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CLINICAL RECOMMENDATIONS ON ASIAN POPULATIONLipoprotein(a)and CardiovascularDisease in Chinese PopulationA Beijing Heart Society Expert Scientific StatementJian-Jun Li,MD,PHD,aChang-Sheng Ma,MD,PHD,bDong Zhao,PHD,bXiao-Wei Yan,MD,PHD,con behalf of the Beijing Heart Society and Expert Committee*ABSTRACTElevated concentration of lipoprotein(a)Lp(a)is an independent risk factor for atherosclerotic cardiovasculardisease,including coronary artery disease,stroke,peripheral artery disease,and so on.Emerging data suggest thatLp(a)contributes to the increased risk for cardiovascular events even in the setting of effective reduction of plasmalow-density lipoprotein cholesterol.Nevertheless,puzzling issues exist covering potential genetic factors,Lp(a)assay,possible individuals for analysis,a cutoff point of increased risk,and clinical interventions.In the Chinesepopulation,Lp(a)exhibited a distinctive prevalence and regulated various cardiovascular diseases in specific ways.Hence,it is valuable to clarify the role of Lp(a)in cardiovascular diseases and explore prevention and controlmeasures for the increase in Lp(a)prevalence in the Chinese population.This Beijing Heart Society expertsscientific statement will present the detailed knowledge concerning Lp(a)-related studies combined with Chinesepopulation observations to provide the key points of reference.(JACC:Asia 2022;2:653665)2022 The Authors.Published by Elsevier on behalf of the American College of Cardiology Foundation.This is an open access articleunder the CC BY-NC-ND license(http:/creativecommons.org/licenses/by-nc-nd/4.0/).Atheroscleroticcardiovasculardisease(ASCVD)is the most common cardiovasculardisease(CVD)worldwide and has become aleading cause of death.1Dyslipidemia is consideredthe core pathogenesis of ASCVD and deemed as areversible risk factor.It has been generally recognizedthat low-density lipoprotein cholesterol(LDL-C)is acritical blood lipid indicator and the primary targetfor blood lipid intervention in ASCVD.However,ran-domizedcontrolledandreal-worldstudieshaveshown that a residual risk of cardiovascular events(CVEs)stillexistsevenwhenLDL-Clevelsarecontrolled within an optimal range specified by cur-rent guidelines.2It has been found that some novelblood lipid indicators are still associated with residualrisk.Much evidence has indicated that lipoprotein(a)Lp(a)is a potential target for blood lipids interven-tion,which has attracted eyes.In fact,Lp(a)was first discovered and named about60 years ago.3Later,clinical observational studieswith a small sample size reported that a 3.5-foldhigher Lp(a)level might increase the risk of coro-nary artery disease(CAD)and general CVEs,particu-larly in those with LDL-C$130 mg/dL.4It was notuntil the Mendelian Randomization Study in 2009that Lp(a)was associated with an increased risk ofmyocardial infarction(MI).5Since then,the signifi-canceofLp(a)hasevokedgrowingattention.ISSN 2772-3747https:/doi.org/10.1016/j.jacasi.2022.08.015From theaFuwai Hospital,Chinese Academy of Medical Sciences,Beijing,China;bBeijing Anzhen Hospital Affiliated to CapitalMedical University,Beijing,China;and thecBeijing Union Medical College Hospital,Beijing,China.*See the SupplementalAppendix for a list of members of the Expert Committee.Michael Shapiro,MD,served as Guest Associate Editor for this paper.Nathan Wong,PhD,served as Guest Editor-in-Chief for thispaper.