Elevated plasma Lp(a) has been linked to development of coronary artery disease
(CAD). There is no data about plasma Lp(a) and atherosclerosis of the retinal arteries.
Therefore the purpose of this study was to assess the risk of retinal vessels atherosclerosis
conferred by elevated plasma Lp(a) levels in 73 adult males. The results were compared
with those in 45 matched apparently healthy males with no retinal vessel
changes. The atherosclerotic changes of the retinal vessels were determined by direct
ophthalmoscopy and graded (1–4) according to Scheie. Plasma levels of Lp(a) were measured
by radial immunodiffusion. The results were compared using chi-square test. Although
a very weak correlation between plasma Lp(a) levels and the incidence of retinal
atherosclerosis was found, no significant association between the degree of atherosclerotic
changes and plasma Lp(a) levels could be proven. Thus it could be concluded that
plasma Lp(a) level is not a significant risk factor for atherosclerosis of the retinal
arteries

E. Tedeschi-Reiner

K. Novak-Lauš

R. Iveković

Ž. Reiner

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Coll. Antropol. 26 (2002) 2: 609–614UDC 617.735-005:616.153Original scientific paperIs Lipoprotein(A) a Risk Factor forAtherosclerosis of the RetinalArteries?E. Tedeschi-Reiner1, @. Reiner2, R. Ivekovi}1 and K. Novak-Lau{11 Department of Ophthalmology, University Hospital »Sestre milosrdnice«, Zagreb, Croatia2 Department of Internal Medicine, University Hospital Center »Zagreb«, Zagreb, CroatiaA B S T R A C TElevated plasma Lp(a) has been linked to development of coronary artery disease(CAD). There is no data about plasma Lp(a) and atherosclerosis of the retinal arteries.Therefore the purpose of this study was to assess the risk of retinal vessels atherosclero-sis conferred by elevated plasma Lp(a) levels in 73 adult males. The results were com-pared with those in 45 matched apparently healthy males with no retinal vesselchanges. The atherosclerotic changes of the retinal vessels were determined by directophthalmoscopy and graded (1–4) according to Scheie. Plasma levels of Lp(a) were mea-sured by radial immunodiffusion. The results were compared using chi-square test. Al-though a very weak correlation between plasma Lp(a) levels and the incidence of retinalatherosclerosis was found, no significant association between the degree of atheroscle-rotic changes and plasma Lp(a) levels could be proven. Thus it could be concluded thatplasma Lp(a) level is not a significant risk factor for atherosclerosis of the retinalarteries.IntroductionAn increasing number of studies sug-gests that lipoprotein(a) /Lp(a)/ might bean independent, discriminating risk fac-tor for atherosclerotic disease in men1,2.This seems to be true not only for coro-nary artery disease (CAD) and myocar-dial infarction3–5 but also atherosclerosisof carotid arteries and ischemic stroke6,7as well as atherosclerosis of peripheralarteries, particularly of lower extremities7,8.Lp(a) is a plasma lipoprotein whose con-centration is stable and genetically deter-mined in an individual and whose compo-sition closely resembles that of atherogenicLDL, but with one additional molecule ofapoprotein(a) /apo(a)/10. Apo(a) is a largeglycoprotein linked to apoprotein B(apoB) by a disulfide bond and structur-ally similar to plasminogen. It has beenpostulated that this similarity is one of609Received for publication September 11, 2002the mechanisms by which Lp(a) promotesatherosclerosis11. Namely, Lp(a) com-petes with plasminogen for binding to fi-brin and to plasminogen receptors