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Lipoprotein (a), an independent cardiovascular risk marker Saeedi, Ramesh; Frohlich, Jiri Mar 31, 2016

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REVIEW ARTICLE Open AccessLipoprotein (a), an independentcardiovascular risk markerRamesh Saeedi1,2 and Jiri Frohlich1,2*AbstractEpidemiological and genetic studies have identified elevated levels of lipoprotein (a) ((Lp(a)) as a causal andindependent risk factor for cardiovascular diseases (CVD). The Lp(a)-induced increased risk of CVD may be mediatedby both its proatherogenic and prothrombotic mechanisms. Several guidelines recommend screening of Lp(a) level;however, there are few treatment options for the management of patients with elevated Lp(a). Severalnew medications for Lp(a) are under development. PCSK9 inhibitors, apolipoprotein (a)-antisense, andapolipoprotein(B-100)-antisense mipomersen have shown promising results. Lp(a) reduction will continue tobe an active area of investigation.Keywords: Lipoprotein(a) [Lp(a)], Coronary artery disease (CAD), Niacin, StatinsBackgroundMost clinical trials research investigating the effects ofcholesterol lowering medications on the prevention ofcardiovascular disease (CVD) have focused on low dens-ity lipoprotein cholesterol (LDL-C). Elevated serum levelof lipoprotein (a) (Lp(a)), an LDL particle linked to theplasminogen-like glycoprotein, has been an independentrisk factor for atherosclerotic CVD, particularly in thosewith high low-density lipoprotein cholesterol (LDL-C) ornon- high-density lipoprotein cholesterol (HDL-C) [1, 2].Effects of Lp(a) on vasculature are not fully understood.Human and animal studies have shown that Lp(a) canenter intima of arteries [3]. Thus, it may have a role in in-flammation of intima, thrombosis, and foam cell forma-tion; all these processes are involved in development ofatherosclerosis [4, 5]. It is estimated that around 1.5 billionpeople have Lp(a) levels greater than 500 mg/L [6]. Lp(a)levels are, to a large extent genetically determined, stableare not significantly influenced by diet, exercise, or otherenvironmental factors [6].This review article addresses the structure, genetics,and function of Lp(a) as well as indications for screeningand therapy.Lp(a) structureThe Lp(a) structure is similar to that of LDL, in which aglycoprotein, apolipoprotein(a) [apo(a)], is covalentlybound to apolipoprotein B (apoB) by a disulfide bridge,in a 1:1 molar ratio [2]. Cholesterol content of Lp(a) aswell as its density are similar to those of LDL particles.Its structure is similar to plasminogen, including a com-mon gene sequence [2]. The apo(a) chain contains fivedomains or kringles; the fourth kringle has a homologywith the fibrin-binding domain of plasminogen whichcauses Lp(a) interference with fibrinolysis. In addition,Lp(a) promotes foam cell formation and cholesteroldeposition in atherosclerotic plaques by binding tomacrophages [7].Lp(a) genetics and serum concentrationSerum levels of Lp(a) are mostly genetically determined.The polymorphism in apo(a) gene [LPA] results in theheterogeneity in its size and molecular weight [1, 2].Lp(a) show high ethnic variability. Atherosclerosis Riskin Communities (ARIC) study has shown that medianLp(a) levels are three times higher in African-Americansascompared to the Caucasions [8]. Matthews et al. [9] alsoreported higher levels of Lp(a) in African-American com-pared to Caucasians.Distribution of Lp(a) concentrations is highly skewed par-ticularly toward extremely high levels [2, 7, 10]. Lp(a) levels* Correspondence: jifr@mail.ubc.ca1Healthy Heart Program, St. Paul’s Hospital, Rm 180-1081 Burrard Street,Vancouver, B.C V6Z 1Y6, Canada2Pathology and Laboratory Medicine Department, University of BritishColumbia, St. Paul’s Hospital, Rm 180-1081 Burrard Street, Vancouver, B.C V6Z1Y6, Canada© 2016 Saeedi and Frohlich. