Lipoprotein(a): From Molecules to Therapeutics

Valmore Bermudez, MD, MPH, PhD,1* Nailet Arraiz, MSc, PhD,1

Daniel Aparicio, BSc,1 Edward Rojas, BSc,1 Daniela Gotera, BSc,1

Xavier Guerra, BSc,1 Roger Canelon, BSc,1 Judith Farıa, BSc,1

Luis Sorell, PhD,2 Anilsa Amell, MgSc,1 Nadia Reyna, MgSc,1

Mayela Cabrera, MD, MPH, PhD,1 Edgardo Mengual, MD, MgSc,1

Raquel Cano, MD,1 Clımaco Cano, PharmD,1 andManuel Velasco, MD, FRCP Edin3

Lipoprotein (a) [Lp(a)] was discovered by Kare Berg in 1963 from the study of low-densitylipoprotein genetic variants. Lp(a) contains a unique protein, apolipoprotein(a), which is linked tothe Apo B-100 through a disulfide bond that gives it a great structural homology with plasminogen,and confers it atherogenic and atherothrombotic properties. Interest in Lp(a) has increased becausean important association between high plasma levels of Lp(a) and coronary artery disease andcerebral vascular disorders has been demonstrated. Numerous case control studies have confirmedthat hyper-Lp(a) is a risk factor for premature cardiovascular disease. Lp(a) is identified as a genetictrait with autosomal transmission, codified by one of the most studied polymorphic genes inhumans. It has been demonstrated that variations in this gene are a major factor in the serum levelsof Lp(a). Variations differ considerably between individuals and sex across populations. Variousapproaches to drug treatment using fibric acid derivatives, growth hormone, insulin-like growthfactor-1, alcohol extracted soy protein, niacin, and exercise have been proven to decrease Lp(a) inhigh risk patients, but none has really been an effective therapeutic option for successfully reducingLp(a) plasma levels.

Keywords: cardiovascular disease, hyperlipoproteinemia(a), lipoprotein(a), atherogenesis, therapeutics

INTRODUCTION AND STRUCTURALFEATURES OF LIPOPROTEIN(a)

In 1963, Kare Berg originally describes lipoprotein (a)[Lp(a)].1 He described it as a new human serumantigen detected by an absorption reaction betweenrabbit antisera against human sera aimed to identifyimmunologic differences.2–5

Besides old world primates,6 humans,7,8 and Euro-pean hedgehogs express Lp(a), which is composed bya common low density lipoprotein (LDL-col) nucleilinked to an apolipoprotein (a) [Apo(a)] by disulfidebonds between a cysteine in the Kringle-IV type 9 (Cys67) and the cysteine 3734 in Apo B-100.8,9 Structurally,Apo(a) is composed of heavily glycosylated tridimen-sional structures called Kringles, because of theirsimilitude with a looped Danish pastry,7,8,11 and eachKringle contains a mean of 80 amino acids stabilizedby 3 internal disulfide bonds, which finally surroundthe LDL molecule.12

Apo(a) has high structural similitude with plasmin-ogen, a key proenzyme of the fibrinolytic pathway.13

Kringle IV domains are classified into 10 distinctsubclasses which compose most of the Apo(a) mole-cule, plus a linked Kringle V domain that resembles thecatalytic region of plasminogen.9 This Apo(a) proteasedomain, despite its 89% structural homology with

1Endocrine and Metabolic Diseases Research Center, University ofZulia, School of Medicine, Maracaibo, Venezuela; 2Angiology andVascular Surgery Institute, Genetic engineering and Biotechnol-ogy Center, La Habana, Cuba; and 3Clinical Pharmacology Unit,Vargas Medical School, Central University of Venezuela, Caracas,Venezuela.*Address for correspondence: The University of Zulia, Endocrineand Metabolic Diseases Research Center, 20th Avenue, Maracaibo,4004, Venezuela. E-mail: valmore@gmail.com

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plasminogen’s catalytic domain14 lacks the fibrinolyticproperties6,9 because of a substitution of valine andarginine for serine and isoleucine.