on thevascular endothelium surface thus inter-fering with fibrinolysis and acceleratingatherothrombosis. Lp(a) also increasesthe activity of plasminogen activator in-hibitor-1 (PAI-1)12 and reduces the activ-ity of transforming growth factor-beta(TGF-beta) resulting in inhibition of fibri-nolysis and promotion of migration andproliferation of smooth muscle cells(SMC)13. It is well known that SMC mi-gration and proliferation is an importantfeature of atherogenesis14. Lp(a) alsobinds to elastin via apo B, resulting in ox-idation and oxidatively modified Lp(a) ina fashion similar to LDL, and such Lp(a)is then taken up by macrophages13,15.Thisprocess promotes the transformation ofmacrophages into foam cells which is animportant step in early atherogenesis.There is currently no information on theeffectiveness on either dietary or drugtreatment which could decrease Lp(a)plasma concentration apart from obser-vation that hormone replacement thera-py16,17 and antiestrogen tamoxifen18 coulddo it.Although atherosclerotic changes havebeen described in the retinal arteries halfa century ago, there is no data in the lit-erature about Lp(a) and retinal arteryatherosclerosis. Therefore, the aim of thisstudy was to assess whether any associa-tion exists between Lp(a) and atheroscle-rosis of retinal arteries in adult men.Material and MethodsSubjectsThe study group consisted of 73 maleswith atherosclerotic changes of retinal ar-teries and an age, smoking and BMImatched control group of 45 males withnormal eye fundus. Neither of the sub-jects was acutely ill nor was receiving anylipid lowering agents, antihypertensives,steroids, or any other drugs known to in-fluence plasma lipids at the time of thestudy and over the 3 months prior to thestudy. Exclusion criteria were: diabetesor impaired glucose tolerance, hyperten-sion (BP higher than 140/90 mmHg), clin-ical hypo- or hyperthyreosis, clinicaladrenocortical hyperfunction or insuffi-ciency, clinical liver disease, clinical renaldisease, chronic or acute pancreatitis, for-mer or present malignant disease, auto-immune diseases, extreme obesity (BMI>35), a history of drug abuse and/or a his-tory of alcohol consumption greater than21 units per week, as well as a history ofmyocardial infarction, angioplasty, stro-ke, or major surgery during the 6 monthspreceding the study.The study complied with the Declara-tion of Helsinki. All subjects received oraland written information concerning thestudy prior to giving written informedconsent.Analysis of the retinal arteriesIn all the subjects the eye fundus ex-amination was carried out by directophthalmoscopy performed after the pu-pil dilatation by the same ophthalmolo-gist. The atherosclerotic vascular lesionsin the retinal arteries were classified ac-cording to Scheie19,20. Namely, Scheie de-veloped a four-scale classification of athe-rosclerotic changes of retinal arterieswhich was used in this study:Stage 1 – A broadening of the light re-flex from the artery can be seen, withminimal or no arteriovenous compres-sion. This is the earliest sign of retinal ar-tery atherosclerosis.Stage 2 – The changes are similar tothose in Stage 1 but more prominent.Stage 3 – The arteries have a »copperwire« appearance and there is much morearteriovenous compression. These are se-610E. Tedeschi-Reiner et al.: Atherosclerosis of the Retinal Arteries, Coll. Antropol. 