Endocrinology and Metabolism Clinics of North America (Acute Endocrinology) PDF
Preview Endocrinology and Metabolism Clinics of North America (Acute Endocrinology)
Lipids Foreword DerekLeRoith,MD,PhD ConsultingEditor Thisissue,writtenbyexpertsinthefieldoflipidologyandcompiledbyDonaldSmith, bringstothereaderbothbasicaspectsandclinicalapplicability. An important question that often arises is the benefit of ordering more advanced lipoprotein profiles. The main reason for the quandary, as pointed out in the article by Lau and Smith, is that calculated low-density lipoprotein (LDL) cholesterol, measured by standard technologies, or non–high-density lipoprotein (non-HDL) cholesterol,arelesspredictiveofischemiccardiovascularriskthanareapolipoprotein B(apoB)andnuclearmagneticresonance(NMR)–measuredLDLparticlesinnumerous studies.Thisisespeciallytrueinthepresenceofhightriglycerides,orlow-HDLcholes- terol.AlthoughapoBlevelsandthenumberofNMR-measuredLDLparticlesmaybe morepredictive,noclinicaltrialscomparingtheuseofthesegoalsversusLDLcholes- terolornon-HDLcholesterolgoalshavebeenperformed.Forthosewhocaninterpret theresults, theirusemaybejustifiedoccasionally toconfirmlipid goal attainmentin those with mixed dyslipidemias and particularly in patients already at standard lipid goalsinthepresenceofprogressivecoronaryheartdisease. Predictionofcoronaryheartdiseaseisextremelyimportantinclinicalpracticefor primary and secondary prevention. Wilson emphasizes in his article the importance of standardizing baseline measurements of the factors involved, such as the lipid profileanddiabetesstatus,toenableoutcomestudiestoleadtodefinitivedecisions. Ithasbeenestablished thattheFraminghamscoreisstillveryusefulasapredictive indexexceptinJapanese-AmericansandinAfricanAmericans.Inaddition,investiga- torsincertainEuropeancountrieshavefoundthat,whileFraminghamisuseful,itmay overestimate cardiovascular disease in some groups, such as Italians. Future esti- mateswillundoubtedlyaddotherbiomarkersandimagingtechniquesforatheroma- tousburden,andeventuallymayaddgeneticmarkerstoaidinthepredictions. Animportantaspectoflipidmanagementinvolveslifestylechanges.Katcher,Hill, Lanford, Yoo, and Kris-Etherton comprehensively discuss dietary components contributing to elevated LDL cholesterol, including saturated fat, trans fats, and cholesterol. They present descriptions and clinical trial evidence of various dietary manipulationsthatcansignificantlyalterthelipoproteinprofile,includingweightreduc- tionanddietsthatincludemoresolublefiber,plantsterols,andsoy,allhavingvariable EndocrinolMetabClinNAm38(2009)xiii–xv doi:10.1016/j.ecl.2009.01.015 endo.theclinics.com 0889-8529/09/$–seefrontmatterª2009PublishedbyElsevierInc. xiv Foreword quantitativeeffects.Inaseparatesection,theeffectsoflow-carbohydrateandMedi- terranean diets, omega 3 fatty acids, mono-unsaturated fatty acids, and alcohol on triglycerides and HDL cholesterol are presented. Finally the lipid-altering effects of physicalexercise arediscussed as animportant component oflifestyle change that shouldalwayscomplementthesedietarymanipulations. The minimal goal for reductions in LDL cholesterol is 40 mg/dL (1 mM/L). This is oftenachievedbyasinglestatindrug,thoughoftenthepractitionerhastoconsider additionaltherapies.HouandGoldbergdiscusstheseoptionsanddescribethemech- anismsofactionandpracticalaspectsoftheirusage.Themajordrugsdiscussedare statins,ezetimibe,andbileacidsequestrants,aswellasniacinandfibrates.Combi- nationtherapieshaveindeedreducedLDLcholesterollevelsfurtherandstudiesare ongoingtoquantifytheirpreventiveeffectsintheclinicalenvironment. Research progresses on other new medications and other methodologies to reduceLDLcholesterol.EvanSteinhasbeeninvolvedinmanyoftheseearly-phase clinical trials. Hedescribes indetail compounds being studiedthat notonly provide possible new therapies, but also illustrate the biochemistry of lipid metabolism and thesafetyproblemsofinterferingwithit.Compoundsdiscussedincludesqualenesyn- thaseinhibitors,apoBantisenseoligonucleotides,smallinterferingRNAsofapoB,and proproteinconvertasesubtilismkexin9. Venero and Thompson in their article describe the etiology and management of statin-inducedmyopathy,animportantclinicalproblemgiventhewidespreaduseof statins.Theincidenceasreportedinclinicaltrialsofapproximately5%islowerthan that found in surveys of patients in clinical practice, where incidence is around 10%. The symptoms range from tolerable myalgias