 Group 3(n= 11) (n= 12) (n= 17) p

Age (yr) (mean (SEM)) 581 (3 8) 65 0 (2 5) 64.9 (1-7) NSSex (M:F) 8:3 9:3 14:3 NSAngina (n(%)) 0 (0) 4 (25) 5 (29) NSHypertensive (n(%)) 1 (9) 6 (50) 8 (47) NSSmoker (n(%)) 9 (82) 10 (83) 16 (94) NSFamily history of CAD (n(%)) 3 (27) 1 (8) 1 (6) NSPrevious MI (n (%)) 0 (0) 5 (42) 4 (23) NSAlcohol intake (n (%)) 18 (4) 22 (10) 22 (10) NS

(units/week) (mean (SEM))

Group 1, no coronary artery disease (CAD); group 2, mild to moderate CAD; group 3, severe CAD.MI, myocardial infarction.

measured by a Beckman Immunochemistryanalyser. After reduction and hydrolysis of theapo(a) peptide from the Lp(a) particle, apo(a)concentrations were measured by an immuno-radiometric assay with monoclonal antibodiesto two different epitopes of apo(a) (PharmaciaDiagnostics AB). 1 U/I of apo(a) is equivalentto 01 mg/dl of Lp(a). A standard curve wasconstructed for each assay and all samples weremeasured in duplicate. The within assaycoefficient of variation was 3 8% and the min-imum detection limit was 8 U/1.

STATISTICAL ANALYSISThe results of biochemical and lipid analysisare expressed as mean (SEM) for the threegroups of patients. Mean apo(a) andtriglyceride concentrations were logarith-mically transformed for the purposes of statis-tical analysis because these data are known tobe positively skewed within the population.The geometric mean with confidence intervalswas calculated for the apo(a) concentrations ineach of the three groups. Data for the threegroups were compared by an analysis ofvariance and the significance of differencesbetween groups was determined by Scheffestest. Categorical variables were compared by Z2test. The association between apo(a) andcoronary artery disease was measured by cal-culating the sample odds ratio24 for apo(a)concentrations above and below the cohortmedian (206 U/1). A p value <0 05 was regar-ded as statistically significant.

ResultsThere was no angiographically demonstrablecoronary artery disease in 1 1 (group 1) of the 40patients, mild to moderate disease in 12 (group2), and severe disease in 17 (group 3). Table 1shows the clinical details of these three groupsof patients. They were of similar age and sexdistribution and the prevalence of risk factorsfor coronary artery disease was comparable inthe three groups. Alcohol intake was similar inthe three groups and none of the patients wasreceiving either nicotinic acid derivatives orhormone replacement therapy, both of whichmay influence circulating concentrations ofblood Lp(a).2927 Three patients in group 2, fourpatients in group 3, but none of the patients ingroup 1 were receiving # blockers. Ninepatients complained of angina and nine hadprevious documentation of myocardial infarc-tion. All these patients had angiographicevidence of coronary artery disease. Fastingblood glucose was similar in the three groups(table 2) and none of the patients was diabetic.Table 2 summarises the results of liver functiontests and shows that there were no significantdifferences between the groups with regard tothese variables.

PERIPHERAL VASCULAR DISEASETable 3 summarises the pattern of peripheralvascular disease in the three groups of patients.The prevalence of aneurysmal dilatation of thedescending aorta and of significant ath-eromatous narrowing of the iliac, femoral, andpopliteal vessels was similar, leading us to

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Table 2 Fasting blood glucose and liver function tests for the three groups of patients(mean (SEM))

Group I Group 2 Group 3Variable (n = 11) (n = 12) (n = 17) p

Blood glucose (mmol/l) 4 6 (0-1) 5-3 (0 2) 5-6 (0 7) NSAspartate transaminase (IU/I) 18 (2) 15 (1) 19 (2) NSAlkaline phosphatase (IU/l) 93 (11) 119 (15) 130 (15) NS

conclude that the distribution of peripheralvascular disease was comparable in the threegroups of patients studied.

APO(a) CONCENTRATIONSCirculating concentrations of apo(a) wereabove the lower detection limit of the assay inall subjects and therefore were quantifiable inall cases. The figure and table 4 show thedistribution of apo(a) in the three groups ofpatients.

Analysis of variance showed a significantdifference in the concentrations of apo(a) bet-ween the groups (p < 0 005) with the apo(a)concentrations progressively increasing withthe severity of coronary artery disease. Apo(a)concentrations were significantly greater ingroup 3 than in group 1 (p < 0 05). Theassociation between high apo(a) concentrationsand coronary artery disease was reflected in acalculated sample odds ratio of 7-4 (p < 0 01)when the median apo(a) of the whole cohort(206 U/1) was used as a cut off point.