The Kringle IV type 2 domain gene can be expresseda different number of times, resulting in a variablecopy number of this structure (3–40 copies)6,7 withinthe Lp(a) molecule. This determines the basis for theisoform size heterogeneity of Apo(a)15; whereas, theremaining 9 subtypes of Kringle IV are expressed justin a single copy into the Apo(a) molecule.9

Each type of Kringle IV has an important role inLp(a) molecule maintenance because Kringle IV types5 and 8 have lysine residues that help establishdisulfide bonds among apo B-100 and Apo(a), andKringle IV type 9 provides a cysteine residue which isessential for disulfide bond formation. Nevertheless,Apo(a) is able to bind other molecules instead of LDL-col. An example of this is a high affinity lysine bindingresidue located in Kringle IV type 10,11 which givesthe ability to bind molecules such as fibrin9 competingwith its union to plasminogen, interfering with thefribrinolytic pathways, and making it a prothromboticparticle. Moreover, 23% of the mass of the Lp(a)complex, due to N and O-Glycosides linked to Apo(a),provides electronegative properties to this particle.8

Marcovina et al, in The Lugalawa Study demon-strated the existence of Lp(a) variable size isoforms(even more than 34 apo(a) size isoforms),15 acceptingthat smaller size apo(a) particles are linked to a higherproatherothrombogenic activity10,11 (Figure 1).

SYNTHESIS AND METABOLISM OFLP(a)

Details of Lp(a) synthesis and metabolism havenot been elucidated yet, mainly due to the lack of anideal in vitro model.16 Investigations show that theliver is the main place for Lp(a) synthesis. Hepatocytessynthesize Apo(a) and the association with ApoB-100occurs at the cell surface.17,18 Lp(a) assembly consists ofa 2-step mechanism19: the first one consists of non-covalent interactions, allowing Apo(a) and ApoB-100to adopt a correct 3-dimensional arrangement thatfacilitates the second step, the disulfide bond forma-tion9 through specific sequences of amino acids.20–26

Lp(a) plasma concentration differ among individualsover 1000-fold and are highly heritable as a result ofApo(a) gene expression. More than 100 alleles havebeen identified in the Apo(a) gene.27,28 Formation rateof Lp(a) affects plasma levels more than its catabo-lism.29 An inverse correlation between Apo(a) size andplasma concentrations has been shown. Apo(a) sizeand secretion efficiency is determined by the Kringle IV

copy number because smaller particles are moreefficiently secreted from the hepatic cells than particleswith higher molecular weight.30 This inverse correla-tion has been attributed to an increase in the retentiontime at the endoplasmic reticulum (ER) of high-sizedApo(a). White et al, using primary cultures of baboonhepatocyte, demonstrated that the production rateof Lp(a) is determined by the capacity of the allelicvariants to escape from ER.28 Proteasomes play animportant role in the secretion rate of Apo(a) fromhepatocytes by mediating presecretory degradation ofthis apoprotein. Chaperon calnexin can avoid thisprocess, probably by retaining of Apo(a) in the ER.31

Metabolic pathways for in vivo Lp(a) catabolism arenot totally clarified. Catabolism occurs primarily in theliver but mechanisms involved are not well known.32,33

LDL receptor does not seem to have a crucial role in Lp(a)metabolism. This affirmation is based on the fact thatstatin administration (which causes LDL receptor upre-gulation) does not affect significantly Lp(a) plasmaconcentration.27 Likewise, studies in mice have shownthat the LDL receptor, apoE, and the asialoglycoproteinreceptor do not participate significantly in Lp(a) catab-olism.32,34 Nonetheless, other receptors that can probablytake part in Lp(a) catabolism have been identified. Anexample, is the glycoprotein megalin 330 that is able todigest and degrade Lp(a) in vitro.35 Finally, macrophageshave the ability to internalize Lp(a) via the very low

FIGURE 1. Lp(a) structural characteristics. The Lp(a)molecule is composed by a lipid-soluble core (cholesterylester and triglycerides) surrounded by polar molecules(phospholipids, unesterified cholesterol) clearly commonto a LDL linked to an apolipoprotein Apo(a) by a disulfidebond. Its 2 main components give it prothrombotic andproatherogenic properties.

