Published online before print May 4, 2006, doi: 10.1161/01.STR.0000222979.34697.bf
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(Stroke. 2006;37:1350.)
© 2006 American Heart Association, Inc.
Editorials |
Lipoprotein(a)
Involved in Events, but Not Burden of Atherosclerotic Disease?
From the Stroke Prevention & Atherosclerosis Research Centre, London, ON, Canada.
Correspondence to Dr David Spence, Stroke Prevention & Atherosclerosis Research Centre, 1400 Western Rd, London, ON, Canada N6G 2V2. E-mail dspence{at}robarts.ca
Key Words: artery plaques, carotid • cerebrovascular disorders • intima-media thickness • Lp(a) • lipoprotein(a) • thrombosis
In this issue of Stroke, the Atherosclerosis Risk in Communities (ARIC) study provides evidence that lipoprotein(a) [Lp(a)] is a significant predictor of stroke.1 This is an important finding, because ARIC is both large and prospective. Over 14 000 patients were enrolled in 1987 to 1989, and during 13.5 years of follow-up, they experienced 496 ischemic strokes. Lp(a) remained a significant predictor of stroke after adjustment for age, race, systolic blood pressure, antihypertensive medication, smoking status, use of postmenopausal hormone therapy, diabetes, LDL cholesterol, HDL cholesterol, fibrinogen, and von Willebrand factor. It thus seems likely that Lp(a) is potentially an important treatable risk factor.
But what is Lp(a), and how does it relate to atherosclerosis and cardiovascular events? A meta-analysis of prospective studies of coronary events2 seems to establish that Lp(a) is also a predictor of myocardial infarction, but numerous studies indicate that it does not seem to predict the burden of atherosclerosis as assessed by intima-media thickness,3,4 except perhaps in patients with renal failure.5 Rossl et al6 found that Lp(a) was not associated with IMT or plaque but was associated with stenosis of carotid arteries.
We have previously shown that carotid plaque area more strongly predicts vascular outcomes than does stenosis assessed by carotid Doppler velocities7,8; an analysis of that database prompted by this commentary (previously unpublished) showed that in multiple regression adjusted for age, sex, systolic blood pressure and pack-years of smoking, Lp(a) was not associated with baseline plaque area (P=0.59), but was associated with baseline carotid stenosis (P=0.049). How can this be? It happens because phenotypes of atherosclerosis assessed by ultrasound, angiography and coronary calcification by computed tomography are biologically and genetically distinct.9,10
Because of compensatory enlargement,11,12 stenosis is probably not the consequence of plaque progression but the consequence of plaque rupture. Plaque area, which represents the burden of atherosclerosis at a point in time, reflects the effects over a lifetime of the traditional risk factors of atherosclerosis, but stenosis probably reflects the effects of factors affecting plaque rupture, such as inflammatory cytokines, matrix metalloproteinases and possibly infection, as well as the effects of factors affecting thrombosis and fibrinolysis.9
It seems likely that Lp(a) is involved in thrombosis and fibrinolysis. Two recent reviews help in the understanding of its mechanism of action and its role in atherosclerosis.
Koschinsky13 emphasized the mechanism of action of Lp(a):
Lp(a) is a challenging lipoprotein to study because it has a complex structure consisting of a low-density lipoprotein-like moiety to which is covalently attached the unique glycoprotein apolipoprotein(a) (apo(a)). Apo(a) contains multiply repeated kringle domains that are similar to a sequence found in the fibrinolytic proenzyme plasminogen; differing numbers of kringle sequences in apo(a) give rise to Lp(a) isoform size heterogeneity. In addition to elevated plasma concentrations of Lp(a), apo(a) isoform size has been identified as a risk factor for coronary heart disease, although studies addressing this relationship have been limited. The similarity of Lp(a) to low-density lipoprotein and plasminogen provides an enticing link between the processes of atherosclerosis and thrombosis, although a clear demonstration of this association in vivo has not been provided. Clearly, Lp(a) is a risk factor for both atherothrombotic and purely thrombotic events; a plethora of mechanisms to explain these clinical findings has been provided by both in vitro studies as well as animal models for Lp(a).
Berglund and Ramakrishnan14 emphasized population differences (higher levels in blacks, possibly related to the finding that Lp(a) was most strongly predictive of stroke in blacks in ARIC) and the role of variation in the size of the apo(a) moiety of Lp(a). Lp(a) is subject to oxidation, and proinflammatory oxidized phospholipids are preferentially bound to Lp(a) and taken up by macrophages,14 contributing to foam cell formation, and possibly to plaque rupture.
Does any of this matter? It may, particularly for patients with renal failure.15 Naruzevicz showed that vitamin therapy reduced Lp(a) along with fibrinogen and total homocysteine in patients with renal failure16; his group has also shown that antioxidant vitamins17,18 and probucol16 reduce oxidation of Lp(a).