to fatal rhabdomyolysis in extremely rare cases. Creatine kinase measurements may be important at baseline withrepeattestingonlynecessarywhenthepatientactuallyexperiencesmyopathic symptoms. Stopping the agent, reintroducing a different statin, increasing the dosing interval, and even trying coenzyme Q10 are suggested therapeutic ways to handle this. IraGoldbergdiscussesthevalueoftreatinghypertriglyceridemia.Whiletreatment ofhypercholesterolemiawithstatinsandotheragentshasshownclear-cutresultsin preventingcardiovascularevents,andwhilethetreatmentofveryelevatedtryglycer- idestopreventpancreatitisisimportant,thevalueoftreatingmoderatehypertriglycer- idemia to prevent such cardiovascular events is debatable. There are numerous dietaryregimensanddrugsthatcaneffectivelylowertriglyceridesandtheyareeffec- tive both for very high levels (>500 mg/dL) as well as for levels below 500 mg/dL. Despite inconsistent evidence in preventive clinical trials, lowering triglycerides to below 150 mg/dL in patients at risk is considered a secondary lipid-altering goal, whichoftenalsoprovidestheadditionalbenefitofraisingHDLcholesterol. An important risk factor for the development of atheromatous cardiovascular disease is reduced HDL cholesterol, and a few trials have shown that raising HDL cholesterol reduces cardiovascular risk. While statins are extremely effective in reducing LDL cholesterol, they are only mildly effective in raising HDL cholesterol. Drugs,suchasniacin,andfibratesinthepresenceofhypertriglyceridemiaaremore effective. Peter Toth describes efforts to find agents that will raise HDL cholesterol. Investigators have looked into therapies involving apolipoprotein A1 (apoA1) itself, apoA1-mimetics, novel peroxisome proliferator-activated receptor alpha agonists, liverXreceptoralphaagonists,cholesterolestertransferproteininhibitors,andfarne- soidXreceptorantagonists.Todatetheseagents,whiledemonstratingeffectiveness inpreclinicalstudiesandinsomeclinicalstudies,arenotyetadequatelydevelopedfor useinpatients. Foreword xv Atherosclerosis can clearly begin in childhood and adolescence. Initially it was thoughttobepurelytheconsequenceofgeneticcauses,suchasfamilialhypercho- lesterolemia. However, withtheepidemic of obesity thatis affectingyouth, environ- mental factors normally involved in atherosclerosis in adults are clearly in play. Dietary intervention and lifestyle changes are clearly indicated to reverse these processes.Ontheotherhand,incasesoffamilialhyperlipidemiaandinthoseadoles- centsthatfaillifestyleinterventionandareathighrisk,pharmacologicalinterventionis clearlyindicated.ZappallaandGiddingdeveloptheseissuesintheirarticle. NairandDarrowaddresstheimportanttopicoflipidmanagementinthegeriatric patient.Asthepopulationages,morepatientsareatriskforcardiovasculardisease. Such patients require lipid-lowering agents for primary and secondary prevention, astrategythat has beenshownto work quiteeffectively in anumber of well-known trials. Statins are particularly useful. However, when statins are inadequate as solo agents, combinations with other lipid-altering therapies should be considered, as in thenongeriatricagegroup.Judicioususageisessential,especiallywhenconsidering high doses, as the elderly are more prone to the known side effects. However, this caution should not result in avoidance of prescribing these agents to the elderly withdyslipidemia. Useofanti-retroviralagentsintreatingHIV-infectedindividualscommonlyresultsin dyslipidemia. Once dyslipidemia appears, there are two therapeutic approaches: alteringtheanti-retroviraltherapyorinitiatingtherapyforthedyslipidemia.Thesether- apies, however, may interfere with each other, as outlined in the article by Judith Aberg.Ifchangesinanti-retrovirals isundertakentoaffectthelipid profile,it should bedoneundersupervisiontomaintainvirologicsuppression.Nutritionalalternatives tolipidtherapyshouldundoubtedlybeconsideredfirst. Chronickidneydiseaseisassociatedwithincreasedcardiovascularmorbidityand mortality.MontagueandMurphydiscussthenotionthat,whilenumerousfactorsmay accountforthiseffect,theroleoflipidabnormalitiesisunclear.Thisarisesfromtwo important aspects. One is the fact that, in end-stage renal disease with patients on dialysis,theprofileoflipidabnormalitieschangesfromthatseeninthegeneralpopu- lation. Total cholesterol, LDL cholesterol, and HDL cholesterol may all be lower, whereas small dense LDL particles and lipoprotein (a) may