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density lipoprotein receptor, a fact that could explain themolecular basis of Lp(a) atherogenicity.36

Reports indicate fractions of ‘‘free’’ circulatingApo(a), composed of interchangeable repetitions ofKringle-4 type 2 structures.37 Molecular mechanismsresponsible for Apo(a) fragmentation have not beenwell elucidated, but it is believed that elastase orcollagenases are involved.38 Lamanuzzi et al39 pro-vided evidence regarding neutrophil participation inthe Apo(a) splicing process, which could explain thepresence of Apo(a) fragments in urine, plasma, andatherosclerotic plaques.40 Healthy individuals excretefew quantities (approximately 1% of plasma concen-tration) of small-sized Apo(a) fragments by urine.6,31

Also, higher Lp(a) plasma levels have been observed inpatients with kidney disease than healthy people,probably due to a compensatory increase in albuminand Lp(a) synthesis to balance hypoalbuminemiacaused by renal damage or as a result of a declinationin the Apo(a) and Lp(a) catabolism by the kidney.41

LP(a): AN ATHEROGENIC ANDTHROMBOGENIC LIPOPROTEIN

Several clinical studies have shown that elevated levelsof Lp(a) in plasma (.30 mg/dL) are an independentrisk factors for atherosclerosis-related events likecoronary disease, premature cardiovascular disease,stroke, and reestenosis after angioplasty, with similarpathogenicity in both men and women.6,42–48

Lp(a) can affect the anti-inflammatory mechanism,nitric oxide–mediated vasodilatation, and the balancebetween procoagulant and anticoagulant agents of theblood vessel wall,14 disrupting normal functions ofendothelium.50 It could also participate in the formationof atheromatous plaque that may develop ischemic andstenotic events. As stated above, the apo(a) has 80%homology with plasminogen, which is a zymogen withserine protease activity.50,51 Although they are signifi-cantly similar, the presence of an arginine residueinstead of serine in apo(a) prevents enzyme action. Thisexplains why Lp(a) is capable of blocking the catalyticactivity of plasmin on fibrin to remove the blood clot ina peripheral vessel injury.50

Plasminogen activation is possible through the for-mation of a multienzymatic complex between plas-minogen, tissue plasminogen activator, and fibrin.Apo(a) of Lp(a) acts in a competitive way, taking placein the plasminogen binding site creating an inhibitionof fibrin degradation. In addition, Lp(a) has been asso-ciated with elevated levels of plasminogen activatorinhibitor (PAI-1) synthesized by endothelial cells, smoothmuscle cells, and macrophages.14,52,53 In fact, PAI-1 is

able to decrease the activity of tissue plasminogenactivator, blocking the activation of plasminogen, andthe degradation of fibrin. In this way, Lp(a) inhibitsfibrinolysis by 2 pathways. One of them by blockingthe path of plasminogen activation and the otherthrough the stimulation of PAI-1, allowing the persis-tence of the clot and generating a thrombotic process.53

Numerous studies54,55 have shown that Lp(a) par-ticles accumulated in the subendothelium becomechemotactic substances, and their activity contributesto an atherosclerotic process by human monocytes.56

These Lp(a) particles are oxidized by superoxide radi-cals, and phagocyted more rapidly, by macrophages,than other lipoproteins, including LDL-c, to form foamcells that stimulate the intercellular adhesion mole-cules, promoting chemotaxis of monocytes.57–59

Other reports have shown that Lp(a) stimulatessmooth muscle cells growth by the inactivation oftransforming growth factor-b (TGF-b). Activated TGF-b prevents the migration and proliferation of SMCs.Thus, TGF-b inhibition stimulates SMC growth andblood vessel stenosis, accelerating the atherosclerosisprocess.53 Moreover, oxidized-Lp(a) inhibits nitricoxide-dependent vasodilatation, worsening the condi-tion in patients with hypertension.57 The same oxidizedparticles stimulate the production of PAI-1 which alsoincreases the proinflammatory and proatheroscleroticcondition by increasing the activation of adhesion ofmonocytes to the vessel wall.58,59

Lp(a) could also modulate platelet interaction by2 different ways. Apo(a) from Lp(a) inhibits the inter-action between collagen fibers of the injured vessel walland platelets, decreasing collagen-induced plateletaggregation. Using recombinant Apo(a), platelet aggre-gation was also enhanced by the activation of thrombinreceptor–activating peptide, probably contributing tothromboembolic complications and atherosclerosis.52