It also matters because levels of Lp(a) can be reduced by therapy. Although statins are not very effective in reducing levels of Lp(a), and fibrates are only slightly effective, there is a moderate effect of niacin, which is now more accessible with the recent availability of slow-release preparations that reduce flushing while maintaining efficacy and avoiding hepatotoxicity19 (features that were not true of older slow-release preparations20). Recently, a more promising therapy for lowering of Lp(a) has appeared on the horizon: Meinertz et al found that alcohol-extracted soy protein reduced Lp(a) by 60% compared with a diet containing unextracted soy protein.21 If that finding is replicated, it suggests a therapeutic approach to lowering of Lp(a) that should be further tested in clinical trials.
Footnotes
The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.
See related article, pages 1407–1412
References
1. Ohira T, Schreiner PJ, Morriset JD, Chambless LE, Rosamond WD, Folsom AR. Lipoprotein(a) and incident ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2006; 37: 1407–1412.
2. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000; 102: 1082–1085.
3. Grebe MT, Schoene E, Schaefer CA, Boedeker RH, Kemkes-Matthes B, Voss R, Tillmanns HH. Elevated lipoprotein(a) does not promote early atherosclerotic changes of the carotid arteries in young, healthy adults. Atherosclerosis. 2006. In press.
4. Brzosko S, Lebkowska U, Malyszko J, Hryszko T, Krauze-Brzosko K, Mysliwiec M. Intima-media thickness of common carotid arteries is associated with traditional risk factors and presence of ischaemic heart disease in hemodialysis patients. Physiol Res. 2005; 54: 497–504.[Medline] [Order article via Infotrieve]
5. Ohkuma T, Minagawa T, Takada N, Ohno M, Oda H, Ohashi H. C-reactive protein, lipoprotein(a), homocysteine, and male sex contribute to carotid atherosclerosis in peritoneal dialysis patients. Am J Kidney Dis. 2003; 42: 355–361.[Medline] [Order article via Infotrieve]
6. Rossl A, Baldo-Enzi G, Ganzaroli C, Coscetti G, Calabro A, Baiocchi MR, Maiolino G, Pessina AC, Rossi GP. Relationship of early carotid artery disease with lipoprotein (a), apolipoprotein B, and fibrinogen in asymptomatic essential hypertensive patients and normotensive subjects. J Investig Med. 2001; 49: 505–513.[Medline] [Order article via Infotrieve]
7. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke. 2002; 33: 2916–2922.
8. Iemolo F, Martiniuk A, Steinman DA, Spence JD. Sex differences in carotid plaque and stenosis. Stroke. 2004; 35: 477–481.
9. Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol. 2004; 24: e188–e189.
10. Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis: similar windows but different views. Stroke. 2004; 35: 649–653.
11. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987; 316: 1371–1375.[Abstract]
12. Clarkson TB, Prichard RW, Morgan TM, Petrick GS, Klein KP. Remodelling of coronary arteries in human and nonhuman primates. JAMA. 1994; 271: 289–294.
13. Koschinsky ML. Lipoprotein(a) and atherosclerosis: new perspectives on the mechanism of action of an enigmatic lipoprotein. Curr Atheroscler Rep. 2005; 7: 389–395.[CrossRef][Medline] [Order article via Infotrieve]
14. Berglund L, Ramakrishnan R. Lipoprotein(a): an elusive cardiovascular risk factor. Arterioscler Thromb Vasc Biol. 2004; 24: 2219–2226.
15. Longenecker JC, Klag MJ, Marcovina SM, Liu YM, Jaar BG, Powe NR, Fink NE, Levey AS, Coresh J. High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients. J Am Soc Nephrol. 2005; 16: 1794–1802.
16. Naruszewicz M, Klinke M, Dziewanowski K, Staniewicz A, Bukowska H. Homocysteine, fibrinogen, and lipoprotein(a) levels are simultaneously reduced in patients with chronic renal failure treated with folic acid, pyridoxine, and cyanocobalamin. Metabolism. 2001; 50: 131–134.[CrossRef][Medline] [Order article via Infotrieve]
17. Naruszewicz M, Selinger E, Davignon J. Oxidative modification of lipoprotein(a) and the effect of beta-carotene. Metabolism. 1992; 41: 1215–1224.[CrossRef][Medline] [Order article via Infotrieve]
18. Naruszewicz M, Selinger E, Dufour R, Davignon J. Probucol protects lipoprotein (a) against oxidative modification. Metabolism. 1992; 41: 1225–1228.[CrossRef][Medline] [Order article via Infotrieve]
19. McCormack PL, Keating GM. Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia. Drugs. 2005; 65: 2719–2740.[CrossRef][Medline] [Order article via Infotrieve]
20. Stern RH, Freeman D, Spence JD. Differences in metabolism of time-release and unmodified nicotinic acid: explanation of the differences in hypolipidemic action? Metabolism. 1992; 41: 879–881.[Medline] [Order article via Infotrieve]
21. Meinertz H, Nilausen K, Hilden J. Alcohol-extracted, but not intact, dietary soy protein lowers lipoprotein(a) markedly. Arterioscler Thromb Vasc Biol. 2002; 22: 312–316.
Related Article:
Stroke 2006 37: 1407-1412.
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