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authorsinstitutions and Food and Drug Administration guidelines,including patient consent where appropriate.For more information,visit the Author Center.Manuscript received December 29,2021;revised manuscript received August 12,2022,accepted August 23,2022.J A C C:AS IAV O L.2,N O.6,2 0 22 2 0 22 T HE AU TH O R S.P UB L I SH E D B Y E LS E V I E R O N B E HA LF O F T H E AM E RI C A NC O L L E G E O FC AR DI O L O G Y F OU ND AT IO N.T HI SI SANO P E NAC C E SSA RT I C LEU ND E RT HE C C B Y-N C-ND L I C E N SE(h t t p:/c r ea t i v ec o m m ons.or g/l i c en se s/b y-nc-n d/4.0/).Recently,various studies have been con-ducted on Lp(a)from different perspectivesorusingdifferentapproaches,includingpathophysiology,6epidemiology,7Mendelianrandomization,5whole-genomeanalysis,8post hoc analysis of randomized controlledclinical trials,9in specific populations such asthosewithfamilialhypercholesterolemia(FH),10orthroughmeta-analyses.11Thefindings consistently indicate that Lp(a)isprobably a pathological risk factor of ASCVD,independent of LDL-C,attracting scholarseyes to Lp(a).CurrentevidenceindicatesthathigherLp(a)levels predict a higher risk of CVE.Thisprediction holds true in either the primary orsecondary prevention populations alreadytaking statins or proprotein convertase sub-tilisin/kexintype9(PCSK9)inhibitors.11However,we are still uncertain or evenconfusedaboutmanyaspectsofLp(a).Severalrecentguidelinespublishedinvarious countries and regions have proposedrecommendations concerning Lp(a)cutoff,targetpopulationsforLp(a)testing,andintervention strategies,although they aredifferent.Comparedwithotherpopulations,theepidemiology of Lp(a)in the Chinese popu-lation shows a unique differentiation.Donget al12found a genetic variation in Lp(a)atsingle nucleotide polymorphisms(SNPs)rs6415084,rs3798221,and rs7770628,which may cause the dif-ferentiation of high Lp(a)plasma levels among theHan Chinese population.A cross-sectional study of3,462 case and 6,125 control subjects also suggestedthat the Lp(a)distribution in the Chinese Han popu-lation differs from that in Caucasian populations,andhigh Lp(a)levels can be modified by some risk factorsin the Chinese Han population.13Therefore,elevatedLp(a)levels may be affected by many distinct factors,and the epidemiology of Lp(a)is different in theChinese population.However,current guidelines onthe prevention and treatment of CVD in China aredeficient in systematic recommendations and guid-ance based on the properties and significance ofLp(a).Moreover,theunderlyingmechanismsofelevated Lp(a)in the Chinese population are stilluncertain.Given the facts in the previous text,we aimed toprovide a scientific statement on the relationshipbetween Lp(a)and CVD risk and management in thisresearch.A modified Delphi method was applied todevelop scientific statement.A Central Illustration ofLp(a)inChinesepopulationwasdesigned.Acomprehensiveliteraturereviewwasperformedregarding Lp(a)in Chinese population using PubMeddatabases.We screened as many people as possiblefrom a Chinese population for a comprehensive andoverall understanding.We used the search terms:“cardiovasculardiseases,”“ischemicstroke,”“calcific aortic valve diseases,”“lipid metabolism,”“lipoprotein(a),”or“Lp(a).”The statements,alongwith literature,were then presented to a panel of 24cardiovascular specialists.They are key experts in thefield of Lp(a)and CVD with years of clinical experi-ence and deep understanding of the mechanisms andtreatment who are from different provinces in China.The expert panel anonymously rated the statementsona1to10scale(1stronglydisagreeand10 strongly agree).An expert scientific statementdevelopment meeting was held virtually to review,discuss,refine,and reformulate statements that didnot meet the criteria for agreement or were ambig-uous.During the meeting,additional statements wereproposed.Panelists then confidentially revoted,andstatements rated$6 by 80%or more of the partici-pants were accepted.Our expert panel summarizedthe current