It is well known that adverse conditions such ashypertension and hypercholesterolemia or habits suchas smoking have a strong relationship with coronaryartery disease. Also, it has been shown that raisingserum Lp(a) stimulates rapid progression of theseconditions.14 Angiographic studies revealed the corre-lation between serum levels of Lp(a), the severity ofstenosis and obstruction of the coronary vessels.14 Ithas been reported that young people with Lp(a) maydevelop elevated myocardial infarction 10 or 20 yearsbefore people with other risk factors.

EPIDEMIOLOGICAL ASPECTS

A vast number of studies have come to consider Lp(a)as a trustworthy predictor for coronary heart disease.Nevertheless, there is no clear a consensus among

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epidemiologic studies linked to Lp(a) levels, rangingfrom a causative relationship between high plasmaLp(a) levels and acute coronary events incidence, to noapparent link between Lp(a) concentrations and cardio-vascular disease.61 Understandable epidemiologic as-sociation between elevated Lp(a) plasma levels andcardiovascular pathogenicity has not been totally reached.

Despite the controversial aspects, several significantstudies consider Lp(a) as a reliable predictor for coro-nary heart disease because low Lp(a) levels are wellcorrelated with a protective factor against coronaryartery disease in Eskimos, French, Native Americans,whites, Hispanic whites, and Chinese populations14;whereby, Lp(a) molecule has been lately recognized asan ‘‘emerging’’ risk factor for cardiovascular disease.6

Serum Lp(a) levels show marked variation betweenethnic groups. This affirmation has been demonstratedby many studies, such as ours in 3 strong Africandescending populations from South of MaracaiboLake, Venezuela.62 Lp(a) levels in these Afro-Americangroups are even higher than those reported previouslyin other black populations from United States andAfrica; although, the prevalence of coronary arterydisease and stroke was not higher when comparedwith other municipalities. Otherwise, in a study con-ducted in United States by Obisesan et al, children andadolescents showed unequal Lp(a) levels accordingto ethnic differences among African American, non–Hispanic whites and Mexican American children.63

On the other hand, serum Lp(a) concentration wouldbe variable due to genetics factors8,64 (nearly 90% ofLp(a) serum concentrations are determined by geneticinfluences), age, sex, dietary habits, smoking, waist–hip ratio, glucose tolerance, alcohol consumption,64

and many other factors such as Apo(a) isoform. Theassociation between Lp(a) levels and smaller or biggerisoforms is inverse,6,65 showing that high serum levelsof Lp(a) generally correlates with smaller Lp(a) iso-forms, which are related to an increased cardiovascularpathogenicity, compared with bigger isoforms.

Although several studies show that Lp(a) concen-trations are not statistically different between menand women,13 some reports have demonstrated thatelevated Lp(a) levels independently predict an in-creased risk of stroke and death from vascular diseasein men but not in women.66 Another recent review byEnas et al shows Lp(a) as an independent risk factor forpremature coronary artery disease (CAD) in bothsexes.14 These contradictory results need to be ex-plained by studies based on standardized assays.

In a study conducted by Tavridou and cols, in SouthAsians, Pakistani, Indian, Bangladeshi, and Europeanpopulations, Lp(a) levels distribution in South Asianswas similar to that observed in white and Chinese

populations,64 in contrast with previous researcheswhich showed South Asians to have higher Lp(a) levelsthan Europeans. Moreover, 27 different Apo(a) sizealleles had been detected in some South Asian groups,fact that may explain the variability in Lp(a) levels seenin these groups.64 Few studies about Lp(a) levels havebeen conducted in Latin America. Nevertheless, ina research based on Cuban population (mostly African-Caribbean origin), elevated serum concentrations ofLp(a) were detected65 both in patients with hyper-cholesterolemia and in those with hypertriacylglycer-idemia. Also, a study conducted by an Uruguayanworking group and published in a Mexican Journal,shows considerable higher concentrations of Lp(a) inpatients with aortic valvulopathy and going throughchronic hemodialysis (n = 116) compared with controls(n = 90; P , 0.01).69 Several reports have documenteda striking relationship between Lp(a) levels and angio-graphic documented disease only among youngerpatients,68 suggesting that the predictor role of Lp(a)for CAD decreases with age progression.14 In thissense, Tsimikas et al studied the relationships betweenoxidized phospholipids, Lp(a), and CAD discoveringthat there was a strong association between serumLp(a) levels plus the oxidized phospholipid:apo B-100ratio and CAD, but this was observed only in patientsunder 60 years of age.68 The reasons for this associationare not entirely understood but these findings affirmthe existence of clear differences according to age, interms of Lp(a) pathogenic influences.