26 (2002) 2: 609–614rious atherosclerotic changes of retinalarteries.Stage 4 – The arteries have a »silverwire« appearance and the arteriovenouscrossing changes are most severe. This isthe most severe form of the atherosclero-sis of the retinal arteries.Measurement of plasma Lp(a)All samples were collected between 8and 9 am, after a 12–14 h overnight fast,and after 15 min of rest in supine posi-tion. Cubital venous blood was drawninto evacuated blood-collection tubeswithout anticoagulant. After clotting, eachspecimen was centrifuged at 1200 x g for20 min at –4°C, immediately frozen andstored at –20°C for a maximum of oneweek. The plasma concentration of Lp(a)was measured by radial immunodif-fusion21 using the antisera from ImmunoAG, Austria. Lp(a) was considered ele-vated if the concentration was higherthat 0.3 g/L.Statistical analysisPlasma Lp(a) concentrations for pa-tients with retinal artery atherosclerosisand subjects with no retinal artery chan-ges were compared by using chi – squaretest. Statistical significance was assumedfor p less than 5% (p < 0.05).ResultsPatients with the atherosclerosis ofretinal arteries were 48.23 +/– 9.71 yearsold (range 25 – 69 years) and had a BMI24.2 +/–2.4. Controls were 47.60 +/–9.22years old (range 22 – 65 years) and had aBMI 24.1 +/– 2.0.A very weak correlation between plas-ma Lp(a) levels and retinal vessels ath-erosclerosis was found (c2 = 4.51008; df =1; p < 0.05). However, no significant asso-ciation between the degree of atheroscle-rotic changes of retinal arteries and plas-ma Lp(a) concentration could be proved(Table 1).DiscussionTo our knowledge, this is the first re-port of a study investigating the relation-ship between Lp(a) and retinal arteryatherosclerosis. Almost four decades agoit was noticed that 73% of patients withatherosclerotic retinal changes haveatherosclerotic changes of other arteriesas well, while 72% of the patients whohad atherosclerosis of the arteries insome other part of the body had also athe-rosclerotic changes of the retinal arte-ries22–24. However, these investigators didnot check Lp(a) in their patients.Atherosclerotic changes of the retinalarteries are characterized by the thicken-ing of the arterial wall and lipid deposi-tion in the intima often associated with fi-611E. Tedeschi-Reiner et al.: Atherosclerosis of the Retinal Arteries, Coll. Antropol. 26 (2002) 2: 609–614TABLE 1THE STAGE OF THE ATHEROSCLEROTICCHANGES OF THE RETINAL ARTERIESAND PLASMA LP(A) CONCENTRATIONLipoprotein(a) (g/l)Retinal arteries < 0.3 > 0.3 TotalNormal a 20b 44.4c 29.92555.649.04538.10Stage 1 a 12b 60.0c 17.9840.015.72016.90Stage 2 a 18b 72.0c 26.9728.013.72521.20Stage 3 a 14b 58.3c 20.91041.719.62420.30Stage 4 a 3b 75.0c 4.5125.02.043.40Total a 67b 56.85143.2118100.0a = number of subjects; b = % horizontal;c = % vertical;  2 = 5.79935, df = 4, p > 0.1brosis and even calcification of largerarteries. Sometimes in the literature theretinal arteries are called arterioles19 butthe arteries that are analyzed by ophthal-moscopy (branches of the central retinalartery) do have all the layers (intima, me-dia, adventitia) and resemble all the smallarteries in other organs including heartand brain25. Arterioles with the diametersmaller than 63 and 134 micrones26 lackan internal elastic lamina, and a con-tinuos layer of smooth muscle cells but theyand the capillary vessels were not ana-lyzed by ophthalmoscopy in this study27.We have recently shown that athero-sclerosis of the retinal vessels stronglycorrelates with plasma total cholesterol,LDL-cholesterol, triglycerides and apo-protein B levels which corresponds to thefindings in CAD and ischemic stroke28.Therefore our results presented in thispaper showing no correlation betweenplasma Lp(a) levels and retinal arteryatherosclerosis were quite surprising.However, despite the reports