LIPID ANALYSISThere was no significant difference betweenthe groups in terms of the concentrations of thestandard lipid variables, total cholesterol andtriglyceride (table 5). While concentrations ofHDL cholesterol and its main protein con-stituent, apolipoprotein Al, tended to decreaseas the severity of coronary artery diseaseincreased, the differences between the groupsdid not reach statistical significance. The con-centrations of LDL cholesterol and its mainprotein constituent apolipoprotein B werecomparable in the three groups of patients.

DiscussionThe results of this study show an associationbetween apo(a) concentrations and angiogra-phically defined coronary artery disease in agroup of otherwise unselected patients under-going peripheral vascular surgery. Circulatingconcentrations of apo(a) are largely geneticallydetermined but may be influenced by hepaticdisease,'8 hormone replacement therapy,27 andby treatment with nicotinic acid derivatives25 orneomycin.26 or both. None of these confound-ing factors was present among the patients inthis study, implying that the concentrations of

Table 3 Distribution (n(%)) of peripheral vascular disease in the three groups ofpatients

Group I Group 2 Group 3Disease (n = 11) (n = 12) (n = 17) p

Aortic aneurysm 5 (45) 6 (50) 7 (41) NSIliac 4 (36) 6 (50) 7 (41) NSFemoral 3 (27) 6 (50) 11 (65) NSPopliteal 3 (27) 0 (0) 5 (29) NS

2000-

1500-

_ 1000-0

500-

I

Nx N

x

Group 1 Group 2 Group 3(n= 11) (n= 12) (n= 17)

Figure Individual apo (a) concentrations in the threegroups ofpatients.

apo(a) that were observed were predominantlya reflection of genetic predisposition. A strongassociation between high apo(a) concentrationsand coronary artery disease was seen in studiesof the general population, 12-14 suggesting acontributory role of apo(a) in the pathogenesisof coronary atheroma. Such an association,however, has not previously been reported inpatients with advanced atherosclerosis else-where. The present results do not rule outother risk factors in the pathogenesis of coron-ary artery disease in patients with peripheralvascular disease but they do imply that varia-tions in the concentration of apo(a) betweenindividuals may partly explain why only aproportion develop important coronary arterydisease. Of perhaps equal interest in this studywas the finding of low apo(a) in the group ofpatients without angiographically demonstra-ble coronary atheroma but with advanced peri-pheral vascular disease. These findings suggestthat the relation between high apo (a) concen-trations and the development of advancedatheroma may vary throughout the circulationand may be less important in peripheral vesselsthan in coronary vessels. Epidemiologicalstudies have identified smoking28 and hyper-tension29 as risk factors that may exert a greaterinfluence on the development of peripheralthan coronary artery disease, and the results ofthis study corroborate the likelihood ofdifferences in the pathogenesis of coronary andperipheral atheroma.The current findings may also have potential

clinical implications for the management ofpatients with large vessel peripheral vasculardisease. The presence or absence of coincidentcoronary artery disease is a crucial factor indetermining both the long-term prognosis30and the risk of surgical intervention in suchpatients.3' In those with severe and symp-tomatic peripheral vascular disease the 10 yearrisk of death due to coronary heart disease orcardiovascular disease is increased 10 to 15fold30 and the risk of vascular surgery four-fold.3' Because coronary artery disease mayoften be clinically silent6 it has been suggestedthat all patients with documented large vesselperipheral arterial disease should receivecareful cardiovascular evaluation,30 especiallybefore vascular surgery is undertaken.32 Simple

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Table 4 Distribution of apo (a) concentrations (U/l) in the three groups ofpatients

Group I Group 2 Group 3(n= 11) (n= 12) (n= 17)