The Strong Heart Study demonstrated that AmericanIndian populations had lower Lp(a) concentrationscompared to white or black populations. These in-terethnic differences in Lp(a) levels64 could be for themost part explained by the well known genetic influ-ences upon Apo(a) expression in hepatic cells, includ-ing all biochemical, anthropometric, and lifestyle riskfactors which would modify in a small sense, serumLp(a) concentrations. Despite these environmental fac-tors and the general consensus that Lp(a) levels arerelatively unaffected by changes in diet and by most ofthe medications currently used to treat hypercholes-terolemia (statins). Few studies have shown that a longterm diet is able to modify Lp(a) plasma levels. Thedietary content of n23 polyunsaturated fatty acids(PUFAs) is able to interfere with the Apo(a) gene. Theseresults were obtained from studies based on fishermenpopulations who had a rich intake of PUFAs. Morestudies are needed to confirm these results linked todietary modifications because of the well-knownvariability in Lp(a) levels.15

Lp(a) levels seem to fluctuate in pregnant womenand return to basal values post partum13 suggesting anhormonal influence. Therefore, premenopausal women

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have lower Lp(a) levels than postmenopausal women.61

Lp(a) levels increase in women after the physiologicdecrease of estrogens by natural or surgical menopauseand could contribute to the postmenopausal increase ofcoronary artery disease incidence. Estrogen replace-ment therapy has shown to be able to decrease plasmaLp(a) levels and this action could contribute to thereduction in coronary artery disease in women whoreceive this therapy.61 In a recent study conducted byour research group in a city based population fromVenezuela,67 we found that the elevation of serumLp(a) levels as a result of estrogen deprivation duringmenopause is a transitory effect, observing a significantdifference on Lp(a) concentration between women withhormonal replacement therapy (HRT) (8.5 mg/dL)versus women not receiving this therapy (21.5 mg/dL,P , 0.001). Nevertheless, differences in Lp(a) levelsamong these groups (with and without HRT) were notobserved after 60 years of age.

There have been discrepancies among results ofdifferent studies due to the absence of accurate immu-noassays through which Lp(a) measurements would beable to display homogeneous results. Therefore, manystudies have aimed efforts to establish an internation-ally accepted standardized assay for Lp(a) measure-ment.49 Trying to satisfy these deficiencies, the IFCCWorking Group for Lipoprotein(a) Assay Standardiza-tion has contributed to a practical solution toharmonize test results of immunoassays for Lp(a).49

In this manner, in 1999, the Framingham Heart Studyestablished a reference of normal ranges of Lp(a)-cholesterol for men and women in a study based onwhite population, indicating that Lp(a) levels of 0.259mmol/L (10 mg/dL) could be used as a guide topredict higher risk of coronary heart disease in men.48

Moreover, other diseases besides atherosclerosis havebeen associated with elevated concentrations of Lp(a).The relation between Alzheimer disease (AD) and Lp(a)serum levels has been suggested by recent studies.Serum levels of low molecular weight Apo(a) isoformsare increased in patients with vascular dementia andcerebrovascular disease. These conditions increase therisk of atherosclerosis and silent cerebrovasculardisease, which produce a decline in cognitive functionsat advanced age. Atherosclerotic events are associatedwith AD with an important interaction between apo(a)and apolipoprotein E polymorphism. Clinical datasuggest possible links between AD and Lp(a) plasmalevels, in which inflammatory events are precursors ofAD.70,71 In this direction, Mooser et al, demonstratedthat Lp(a) is an additional risk factor for late-onset ADin carriers of the apoE e4 allele.