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Saeedi and Frohlich Clinical Diabetes and Endocrinology  (2016) 2:7 DOI 10.1186/s40842-016-0024-xrange between 20 to more than 2000 mg/L with almost20 % of individuals at the extreme levels [2, 7, 10].There is a heterogeneity in size of Lp(a), ranging from187 to 662 KDa, it depends on the number of Kringle ofIV type 2 repeats in the Lp(a) gene [11]. There is astrong inverse relationship between the size of Lp(a) andits serum levels with smaller size correlating with higherserum levels [2]. Also smaller Lp(a) is associated with in-creased risks of cardiovascular disease (CVD). Due to itsstrong genetic determination, Lp(a) levels are stable andare not significantly influenced by gender, age, or envir-onmental factors [7, 10].Lp(a) measurementOriginally Lp(a) was detected by gel electrophoresis as a“sinking pre-beta lipoprotein” band [2]. There are issuesregarding Lp(a) measurement and standardization whichhave complicated Lp(a) level interpretations in the con-text of CVD risk. There are several diferent methods ofreporting Lp(a) leves that may confuse physicians. Somelaboratories report Lp(a) mass, while others report it asLp(a) concentration, or Lp(a) protein. Efforts has beenmade in standardization on measurement and reportingthe Lp(a) levels. Several assays for measurement of Lp(a)are available, such as enzyme-linked immunosorbent as-says (ELISAs), non-competitive ELISA, immunonephelo-metry, immunoturbidometry, and latex immunoassays[11–13]. The European Atherosclerosis Society guide-lines [12] recommended use of method which is robust,accurate, economically priced with coefficient of varia-tions (CV) <10 %. Also they have recommended thatantibodies which are used in assay kits should be apo(a)isoform-insensitive in which Lp(a) is measured inde-pendently of Lp(a) size and number of kringle-IV re-peats. Immunoassays, protocols for blood collection,plasma/serum isolation should be standardized for qual-ity control. A secondary reference Lp(a) preparation atan international level approved organizations such asInternational Federation of Clinical Chemistry and theWorld Health Organization. Manufactures making assaysfor measurement of Lp(a) should seek to minimize the ef-fects of apo(a) size on Lp(a) levels and use isoform-insensitive polyclonal antibodies (anti-apo(a) capture andanti-apo(B) [11–15].Denka-Seiken immunoturbidimetric assay (AtherotechDiagnostics Lab; Berkeley Extended-Range Lp(a) Test) isa high-duality and validated assay that measures Lp(a)mass with CV <3 %.Lp(a) and cardiovascular disease (CVD)Serum levels of Lp(a) are an independent risk factors forCVD. Several studies have indicated that the risk ismarkedly elevated at the extreme Lp(a) levels [16, 17].For example, the Copenhagen Heart Study showed thatpatients with Lp(a) levels above 500 mg/L have 2–3 foldincrease in the risk of myocardial infarction. A largeMendelian randomized study as well as the EPIC-Norfolk, and Brunek cohort studies demonstrated thatpatients with high Lp(a) levels have two-fold increase inCVD [7]. Recently Willeit et al. suggested that Lp(a)measurement, particularly in intermediate risk categoryof patient (as determined by Framingham risk score)predicts CVD outcomes and improves CVD risk predic-tion [18].HIgh levels of Lp(a) are commonly detected in pa-tients with premature coronary heart disease (CHD).Genest have reported elevated Lp(a) levels in 18.6 % ofpatients with premature CHD with 12.7 % of them havingno dyslipidemia [19]. The National Cholesterol EducationProgram for the Detection, Evaluation and treatment ofhypercholesteremia in adult (NCEP-ATP III) states thatLp(a) levels are predictor of CV risks with higher levels as-sociated with greater risk of having an CV events [20].The Emerging Risk Factors Collaboration have found thateach 3.5-fold increase in Lp(a) resulted in a 13 % increasein CVD risk [21]. They also found that this associationwas continuous and become proportionally more import-ant with higher Lp(a) levels. Moreover, they