knowledge about Lp(a)and reviewed theresearch data on the Chinese population.Lp(a)wassystematicallyreviewed,andwehavepresentedsome key points(Table 1)concerning the clinicalmanagement of Lp(a)in the Chinese population toguide clinical practice.STRUCTURAL AND EPIDEMIOLOGICALFEATURES OF LP(a)Lp(a)is an LDL-like particle with a single apolipo-protein(apo)B100,which is covalently linked by adisulfide bond to a single apo(a).14Under an electronmicroscope,Lp(a)isasphericalparticlewithadiameter of about 21 nm and a density of about 1.05 to1.10 g/mL.The structural diagram of Lp(a)is shown inFigure 115:the LDL-like particle contains roughly 30%to 46%cholesterol,apoB100,and oxidized phospho-lipids(OxPL).Apo(a)is a highly glycated hydrophilicprotein,accounting for approximately 25%to 40%ofLp(a).Lp(a)isknownforitsnoticeablepoly-morphism,which is derived from varying lengths ofapo(a)peptide.Apo(a)contains 10 homologous plas-minogen Kringle IV(KIV)domains.The similar Krin-gle in the second domain of KIV has 2 to 40 copies,whereas there is only 1 copy for other domains,A B B R E V I A T I O N SA N D A C R O N Y M SAMI=acute myocardialinfarctionApo=apolipoproteinASCVD=atheroscleroticcardiovascular diseaseCAD=coronary artery diseaseCAVS=calcific aortic valvestenosisCVD=cardiovascular diseaseCVE=cardiovascular eventFH=familialhypercholesterolemiaGWAS=genome-wideassociation analysisKIV=Kringle IVLA=lipoprotein apheresisLDL-C=low-densitylipoprotein cholesterolLp(a)=lipoprotein(a)MACE=major adversecardiovascular eventsOxPL=oxidized phospholipidsPCSK9=proproteinconvertase subtilisin/kexintype 9SNP=single nucleotidepolymorphismT2DM=type 2 diabetesmellitusLi et alJ A C C:A S I A,V O L.2,N O.6,2 0 2 2Expert Scientific Statement on Lp(a)N O V E M B E R 2 0 2 2:6 5 3 6 6 5654leading to large individual variations in the molecularweight of Lp(a)and plasma Lp(a)levels.In addition,the polymorphism of apo(a)also depends on its de-gree of glycation.Unlike LDL,Lp(a)cannot be converted from very-low-density lipoprotein.Neither can it be turnedinto other lipoproteins.In a word,Lp(a)is exclusivelysynthesized in the liver.However,the site for Lp(a)assembly is not fully identified.The assembly may bein the liver cells,space of Disse,or blood circulation.The steps of assembly include apo(a)docking to LDLand then the formation of a covalent disulfide bondbetween KIV-9 of apo(a)and apoB of LDL.However,itis still unclear whether this process is reversible.Moreover,littleisknownabouttheclearancepathway and mechanism of Lp(a).So far,it is believedthat Lp(a)is cleared primarily by LDL receptors in theliver and partially by kidneys and other pathways.14Studies have shown that scavenger receptor B type 1,plasminogenreceptor,low-densitylipoproteinreceptor-related protein 1,and other receptors arealso involved in the Lp(a)clearance in the liver.Unlike LDL-C levels obeying a normal distributionin the population,Lp(a)levels are usually featured bya skewed distribution.In most individuals(about70%),Lp(a)levels are 90 mg/dL(200 nmol/L)Target Population for Lp(a)TestingLp(a)Levels Show a Skewed Distribution inthe Chinese PopulationFraction of Population(%)0.10.20.30.40.50Lp(a)Level(mg/dL)5020%cut-off value:30 mg/dL100150Apo(a)LDLKIV2(2-40)KIV1KIV3KIV4KIV5KIV6KIV7KIV8KIV9KIV10KVOxPLPOxPLLi J-J,et al.JACC:Asia.2022;2(6):653665.A summary of lipoprotein(a)Lp(a)in Chinese population and the key recommendations of the statements of this review,including Lp(a)level distribution,independent risk factors,comprehensive management,and Lp(a)testing.ASCVD atherosclerotic cardiovascular disease;ASO Antisense Oligomer;CAD coronaryartery disease;CAVS calcific aortic valve stenosis;LA lipoprotein apheresis;LDL-C low-density lipoprotein cholesterol;PCSK9 proprotein