Furthermore, other studies have described increasesin Lp(a) level after a myocardial infarction, in

postoperative patients and in other acute-phase re-sponses,72 clearly suggesting that Lp(a) might be anacute-phase reactant molecule. Likewise, high Lp(a)levels in renal disease and poorly controlled diabetesmellitus have been observed.6 Because Lp(a) patho-genicity has been correlated with other plasma lipo-proteins such as high density lipoprotein (HDL-c),LDL-c, and plasma triacylglycerides, high Lp(a) levelsassociated with low HDL-c, and elevated LDL-c mayhave a synergistic role in increasing CAD risk.13

TREATMENT APPROACHES

Lp(a) plasma levels are relatively resistant to manypharmacologic and nonpharmacologic agents, unlikeother plasmatic lipoproteins. Nevertheless, numerousstudies indicate that serum Lp(a) levels could be modi-fied by agents such as niacin, growth hormone andinsulin-like growth factor-1 (IGF-1),73 soy protein,74

casein,75 steroid hormones such as androgens, testos-terone and estrogen, aspirin, long-term administrationof PUFAs, and exercise (Tables 1 and 2). However,plasmapheresis, an expensive procedure reserved forfamiliar hypercholesterolemia cases,6 is the only ablemethod to reduce Lp(a) levels in 50%.

Diet

Some studies have shown the beneficial effects of fishand fish oil on lowering Lp(a) levels. Two raciallyhomogeneous Bantu populations from Tanzania wereanalyzed by Marcovina et al finding that those groupswhose diet was based on fish had high frequency oflarge-size isoforms of apo(a), showing Lp(a) plasma levels48% lower when compared with vegetarian subjects ofthe same population, expressing small-size isoforms ofApo(a). Nevertheless, in this research it was not clearwhich were the quantities consumed and the specificintakes in the vegetarian group. These investigatorsconcluded that a long-term diet rich in PUFAs decreasedLp(a) plasmatic levels, suggesting that a diet based on fishis capable of decreasing serum levels of Lp(a).15

Dietary proteins have some diminishing effects onLp(a) plasma concentrations, finding that soy protein mayhave an Lp(a)-raising effect and that casein could be ableto decrease Lp(a) levels in studied subjects.75 Neverthe-less, years later Meinertz et al in a similar research foundthat alcohol-extracted soy protein lowers lipoprotein(a)levels, in contrast with intact soy protein, proving thehypothesis that intact soy protein contains Lp(a)-raisingalcohol-removable components.74

Niacin

Niacin is a unique therapeutic agent defined with theability of effectively decreasing Lp(a) concentrations in

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a dose-dependent effect.14 Carlson et al found thatpatients who received niacin at doses of 2 and 4 g/dexhibited a decrease in Lp(a) levels by 25% and 38%,respectively.76 However, because side effects such asflushing, pruritus, and hyperuricemia14 are common,and the pharmacologic management must be main-tained throughout life, many researchers do not agreein the use of niacin as an effective Lp(a) diminishingtreatment. However, in some patients these side effectscould be diminished with administration of aspirin 30minutes before niacin.77 Recently, the Food and DrugsAdministration approved an extended-release niacin(niacin ER),78 as an agent used in mixed dyslipidemiasto reach adequate levels of serum lipids.79–81 In 2002,Pan et al assessed the effects of the niacin ER on LDL-cand HDL-c abnormalities and Lp(a) levels in patientswith diabetes (n = 36), concluding that niacin couldbe a useful drug for diabetic patients who also haddyslipidemia, including a lowering effect on Lp(a)levels (from 37 6 10 to 23 6 10 mg/dL; P , 0.001),thus, preventing the establishment of a proathero-sclerotic lipid profile,82 becoming niacin ER a probableuseful agent in Lp(a) management.