Geometric mean 112 214 53795% CI (52-242) (129-355) (271-1064)Median 152 160 1302Range (19-819) (82-777) (33-1638)

and cost-effective screening methods aretherefore required to identify those at greatestrisk in whom modification of risk factors,intensive monitoring, or appropriate coronaryintervention or both may improve prognosis.In patients undergoing vascular surgery non-invasive cardiac investigations includingdipyridamole thallium scintigraphy3233 andambulatory electrocardiographic monitor-ing"3' have been helpful, especially wheninterpreted in combination with clinical riskfactors.36 In the present study patients withcirculating concentrations of apo(a) that weregreater than the cohort median had anestimated 7 4 fold increase in the likelihood ofunderlying coronary artery disease. Theseresults suggest that the measurement of apo(a)may prove a useful additional screening tool inthe assessment of patients with large vesselperipheral vascular disease and may help toidentify those in whom further coronary inves-tigation and appropriate intervention may bewarranted.The precise mechanism by which Lp(a) (and

therefore apo(a)) promotes atherogenesisremains obscure, though the different anatomyand haemodynamic profile of the peripheraland coronary circulations may explain thevariable effects of circulating Lp(a) concentra-tions at these sites. The close structuralhomology between apo(a) and plasminogen3783has suggested a link between lipoproteinmetabolism and the clotting/fibrinolyticsystems. Lp(a) competes in vitro withplasminogen for binding to fibrin,'940 fibrin-ogen,4' and cell membrane binding sites4' 42 andmay therefore interfere with plasminogenactivation thereby promoting local thrombosisat the sites of pre-existing atheroma. Haemo-static factors43 and fibrin44 have been demon-strated within atheroma and the increase infibrin content of growing atheromatouslesions45 suggests that its rate of accumulationmay influence the rate of plaque growth. Whencirculating concentrations of Lp(a) are high areduction in endogenous fibrinolysis couldenhance the deposition and incorporation offibrin at sites of atheroma and thereby result in

Table 5 Lipid profile of the three groups ofpatients (mean (SEM))

Group I Group 2 Group 3Variable (n= 11) (n = 12) (n = 17) p

Total cholesterol 6-3 (0-6) 5 5 (0-4) 6-2 (0 4) NS(mmol/l)

HDL cholesterol 1 19 (0 16) 1 03 (0 06) 0 93 (0-06) NS(mmol/l)

LDL cholesterol 4 0 (0-5) 3-6 (0 4) 4 2 (0 3) NS(mmol/l)

Log TG (mmol/l) 0 22 (0 09) 0 25 (0 06) 0 26 (0-04) NSApoAl (mg/dl) 114 (10) 113(6) 102 (10) NSApo B (mg/dl) 110 (14) 110 (9) 122 (8) NS

HDL, high density lipoprotein; LDL, low density lipoprotein; TG, triglyceride.

accelerated growth of atheromatous lesions.Alternatively, the importance of Lp(a) mayrelate specifically to atherogenesis rather thanto thrombosis. Lp(a) competes with plasmin-ogen for binding to receptors on the surface ofhuman monocyte-like cells.' Since lipid-ladenmacrophages are the predominant cellularcomponent of arterial fatty streaks47 enhancedmacrophage uptake of Lp(a) may lead to itsincorporation at an early stage into ath-eromatous lesions where it is known to bepreferentially retained bound to fibrin.45

In summary, the results of this study showedan association between apo(a) concentrationsand the presence of angiographically definedcoronary artery disease in patients with advan-ced atheromatous peripheral vascular disease.The findings corroborate the link between highapo(a) concentrations and the development ofcoronary artery disease but also imply differen-ces in the pathogenesis of coronary and peri-pheral atheroma. Patients with both coronaryand peripheral vascular disease have anincreased risk associated with peripheral vas-cular surgery and also have a poor long-termprognosis. The findings in this study of anincreased prevalence of underlying coronaryartery disease in patients with high concentra-tions of apo(a) also imply that the measurementof apo(a) may prove to be a useful additionaltool in the risk factor assessment of patientswith large vessel peripheral vascular disease.

We thank DrT J Peters, Department ofMedical Computing andStatistics, University of Wales College of Medicine, for hishelpful statistical advice and comments. PG is a British HeartFoundation Junior Research Fellow.

1 Tomatis LA, Fierens EE, Verbrugge GP. Evaluation ofsurgical risk in peripheral vascular disease by coronaryarteriography: a series of 100 cases. Surgery 1972;71:429-35.

2 Reid DD, Holland WW, Humerfelt S, Rose G. A cardiovas-cular survey of British postal workers. Lancet 1966;i:614-8.

3 Hughson WG, Mann JI, Garrod A. Intermittent claudi-cation: prevalence and risk factors. Br Med J 1978;i:1379-81.

4 Jamieson WRE, Janusz MT, Miyagishima RT, Gerein AN.Influence of ischaemic heart disease on early and latemortality after surgery for peripheral occlusive vasculardisease. Circulation 1982;66 (suppl 1):92-7.

5 Hertzer NR, Beven EG, Young JR, et al. Coronary arterydisease in peripheral vascular disease: a classification of1000 coronary angiograms and results of surgical man-agement. Ann Surg 1984;199:223-33.