found thatthis association still persist even after correction for otherlipid parameters.Size of Lp(a) also modulates CHD risk with the smallerapo(a) isoforms associated more strongly with the risk ofCHD compared to larger isoforms [21]. Genome-wide as-sociation studies (GWAS), Mendelian randomization, andepidemiologic studies revealed a link between LPA geno-type with high Lp(a) levels and adverse CV events [6]. In asystemic review of 40 studies involving 58,000 partici-pants, Erqou et al. have shown that people with smallerapo(a) isoforms have approximately 2-fold higher risk ofCHD or ischemic stroke than those with larger isoforms[21]. Interestingly, they found that after adjustment forcholesterol and other CVD risk factors, the associationwas only slightly attenuated, strengthening the conceptthat Lp(a) is an independent risk factor for CHD. Likewise,European Prospective Investigation of Cancer cohort haveobserved that after adjustment for LDL-C, there is an as-sociation between Lp(a) levels and CVD [7]. Recently,Khera et al. analysed a subgroup of white participantsof the JUPITOR study and showed that in statin-treated patients with very low level of LDL-C, elevatedLp(a) levels represent a significant determinant of re-sidual risk for CVD [22].LPA gene polymorphism influences Lp(a) levels andthe risk of myocardial infarction with some commonvariants of LPA gene associated with more than 50 %risk of heart diseases [1, 2]. Two gene association studieshave suggested a causative relationships between ele-vated levels of Lp(a) and increased risk of CVD events.Saeedi and Frohlich Clinical Diabetes and Endocrinology  (2016) 2:7 Page 2 of 6The 10 years Framingham cardiovascular risk score doesnot include Lp(a) levels. However, including it may im-prove risk assessment. To support this idea, several cohortof patients (both Caucasian and African-American pa-tients) were used to develop 2013 American College ofCardiology/American Heart Association (ACC/AHA) car-diovascular risk calculator [20]. This model incorporatedsame parameters as the 2008 Framingham cardiovascularrisk score except that it included only hard endpoints(both fatal and not fatal myocardial infarction and stroke).Thus, this calculator may be used in some populations;while it is not accurate in others (Rotterdam) [23, 24].In addition, elevated levels of Lp(a) are associated withstroke, which is more common in men than women. El-evated Lp(a) in patients with essential hypertensionseems to play a role in the development of target-organdamage. In one study, Sechi et al. have shown that re-gardless of blood pressure, Lp(a) levels were the bestpredictor of target-organ damage involving arterial wall,heart, and kidney [25].Lp(a) may also play a role in plaque rupture and cor-onary thrombosis[23–26]. In patients with acute cor-onary syndrome, Lp(a) levels are predictive of risk ofcardiac death.ScreeningRecommendations for Lp(a) screening are not standard-ized among atherosclerosis, lipid, and CV prevention so-cieties. The 2013 ACC/AHA treatment guideline did notexamine Lp(a) role and thus did not recommend Lp(a)screening [26]. However, both the National Lipid Associ-ation (NLA) and the European Atherosclerosis SocietyConsensus Panel recommended Lp(a) measurement forpatients with familial hypercholesteremia, strong familyhistory of CVD and/or elevated Lp(a), personal historyof premature CVD, recurrent CVD despite statin treat-ment, inadequate response to statins, and ≥ 3 % 10-yearrisk of fatal CVD according to the European guideline,and ≥ 10 % 10-year risk of fatal or non-fatal CHD ac-cording to the US guidelines [12, 27]. The 2012 CanadianCardiovascular Society recommend considering secondarytesting, including Lp(a) measurement, in a moderate riskpatients [28]. They emphasize that LDL-C reduction is theprimary target in management of dyslipidemia.Cardiovascular risk in patients with elevated Lp(a)There is no definite clinical trial investigating effect