Aspirin

Aspirin was extensively studied regarding Lp(a) levels.In 1999, Kagawa et al83 analyzed the impact of aspirin

on Apo(a) mRNA expression and the transcriptionalactivity of the Apo(a) gene promoter in cultures ofhuman hepatocytes. The Apo(a) mRNA expressionwas reduced in 73%, suggesting that aspirin could beable to decrease Apo(a) production by hepatic cells.This effect would play an antiatherogenic role incardiovascular disorders, mediated by an unknowntranscriptional factor, but further studies are requiredto clarify the mechanism of this transcriptional regula-tion. The same authors, in 2002, studied 70 Japanesepatients with CAD pharmacologically treated withaspirin.84 They found that aspirin decreased Lp(a)levels in 80% of the studied patients who had highserum Lp(a) concentration (.300 mg/L) but there wereno significant changes in groups with serum Lp(a)concentrations below 300 mg/L. Nevertheless, theseparadox results need studies using larger populationsand standardized assays to reinforce these findings.

HMG-CoA reductase inhibitors and fibrates

Goudevenos et al developed statin-related studies,with a group of 90 dyslipidemic, nonsmoking patientswho were treated with 20 mg/d of atorvastatin during24 weeks. They concluded that atorvastatin was highlyeffective in serum lipid profile but Lp(a) levels did notexperience significant changes after atorvastatin treat-ment.85 Equally, Kaur et al show that simvastatintreatment likely improved lipid profile parameters butdid not exert significant changes on Lp(a) levels.86

When lovastatin was compared with gemfibrozil,regarding their effects on Lp(a) in patients with hyper-cholesterolemia, Ramirez et al found that gemfibrozilreduced more significantly triacylglycerides, total cho-lesterol, LDL, very low density lipoprotein, and Lp(a)levels and increased HDL-c when compared withlovastatin.87 Similar observations were found whilecomparing gemfibrozil with simvastatin.88 Although themechanism is still unknown, gemfibrozil reduced Lp(a)levels during the first month of treatment (P = 0.004) andstabilized them during the rest of the treatment.87

Table 1. Modifiers of Lp(a) serum levels.

Nonpharmacologic agents Pharmacologic agents

Exercise Decreasing agents Ascending agentsRising Lp(a) plasma

levelsDecreasing Lp(a) plasma

levelsPUFAs (long-term administration),

casein protein, alcohol-extractedsoy protein, IGF-1, niacin/acipimox,aspirin, gemfibrozil, HRT,androgenic-anabolic steroids,L-carnitine

hGH, soy protein

High intensity sports Moderate intensity sports

hGH, human growth hormone.

Table 2. Modifiers of Lp(a) serum levels.

Decreasing agents % Lower P

Niacin76 38% ,0.01Acipimox94 36.4% ,0.01Aspirin84 80% ,0.01PUFAs (long-term

administration)1548% ,0.0001

Casein protein75 50% ,0.001Alcohol-extracted soy

protein7460% ,0.01

Gemfibrozil vs. lovastatin67 25.3% vs. 4.9% ,0.05L-carnitine97 7.7% ,0.01

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Hormonal therapy

The use of human growth hormone (hGH) therapy ingrowth hormone deficient patients has been involved inthe elevation of serum Lp(a) concentrations and shouldbe employed with caution in subjects with concomitantcardiovascular disease.73,89,90 In addition, it is suggestedthat hGH mediates expression of Apo(a) in transgenicmice.90 Paradoxically, IGF-1 has been strongly related todecreasing this serum lipoprotein concentrations.89

Although the molecular basis of these findings has notbeen successfully established, we could assume thatthere must be unknown physiologic effects of hGH uponlipid metabolism which are not mediated by IGF-1.

On the other hand, results of a recent study carriedout by our research group, HRT has demonstrateda reductive effect on Lp(a) concentrations.67 It was alsoobserved that the increase of Lp(a) levels duringmenopause was a transitory effect due to estrogendeprivation. Likewise, Shlipak et al suggested that thebenefit of this management must be evaluated withinthe context of the Heart and Estrogen/ProgestinReplacement (HERS) study which concludes that theseagents have no benefit or utility on the prevention ofcardiovascular disease. On the contrary, they suggestan increase of cardiovascular risk in the group treatedwith hormone replacement therapy.91

Other therapeutic options like plant sterols,92 diac-ilglycerol,93 and anabolic steroids94 have shown a posi-tive effect on Lp(a) levels; however, due to the limitedsize sample, further studies are required to confirm theefficacy of these agents.