6 Hertzer NR. Basic data concerning associated coronarydisease in peripheral vascular patients. Ann Vasc Surg1987;1:616-20.

7 Fowkes FGR. Aetiology of peripheral atherosclerosis. BrMed J 1989;i:405-6.

8 Utermann G. The mysteries of lipoprotein (a). Science1989;246:904-10.

9 Utermann G, Menzel HJ, Kraft HG, Duba HC, KemmlerHG, Seitz C. Lp(a) glycoprotein phenotypes. Inheritanceand relation to Lp(a)-lipoprotein concentrations inplasma. J Clin Invest 1987;80:458-65.

10 Durrington PN, Ishola M, Hunt L, Arrol S, Bhatnagar D.Apolipoproteins(a), Al and B and parental history in menwith early onset ischaemic heart disease. Lancet 1988;ii: 1070-3.

11 Rosengren A, Wilhelmsen L, Eriksson E, Risberg B, WedelH. Lipoprotein(a) and coronary heart disease: a prospec-tive case-control study in a general population sample ofmiddle aged men. Lancet 1990;ii: 1248-51

12 Kostner GM, Avogaro P, Cazzolato G, Marth E, Bittolo G,Quinci GB. Lipoprotein Lp(a) and the risk for myocardialinfarction. Atherosclerosis 1981;38:51-61.

13 Armstrong VW, Cremer P, Eberle E, et al. The associationbetween serum Lp(a) concentrations and angiographicallyassessed coronary atherosclerosis. Dependence on serumLDL levels. Atherosclerosis 1986;62:249-57.

14 Dahlen GH, Guyton JR, Attar M, Farmer JA, Kautz JA,Gotto AM. Association of levels of lipoprotein (a), plasmalipids, and other lipoproteins with coronary artery diseasedocumented by angiography. Circulation 1 986;74:758-65.

29



/B


ownloaded from


Groves, Rees, Bishop, Morgan, Ruttley, Lewis, Lane, Hall

15 Murai A, Miyahara T, Fujimoto N, Matsuda M, KameyamaM. Lp(a) lipoprotein as a risk factor for coronary heartdisease and cerebral infarction. Atherosclerosis 1986;59:199-204.

16 Jurgens G, Koltringer P. Lipoprotein(a) in ischaemiccerebrovascular disease; a new approach to the assessmentof risk for stroke. Neurology 1987;37:513-5.

17 Zenker G, Koltringer P, Bone G, Niederkorn K, Pfeiffer K,Jurgens G. Lipoprotein(a) as a strong indicator forcerebrovascular disease. Stroke 1986;17:942-5.

18 Marth E, Cazzolato G, Bittolo Bon G, Avogaro P, KostnerGM. Serum concentrations of Lp(a) and other lipoproteinparameters in heavy alcohol consumers. Ann Nutr Metab1982;26:56-62.

19 Brandt PW, Partridge JB, Wattie WJ. Coronary arterio-graphy; method of presentation of the arteriogram reportand scoring system. Clin Radiol 1977;28:361-5.

20 Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC.Enzymatic determination of total serum cholesterol. ClinChem 1974;20:470-5.

21 Wahlefeld AW. Triglycerides. Determination afterenzymatic hydrolysis. In: Bergmeyer HU, ed. Methods ofenzymatic analysis. 2nd English edition. New York:Verlag Chemie Weinheim/Academic Press, Inc. 1974:1831-5.

22 Warnick GR, Nguyen T, Albers AA. Comparison of im-proved precipitation methods for quantification of high-density lipoprotein cholesterol. Clin Chem 1985;31:217-22.

23 Friedewald WT, Levy RI, Fredrickson DS. Estimation ofthe concentration of low-density lipoprotein cholesterol inplasma, without use of the preparative ultracentrifuge.Clin Chem 1972;18:499-502.

24 Emery AEH. Disease associations. In: Methodology inmedical genetics. 2nd ed. Edinburgh: Churchill Living-stone, 1986:114-25.

25 Carlson LA, Hamsten A, Asplund A. Pronounced loweringof serum levels of lipoprotein(a) in hyperlipidaemicsubjects treated with nicotinic acid. J Intern Med 1989;226:271-6.

26 Gurakar A, Hoeg JM, Kostner G, Papadopoulos NM,Brewer HB. Levels of lipoprotein Lp(a) decline withneomycin and niacin treatment. Atherosclerosis 1985;57:293-301.