oflowering Lp(a) on prevention of CHD; thus, all recom-mendations for the treatment are speculative. ThusACC/AHA guidelines does not identify Lp(a) as the pri-mary target for lipid-lowering therapy [26]. The EuropeanAtherosclerosis Society Consensus Panel (EASCP) sug-gested that Lp(a) level below 500 mg/L are desirable [12].The primary goal of treatment of elevated Lp(a) is tolower LDL-C to the patient’s target LDL-C level based onpatient’s risk category. For reduction in CHD, EASCP con-siders assessing and possibly treating Lp(a) as a priorityafter lowering LDL-C. Studies suggest that risk of CVD-associated elevated Lp(a) levels is much higher in the pres-ence of other CV risk factors including high LDL-C levels[29]. Several studies showed that lowering LDL-C in thepresence of high Lp(a) resulted in a reduction in CVDevents [30]. Thus, statins should be considered as a first-line therapy for the treatment of elevated LDL-C andLp(a). Interestingly some studies recommend more ag-gressive treatment of LDL-C in the presence of high Lp(a)[2]; the effectiveness of this approach has not been fullystudied. It should be noted that there is ongoing contro-versy about specific cholesterol targets. In patientswith elevation of Lp(a) without an indication forLDL-C therapy, beneficial effect of statin for risk re-duction is not clear.Clinical studies investigating the effect of loweringLp(a) and CHD risks seem to lack consistency in regardsto patient selection, drugs used, and the method forLp(a) measurement. LDL-C levels are frequently calcu-lated using Friedwald equation which includes Lp(a).Using Dahlen equation, we and others have shown thatin patients with high levels of Lp(a) this equation overes-timates LDL-C [31, 32]. In patients with extreme Lp(a)levels this overestimation is high (up to 40 %) [32]. Thus,in a patient with very high Lp(a) level, if LDL-C is drivenlower pharmacologically, a larger proportion of calcu-lated LDL-C is actually contributed by Lp(a). The recentIMPROVE-IT study proposed that lowering LDL-C levelto 1.3 mmol/L is associated with lower repeated CVevents compared to the higher levels [33]. However, it isimportant to estimate the true levels of LDL-C in thisstudy and its relationship with CV events.TreatmentDifferent classes of lipid-lowering medications have dis-tinct effects on LDL and Lp(a). Statins and bile acid se-questrates reduce LDL-C, but lower Lp(a) only slightly.In patients with the familial hypercholesteremia statinsdecrease Lp(a) by 17–22 % [34]. Some studies showedthat statins may raise Lp (a) mass by 10–50 % [6]. Fibricacid derivatives do not decrease Lp(a) except for bezafi-brate which lowered Lp(a) by 39 % [35]. Bezafibrate isnot approved for use in North America.High dose of nicotinic acid (2–4 g/day) is the most ef-fective agent that lowers Lp(a) by up to 40 % [1, 2]. Per-centage lowering appears to be greater at extreme Lp(a)levels. It also has other beneficial effects including re-duction of LDL-C, apoB, small LDL-C, and triglycerides,and raises HDL-C. However, no study has correlatednicotinic acid-induced reduction in Lp(a) with CVD out-comes. In Post hoc analysis of the AIM-HIGH trial,Saeedi and Frohlich Clinical Diabetes and Endocrinology  (2016) 2:7 Page 3 of 6Albers et al. have suggested that despite the fact thatniacin induced favorable changes in lipid profile; it didnot improved CV risk [36]. They suggested that in pa-tients with elevated Lp(a) statins remain the basis oftreatment with the target of reducing LDL-C below1.8 mmol/L. But this notion has not been studied in pa-tients with extreme Lp(a) levels. The subsequent study,HSP-2-THRIVE study also failed to show a significantbenefit in reducing major vascular events with nicotinicacid despite reduction in Lp(a) levels [37]. Also, the Na-tional Cholesterol Education Program Adult TreatmentPanel III stated that the clinical utility of niacin is notfully established due to the fact that the frequency of ex-tremely