Acipimox, L-carnitine, and exercise

Niacin use is related with several side effects, however,a nicotinic acid–derivative drug, Acipimox, has beenused in patients with hyperlipoproteinemia(a) showingslight decrease in the Lp(a) concentration. Patients cantolerate this drug better than nicotinic acid, whichmeans fewer side effects such as cutaneous flushing.94,95

Similarly, Sposito et al96 studied type IIb dyslipi-demic patients with Lp(a) . 40 mg/dL, triglyceridelevels = 200–400mg/dL and total cholesterol .240mg/dL, compared the effects of etofibrate, a syntheticcompound drug of niacin and clofibrate versuscontrolled-release niacin on those parameters. Thepatients were randomly assigned to a double-blind16-week treatment period with either etofibrate (500 mgtwice daily; N = 14; 12 males; age: 56 6 5 years) orniacin (500 mg twice daily; N = 11; 8 males; age: 57 6

7 years). In their results both drugs improved lipidprofile; nevertheless, the reduction of Lp(a) and LDLcholesterol concentrations was not statically significant

in the group treated with niacin. In contrast, etofibratesignificantly reduced Lp(a) concentration by 26%.

L-carnitine is a supplement that affects Lp(a) serumconcentrations in the range of 40–80 mg/dL. Sirtoriet al,97 based on a double blinded study, determined that2 g/d of L-carnitine reduce hyper-Lp(a) in 77.8% oftreated patients (27.7% vs. baseline group and 211.7%vs. placebo), and explained that is a well-tolerated agent.Also, Derosa et al98 conducted an investigation in 94hypercholesterolemic patients with a recent diagnosis oftype 2 diabetes mellitus. L-carnitine significantly low-ered Lp(a) plasma levels in the treatment group (men =24, women = 22) compared with baseline (P, 0.05) andthe placebo group (men = 23, women = 25; P , 0.01).

Many studies have shown that regular exercise canhave beneficial effects in serum lipid profile, thusdecreasing coronary atherosclerosis risk and cardiovas-cular mortality.99 Contradictory results have been foundin other investigations between sedentary patients andathletes, because patients with regular training can havehigher Lp(a) plasma concentration.99,100 Variability ofphysical condition, ethnicity, age, sex, weight, type ofexercise, and body fat percentage should be consideredto regulate oxygen and caloric contribution, duration,and intensity of exercise and resistance.99,101

Ruiz et al designed a study in high performanceathletes from volleyball, swimming, and soccer teamsand a control group of healthy sedentary patients withsimilar anthropometrics and sociologic characteristics.They determined that soccer players had the highestLp(a) plasma levels, whereas swimmers had lowerLp(a) plasma levels. There are no satisfactory explan-ations for this phenomenon. It has been suggested thatthe elevated intensity, hits and falls of soccer, producean enhancement of proinflammatory cytokines andendotoxins (LPS), whereas the aerobic condition andmoderated intensity of swimming did not elevate thoseelements that mediate inflammation. Also, recentstudies suggest that after intense exercise (about 9–12months), in some persons, there might be an increaseLp(a) in plasma levels by 10%–15%.99

In a very interesting paper by our group in a largecohort of Venezuelan-mixed individuals and publishedin this issue we found that individuals with higherMetabolic Equivalent Tasks (METs) from the InternationPhysical Activity Questionaire (IPAQ) presented a lowerLp(a) plasmatic concentration when compared withindividuals with low and medium physical activity.

THE FUTURE . . .

Science advances have allowed to produce a syntheticpeptide that is able to inhibit Lp(a) assembly.

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ApoB4372–4392 peptide works as an inhibitor of thefirst step in the Lp(a) assembly by affecting a sequenceinside ApoB-100 (the apoB4372–4392 sequence) thatmediates the initial noncovalent binding betweenApo(a) and LDL-c.102,103 This is a drug that provideshope for the future control of hyperlipoproteinemia(a).Nevertheless, feasibility of large-scale production ofthis peptide and effectiveness in clinical trials should bestudied.

ACKNOWLEDGMENTS

Supported by research grant N� S1-2002000445 fromthe National Fund for Science, Technology and In-novation (FONACIT), Ministerio del Poder Popularpara la Ciencia y la Tecnologıa, Republica Bolivarianade Venezuela.

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