indicat-ing that increased plasma Lp(a) is a riskfactor for restenosis after balloon coro-nary angioplasty29 and coronary by passsurgery30 as well as several studies pub-lished in the last 20 years starting from thefirst one by Kostner et al31 suggesting anassociation between Lp(a) and CAD5,32–34,there were opposing reports too. Severalstudies showed that plasma Lp(a) wasnot a predictor of future coronaryevents35–38 thus questioning the previ-ously presented hypothesis. Our resultsare congruent with the results of thesestudies suggesting that clinical signifi-cance of increased Lp(a) concentration asa risk factor for atherosclerosis is ques-tionable, at least for retinal artery ath-erosclerosis.Although there was no previous studyabout Lp(a) and atherosclerosis of theretinal arteries, several studies havefound an association between increasedLp(a) and central or branch retinal arteryocclusion39–42.There is no readily apparent source ofbias to explain the discrepancy betweenthe findings of our study which demon-strated a lack of association betweenLp(a) and the risk of retinal artery ath-erosclerosis as well as other studiesshowing similar data for Lp(a) and CADand studies which have found a link be-tween elevated Lp(a) levels and the riskfor CAD or retinal vascular occlusion.The results from any one study should beconsidered in the context of all other in-formation. Thus our results do not negatethe role of Lp(a) in atherogenesis in gen-eral and in all types of the arteries butfurther prospective studies are needed toexplain whether susceptibility to athero-sclerotic damage of the vascular wallsand the role of Lp(a) in it is synchronousand uniform in different organs.R E F E R E N C E S1. DANESH, J., R. COLLINS, R. PETO, Circula-tion, 102 (2000) 1082. — 2. VON ECKARDSTEIN, A.,H. SCHULTE, P. CULLEN, G. ASSMANN, J. Am.Coll. Cardiol., 37 (2001) 434. — 3. CREMER, P., D.NAGEL, B. LABORT, H. MANN, R. MUCHE, H.ELSTER, D. SEIDEL, Eur. J. Clin. Invest., 24 (1994)444. — 4. WILSON, P., R. MYERS, M. LARSON, J.ORDOVAS, P. WOLF, E. SCHAEFER, J. Am. Med.Assoc., 272 (1994) 1666. — 5. CANTIN, B., F.GAGON, S. MOORJANI, J. P. DESPRES, B. LA-MARCHE, P. J. LUPIEN, G. DAGENAIS, J. Am.Cardiol. Col., 31 (1998) 519. – 6. SHINTANI, S., S.KIKUCHI, H. HAMAGUCHI, T. SHIIGAI, Stroke, 24(1993) 965. — 7. JURGENS, G., W. C. TADDEI-PE-TERS, P. KOLTRINGER, W. PETEK, Q. CHEN, J.GREILBERGER, Stroke, 26 (1995) 1841. — 8.BROWN, S., J. MORRISETT, E. BOERWINKLE, R.HUTCHINSON, W. PATSCH, Atheroscler. Throm.,13 (1993) 558. — 9. VALENTINE, R. J., P. A.GRAYBURN, G. L., VEGA, S. M. GRUNDY. Arch. In-tern. Med., 154 (1994) 801. — 10. REINER, @., Lipidi,4 (1994) 3. — 11. KOSCHINSKY, M. L., S. M.612E. Tedeschi-Reiner et al.: Atherosclerosis of the Retinal Arteries, Coll. Antropol. 26 (2002) 2: 609–614MARCOVINA, Int. J. Clin. Lab. Res., 27 (1997) 14. —12. BERGE, K. E., C. DJUROVIC, H. J. MULLER, P.ALESTROM, K. BERG, Clin. Genet., 52 (1997) 314.— 13. POON, M., X. ZHANG, K. DUNSKY, M. B.TAUBMAN, P. C. HARPEL, Clin. Genet., 52 (1997)308. — 14. REINER, @., E. TEDESCHI-REINER,Lije~. Vjesn., 123 (2001) 26. — 15. KOSTNER, G. M.,X. WO, S. FRANC, R. ZIMMERMANN, E. STEY-RER, Clin. Genet., 52 (1997) 347. — 16. THEWRITING GROUP FOR THE PEPI TRIAL, J. Am.Med. Assoc., 273 (1995) 199. — 17. SHLIPAK, G., J.A. SOMIN, E. VITTINGHOFF, J. Am. Med. Assoc.,283 (2000) 1845. — 18. VRBANEC, D., @. REINER, B.BELEV, S. PLE[TINA, Tumori, 84 (1998) 687. — 19.SCHEIE, H. G., Arch. Ophtalmol., 49 (1953) 117. —20. SCHEIE, M., A. ALBERT: Textbook of ophthal-mology. (W. B. Saunders, Philadelphia, 1977). — 21.UTERMANN, G., W. WEBER, FEBS, 154 (1983) 357.