high Lp(a) level is low [20]. Interestingly, in acase report of a patient with normal lipid profile but ex-tremely elevated Lp(a) who developed a non-ST elevationmyocardial infarction, we have shown that treatment witha combination of nicotinic acid and statin may be benefi-cial in reducing further CHD events [38]. It is unclear ifnicotinic acid has a role in reduction of CVD events.However, a recent meta-analysis suggests that nicotinicacid is useful for CV event reduction [39]. In patients withelevated Lp(a), EASCS recommends treatment with nico-tinic acid 1–3 g/d in high risk patients to achieve Lp(a)levels below 500 mg/L as a secondary goal after reductionof LDL-C [12].There are also several recent pharmacologic develop-ments pertinent to lowering Lp(a). One is mipomersen,an apoB antisense oligonucleotide that inhibits synthesisof apoB. This drug has been approved by FDA for lower-ing LDL-C, apoB, TC, and non-HDL-C in patients withhomozygous familial hypercholesteremia [1, 2, 40]. Ameta-analysis investigating the effect of this agent onLp(a) levels have found a reduction of 26 % in Lp(a)from baseline [1]. Due to its hepatotoxicity, this agentcan only be prescribed by specially certified physicians.Another development is human monoclonal antibodyto Proprotein convertase subtilisin/kexin9 (PCSK9)[1, 2, 40]. PCSK9 is a protein which binds to LDL-receptor (LDL-R). This complex is subject to proteolyticdegradation, thus preventing recycling of LDL-R to thecell surface and impairing the clearance of plasma LDL-C.The PROFICIO (Program to Reduce LDL and CV Out-comes Following Inhibition of PCSK9 In Different Popula-tions) has shown that administration of Evolocumab, aPCSK9 inhibitor resulted in significant dose-dependentdecrease in Lp(a) by up to 29.5 % and LDL-C by 52 %[41]. Alirocumab, another monoclonal antibody, showedsimilar results as evolocumab in terms of Lp(a) reduction[1, 40]. In a meta-analysis of 20 randomized controlled tri-als, Li et al. demonstrated that treatment with PCSK9 in-hibitor resulted in reduction in Lp(a) as well as other lipidparameters such as LDL-C, TC, triglycerides, and apoB.Even though PCSK9 inhibitors reduce Lp(a), their effecton CVD outcome remains unclear [1, 40]. Also, it is un-clear where PCSK9 inhibition fits into current thera-peutic guidelines and whether this agent will be used tospecifically lower Lp(a) in addition to the robust LDL-Creduction.Lomitapide, and microsomal triglyceride transfer pro-tein (MTP) inhibitor, approved by FDA as an adjunct todiet and lipid lowering therapy lowers LDL-C, TC, apoB,and non-HDL-C in patients with homozygous FH [42].MTP transfers lipids to apoB in hepatocytes and entero-cytes. MTP inhibition impair VLDL formation. In phaseII clinical trial this agent has been shown to lower Lp(a)by 17 % [40]. There is concern about its hepatotoxicity,thus, it should be prescribed by specifically certified phy-sicians. The long-term effect of this agent on Lp(a) re-duction needs to be determined.Inhibitors of cholesterol ester transfer protein (CETP),a plasma protein that transfers cholesterol esters fromHDL to apoB-containing particles raise HDL-C levels[40]. While the first trials of these inhibitors, torcetrapiband dalcetrapib were terminated due to side effects,newer agents anacetrapib and evacetrapib showed bene-ficial lipid effects without serious side effects. In the DE-FINE trial, anacetrapib resulted in HDL-C elevation of138 % and lowering of LDL-C and Lp(a) by 40 and 36 %,respectively [43]. The effect of this agent on loweringCVD is under investigation.Recently both animal and human studies have shownthat specifically targeting Lp(a) with second generationantisense oligonucleotides lowers plasma level of Lp(a)by inhibiting apo(a) mRNA translation and thereby syn-thesis [44]. In a randomized, double-blind, placebo-controlled phase I study, Tsimikas et al. [45] have shownthat treatment of volunteers with second generationantisense oligonucleotides