convertase subtilisin/kexin type 9;siRNA small interfering RNA.J A C C:A S I A,V O L.2,N O.6,2 0 2 2Li et alN O V E M B E R 2 0 2 2:6 5 3 6 6 5Expert Scientific Statement on Lp(a)65517 mg/dL(quartile:7-47 mg/dL).Lp(a)levels$30and$50 mg/dL were found in 35%and 24%of out-patients,respectively.16Similarly,Lp(a)levels alsoshow a skewed distribution in the Chinese popula-tion,with a relatively lower 80th percentile.Among9,238healthypeoplereceivingroutinephysicalcheck-ups in Jiangsu Province,the median Lp(a)levels were 5.6 mg/dL.The 80th percentile was20.7 mg/dL among women and 14.5 mg/dL amongmen.17Apo(a)polymorphism largely explains racial andgeographic differences in plasma Lp(a)levels.Onestudy compared Lp(a)levels among Chinese,Cauca-sians,andAfricanAmericans,andtheirresultsshowed that median Lp(a)levels were 8.0,9.0,and33 mg/dL,respectively.It was also found that plasmaLp(a)levels of the Chinese and Caucasians wereslightly different(P 0.06).However,the differencewas much more noticeable when compared with Af-rican Americans(P 0.001).18As for the geographicalvariation of populations with increased Lp(a)levelsthroughout the world,a working group under theNational Heart,Lung,and Blood Institute pointed outin 201819that over 1.4 billion people had Lp(a)levelsabove 50 mg/dL.About 30%of such people live inAfrica;about 20%in Europe,North America,andOceania;and about 15%in South America.Except forSouth Asia,where Lp(a)levels above 50 mg/dL werefound in about 25%of the population,Lp(a)levelsabove50mg/dLwerefoundinabout10%ofpopulations in other parts of Asia.These resultsindicated racial variation of Lp(a)levels.EXPERT OPINION 1.Lp(a)levels show a skewed dis-tribution,and geographic and racial variations havebeen observed.Generally speaking,Lp(a)levels arelower in the Chinese population than in populationsin other countries and regions.GENOMICS RESEARCH AND FACTORSRELATED TO INCREASED LP(a)LEVELSThe genomics research has verified the correlationbetween Lp(a)and CAD and ischemic stroke.A Men-delian randomization study suggests that Lp(a)isrelated to CAD.5Data from the PROCARDIS(Preco-ciousCoronaryArteryDisease)cohortandthegenome-wide association analysis(GWAS)showedthat 2 LPA SNPs(SNP rs10455872 and rs3798220)wereassociated with an increased risk of Lp(a)elevationand CAD.8One GWAS recruited 1,403 CAD patientsreceiving percutaneous coronary intervention.Theresults showed that LPA polymorphisms rs7770628,rs73596816,andrs6926458andSLC22A2poly-morphism rs144217738 were independently corre-latedwithLp(a)levels.Amongthem,LPApolymorphismsrs7770628andrs73596816weresignificantly correlated with the severity of CAD.20Another GWAS recruited 3 cohorts of European Cau-casians,including 6,942 patients with aortic valvecalcification and 3,795 patients with mitral annularTABLE 1A Summary of 7 Expert OpinionsExpertOpinion No.Recommendation1Lp(a)levels show a skewed distribution,and geographic and racial variations have been observed.Generally speaking,Lp(a)levels are lower in the Chinesepopulation than in populations in other countries and regions.2Although serum Lp(a)levels are primarily determined by genetic factors,they may also be related to some nongenetic factors.3Increased Lp(a)levels are an independent risk factor for CAD,ischemic stroke,and CAVS.4Lp(a)testing is recommended for the following populations:1)populations at extremely high risk for ASCVD;2)individuals with a family history of early-onset ASCVD(men 55 y of age,women 65 y of age);3)individuals whose lineal relatives have Lp(a)levels$90 mg/dL(200 nmol/L);4)FH or othertypes of hereditary dyslipidemia;and 5)CAVS patients.5Guidelines and consensuses in different countries recommend different Lp(a)cutoff va
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