27 Soma M, Fumagalli R, Paoletti R, et al. Plasma Lp(a)concentration after oestrogen and progestagen in post-menopausal women. Lancet 1991;337:612.

28 Dawber TR. The Framingham study. Cambridge, Massa-chusetts: Harvard University Press, 1980:186-9.

29 Schroll M, Munck 0. Estimation of peripheral athero-sclerotic disease by ankle blood pressure measurements ina population studyof 60 year old men and women. JChronic Dis 1981;34:261-9.

30 Criqui MH, Langer RD, Fronek A, Feigelson HS, KlauberMR, McCann TJ, Browner D. Mortality over 10 years inpatients with peripheral arterial disease. N Engl J Med1992;326:381-5.

31 Gersh BJ, Rihal CS, Rooke TM, Ballard DJ. Evaluation andmanagement of patients with both peripheral vascular andcoronary artery disease. J Am Coll Cardiol 1991;18:203-14.

32 Leppo J, Plaja J, Gionet M, Tumulo J, Paraskos JA, CutlerBS. Noninvasive evaluation of cardiac risk before electivevascular surgery. J Am Coll Cardiol 1987;9:269-76.

33 Boucher CA, Brewster DC, Darling RC, Okada RD, StraussHW, Pohost GM. Determination of cardiac risk bydipyridamole-thallium imaging before peripheral vascularsurgery. N Engl J Med 1985;32:389-94.

34 Raby KE, Goldman L, Creager MA, et al. Correlationbetween preoperative ischaemia and major cardiac eventsafter peripheral vascular surgery. N Engl J Med 1989;321:1296-3000.

35 Mangano DT, Browner WS, Hollenberg M, et al. Associa-tion of peri-operative myocardial ischaemia with cardiacmorbidity and mortality in men undergoing noncardiacsurgery. N Engl J Med 1990;323:1781-8.

36 Eagle KA, Coley CM, Newell JB, et al. Combining clinicaland thallium data optimizes preoperative assessment ofcardiac risk before major vascular surgery. Ann InternMed 1989;110:859-66.

37 Eaton DL, Fless GM, Kohr WJ, et al. Partial amino acidsequence of apolipoprotein(a) is homologous to plasmin-ogen. Proc Natl Acad Sci USA 1987;84:3224-8.

38 McLean JW, Tomlinson JE, Kuang JW, et al. cDNAsequence of apolipoprotein(a) is homologous to plasmin-ogen. Nature 1987;330:132-7.

39 Loscalzo J, Weinfeld M, Fless GM, Scanu AM.Lipoprotein(a), fibrin binding and plasminogen activa-tion. Arteriosclerosis 1990;10:240-5.

40 Harpel PC, Gordon BR, Parker TS. Plasmin catalyzesbinding of lipoprotein(a) to immobilized fibrinogen andfibrin. Proc Natl Acad Sci USA 1989;86:3847-51.

41 Hajjar KA, Gavish D, Breslow JL, Nachman RL.Lipoprotein(a) modulation of endothelial cell surfacefibrinolysis and its potential role in atherosclerosis. Nature1989;339:303-5.

42 Gonzalez-Gronow M, Edelberg JM, Pizzo SV. Furthercharacterization of the cellular plasminogen binding site:evidence that plasminogen 2 and lipoprotein(a) competefor the same site. Biochemistry 1989;28:2374-7.

43 Smith EB, Staples EM. Haemostatic factors in human aorticintima. Lancet 1981;i:1171-4.

44 Haust MD, Wyllie JC, More RH. Atherogenesis and plasmaconstituents. I. Demonstration of fibrin in the whiteplaque by the fluorescent antibody technique. Am J Path1964;44:255-67.

45 Bini A, Fenoglio JR, Sobel J, Owen J, Fejgl M, Kaplan KL.Immunochemical characterization of fibrinogen, fibrin Iand fibrin II in human thrombi and atheroscleroticlesions. Blood 1987;69:1038-45.

46 Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF. Apotential basis for the thrombotic risks associated withlipoprotein(a). Nature 1989;339:301-2.

47 Steinberg D, Parthasarathy S, Carew TE, Khoo JC,Witztum JL. Beyond cholesterol. Modifications of lowdensity lipoprotein that increase its atherogenicity. N EnglJ Med 1989;320:915-24.

48 Smith EB, Cochran S. Factors influencing the accumulationin fibrous plaques of lipid derived from low densitylipoprotein II; preferential immobilization of lipo-protein(a) (Lp(a)). Atherosclerosis 1990;84:173-81.

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