that inhibits Lp(a) mRNAtranslation reduces Lp(a) levels and oxidized phospho-lipid associated with apo(B) levels, in a dose dependentmanner, up to 89 and 93 %, respectively. They alsoshowed this drug is safe and tolerable. It is a potent andselective in reducing Lp(a) levels, thus, it could be usedas a potential therapeutic drug to reduce CVD eventsand progression.Lipoprotein apheresis, an extracorporeal therapy, isthe most effective way to lower Lp(a) [1, 2, 40]. Severalstudies have shown its lowering effect on serum lipidsand Lp(a) as well as its safety [1, 40]. Currently, mostlipid societies recommend apheresis mainly for patientswith familial hypercholesteremia [40, 46]. The GermanCommittee of Physicians and Health Insurance Fundsand England’s HEART-UK recommend apheresis forpatients with Lp(a) > 600 mg/L with progressive CHD[46, 47]. Both longitudinal cohort study and prospect-ive observational study of patients with CHD and ele-vated Lp(a) levels showed that lipoprotein apheresisSaeedi and Frohlich Clinical Diabetes and Endocrinology  (2016) 2:7 Page 4 of 6resulted in Lp(a) level reduction of more than 60 %after each apheresis session as well as lowering majoradverse coronary events rate per patient by almost80 % [40]. In a randomized controlled interventionalstudy on patients receiving weekly lipoprotein apher-esis, Safarova et al. demonstrated that lipoproteinapheresis resulted in Lp(a) level reduction by 73 ± 12 %[48]. Also, coronary angiography showed a reductionin median percent diameter stenosis by 2.0 comparedto the group receiving only atorvastatin. Julius et al.demonstrated that lipoprotein apheresis resulted in re-duction of CV events more significantly in patientswith elevated Lp(a) levels compared to patients with el-evated LDL-C levels [49]. Given that apheresis removesboth Lp(a) and LDL-C, the therapeutic effects ofapheresis seen in above studies is likely related to re-duction in these particles. A major limitation of apher-esis is that both Lp(a) and LDL-C levels, particularlyLp(a) levels, rebound to baseline levels within 2 weeksof treatment [40]. Other limitations include its costand limited access.Future studiesLp(a) is considered as an risk factor for CVD. In orderto be used for risk stratification and as a major cardio-vascular risk factor, further studies should be conductedto show Lp(a) predictive power for CVD and beneficialeffects of its lowering.ConclusionsEpidemiologic and genetic studies provide evidence thatLp(a) is an independent, causal risk factor for CVD. Ele-vated Lp(a) levels promote atherosclerosis and throm-bosis. Screening and treatment of selected patients arerecommended. Diet, exercise, and lifestyle modificationhave no effect on Lp(a). Niacin and lipoprotein apheresisare the most effective ways currently available to lowerLp(a). Recent pharmaceutical developments show prom-ising results on reduction in Lp(a) levels, but there is nostudy investigating their effect on CV events. Thus, largeprospective randomized-controlled trials are needed toinvestigate relationship between lowering Lp(a) and re-duction in CVD.Competing interestThe authors declare that they have no competing interests.Authors’ contributionRS wrote the first draft of the manuscript and JF edited it. Both authors readand approved the final manuscript.AcknowledgementN/AReceived: 29 July 2015 Accepted: 10 March 2016References1. Kassner U, Schlabs T, Rosada A. Lipoprotein(a)-An independent causal riskfactor for cardiovascular disease and current therapeutic options.Atheroscler Suppl. 2015;18:263–7.2. Jacobson TA. Lipoprotein(a). Cardiovascular Disease, and ContemporaryManagement. Mayo Clin Proc. 2013;88(11):1294–311.3. 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Atheroscler Suppl. 2013;14(1):39e44.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Saeedi and Frohlich Clinical Diabetes and Endocrinology  (2016) 2:7 Page 6 of 6


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