— 22. SAUTTER, H., Ber. Dtsch. Ges. Ophtalmol., 65(1964) 379. — 23. UTERMANN, D., E. J. KLEMPI-EN, Doc. Ophthalmol., 24 (1968) 201. — 24. UTER-MANN, D., Internist, 28 (1987) 357. — 25. HOGAN,M. J., L. FEENEY, J. Ultrastr. Res., 29 (1963) 29. —26. MAUSOLF, F. A.: The eye and systemic disease.(Mosby, London, 1980). — 27. HOGAN, M. J., L. FE-ENEY, J. Ultrastr. Res., 29 (1963) 10. — 28. TEDES-CHI-REINER, E., @. REINER, Ophtalmologica, inpress. — 29. DESMARAIS, R. L., I. J. SAREMBOCK,C. R. AYERS, S. M. VERNON, E. R. POWERS, L. W.GIMPLE, Circulation, 91 (1995) 1403. — 30. HOFF,H. F., G. J. BECK, C. I. SKIBINSKI, G. O. JUR-GENS, J. A. NEIL, J. KRAFT, B. LYTLE, Circulation,77 (1988) 1238. — 31. KOSTNER, G. M., P. AVOGA-RO, G. CAZZOLATO, E. MARTH, G. BITTOLO--BON, G. B. QUINICI, Atherosclerosis, 38 (1981) 51.— 32. DAHLEN, G. H., J. R. GUYTON, M. ATTER, J.A. FARMER, J. A. KAUTZ, A. M. GOTTO, Circula-tion, 74 (1986) 758. — 33. ROSENGREN, A., L. WIL-HELMSEN, E. ERIKSSON, B. RISBERG, H. WE-DEL, Br. Med. J., 301 (1990) 1248. — 34. SIGURD-SSON G., A. BALDURSDOTTIR, H. SIGVALDA-SON, U. AGNARSON, Am. J. Cardiol., 69 (1992)1251. — 35. JAUHIANEN, M., P. KOSKINEN, C.EHNHOLM, M. HEIKK, I. FRICK, M. MANTTARI,V. MANNINEN, J. K. HUTTENEN, Atherosclerosis,89 (1991) 59. — 36. HAFFNER, S. M., S. E. MOSS, B.E. KLEIN, Metabolism, 41 (1992) 194. — 37. RID-KER, P. M., Ch. H. HENNEKENS, M. J. STAMPFER,J. Am. Med. Assoc., 270 (1993) 2195. — 38. ALF-THAN G., J. PEKKANEN, M. JAUHIANEN, Athero-sclerosis, 106 (1994) 9. — 39. DIEKSTALL, F., H.CANZLER, E. SCHMIDT, U. DEMELER, Fortschr.Ophtalmol., 84 (1987) 369. — 40. MULLER, H. M., F.F. DIEKSTAL, E. SCHMIDT, W. MARZ, H. CANZ-LER, U. DEMELER, Ger. J. Ophtalmol., 1 (1992) 338.— 41. TAVOLA, A., S. V. D’ANGELO, F. BANDELLO,Thromb. Res., 80 (1995) 327. — 42. LIP, P. L., A. D.BLANN, A. F. JONES, G. Y. H. LIP, Eye, 12 (1998) 245.613E. Tedeschi-Reiner et al.: Atherosclerosis of the Retinal Arteries, Coll. Antropol. 26 (2002) 2: 609–614E. Tedeschi-ReinerDepartment of Ophthalmology, University Hospital »Sestre milosrdnice«, Vinogradska29, 10000 Zagreb, CroatiaJE LI LIPOPROTEIN(A) ^IMBENIK RIZIKA ZA ATEROSKLEROZUARTERIJA MRE@NICE?S A @ E T A KPove}ana koncentracija Lp(a) u plazmi povezuje se s aterosklerozom koronarnih ar-terija srca. Me|utim, nema nikakvih podataka o Lp(a) i aterosklerozi mre`ni~nih arte-rija. Stoga je cilj ovog istra`ivanja bio ustanoviti da li pove}ana koncentracija Lp(a) uplazmi predstavlja ~imbenik rizika za aterosklerozu arterija mre`nice. U ispitivanje suuklju~ena 73 odrasla mu{karca s aterosklerozom arterija mre`nice, a rezultati su us-pore|eni s onima u 45 zdravih mu{karaca podjednake dobi, uhranjenosti i ostalihobilje`ja koji nisu imali nikakvih promjena na arterijama mre`nice. Ateroskleroti~kepromjene arterija mre`nice procjenjivane su uz pomo} direktne oftalmoskopije i stup-njevane su od 1 do 4 prema Scheieu. Koncentracije Lp(a) u plazmi odre|ivane su ra-dijalnom imunodifuzijom. Rezultati su uspore|eni hi-kvadrat testom. Iako je uo~ena614E. Tedeschi-Reiner et al.: Atherosclerosis of the Retinal Arteries, Coll. Antropol. 26 (2002) 2: 609–614vrlo slaba povezanost izme|u koncentracije Lp(a) i pojave ateroskleroze arterija mre-`nice, nije se uspjela dokazati povezanost izme|u stupnja ateroskleroti~kih promjenamre`ni~nih arterija i koncentracije Lp(a). Stoga autori zaklju~uju da pove}ani Lp(a)nije zna~ajan ~imbenik rizika za aterosklerozu mre`ni~nih arterija.

Is Lipoprotein(A) a Risk Factor for Atherosclerosis of the Retinal Arteries?

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