increase. Furthermore, onlyafewclinicaltrialsusinglipid-loweringdrugshavebeencompleted,whileothers areongoing.Allinall,theclinical-trialpreventiveevidenceisnotyetclear-cut. Ibelievethatthisup-to-datepresentationwillbeoftremendousvalueandwillbe mostappreciatedbyallofusinvolvedinanimportantareaofendocrinology. Derek LeRoith, MD,PhD Divisionof Endocrinology,Metabolism, andBoneDiseases MountSinai School ofMedicine OneGustave L.Levy Place Box1055,Altran 4-36 NewYork,NY 10029,USA E-mail address: [email protected](D.LeRoith) Lipids Preface DonaldA.Smith,MD,MPH GuestEditor Thefieldofclinicallipidologyhasrapidlyprogressedbeyondthesimplelipidprofileand the highly useful and simple paradigm of the National Cholesterol Education’s Adult Treatment Panel III and its more recent modifications. More advanced measures of lipoprotein testing are being heavily marketed, newer risk-factor prediction models are being tested, more data are being accumulated on the benefits of lifestyle and pharmacologictherapiesandtherisksofthelatter,andtheuseoflipid-loweringther- apiesareextendingtoyoungerandolderpatients,andtopatientswithrenaldiseaseor HIVwherelipid-loweringtherapybecomesmorecomplex.Inaddition,newermedica- tionstofurtherlowerlow-densitylipoproteincholesterolandraisehigh-densitylipopro- teincholesterolhelpusbetterunderstandlipoproteinbiochemistryandtheenormous creativity and difficulty required to develop a new safe and effective pharmaceutical compound.IhavebeenextremelyprivilegedinthisissueofEndocrinologyandMetab- olismClinicsofNorthAmericatohaveworkedandwrittenwithanextraordinarilygifted and informed group of experts in all these areas with the hope of helping clinicians responsible for lipid-altering therapy become more knowledgeable and thus in the endmoreeffectiveinmanagingtheirpatients. Donald A. Smith,MD, MPH Associate Professorof Medicine,Community and Preventive Medicine Zena andMichael A. Wiener CardiovascularInstitute Marie-JoseeandHenry R.Kravis Center for Cardiovascular Health MountSinai School ofMedicine Box1014, 1GustaveLevy Place NewYork,NY 10029-6574,USA E-mail address: [email protected] (D.A. Smith) EndocrinolMetabClinNAm38(2009)xvii doi:10.1016/j.ecl.2009.01.014 endo.theclinics.com 0889-8529/09/$–seefrontmatterª2009PublishedbyElsevierInc. Advanced Lipoprotein Testing: Recommendations Based on Current Evidence JoeF.Lau,MD,PhDa,DonaldA.Smith,MD,MPHb,* KEYWORDS (cid:2)Advancedlipoproteintesting (cid:2)Non-HDLcholesterol (cid:2)ApolipoproteinB (cid:2) LDLparticlenumber (cid:2) LDLparticlesize (cid:2)Verticaldensitygradientultracentrifugation (cid:2)Segmentedgradientgelelectrophoresis (cid:2)Nuclearmagneticresonancespectroscopy(NMR) As information has emerged from recent clinical trials, it has become clear that the incidence of ischemic atherosclerotic events is related to low-density lipoprotein (LDL) cholesterol concentration as measured using the Friedewald equation.1 Up to 50% of secondary cardiovascular events can be prevented simply by lowering the LDL cholesterol level to 70 to 80 mg/dL by using high-dose statin drugs.2 Because there may be a discrepancy between the LDL cholesterol concentration and the numberofLDLparticles,andbecausethesizeofLDLparticlesmaymodifytherisk associated with LDL cholesterol at any concentration, it has become important to understandbetterthemoreadvancedmethodsoflipoproteintestingforallpotential atherogeniclipoproteins—very-low-densitylipoproteins(VLDL),intermediate-density lipoproteins(IDL),lipoprotein(a),andLDL.Thisarticlebrieflydescribesthesemethods and possible therapeutic target values, with special attention to target values for patientswhohavecoronaryheartdisease(CHD). NationalguidelineshavebeenbasedpredominantlyonLDLcholesterollevels.3–5By examining these goals, it is possible to determine at what percentiles these LDL cholesterol values lie within the Framingham Offspring population. One then can look at advanced lipoprotein measures of apolipoprotein B (apoB) and the number ofLDLparticleswithinthesamepopulationorwithinotherpopulationsrepresentative a MountSinaiMedicalCenter,Box1030,1GustaveLevyPlace,NewYork,NY10029-6574,USA b ZenaandMichaelA.WienerCardiovascularInstitute,Marie-JoseeandHenryR.KravisCenter forCardiovascular Health, MountSinaiSchoolofMedicine,Box1014, 1Gustave LevyPlace, NewYork,NY10029-6574,USA *Correspondingauthor. E-mailaddress:[email protected](D.A.Smith). EndocrinolMetabClinNAm38(2009)1–31 doi:10.1016/j.ecl.2008.11.008 endo.theclinics.com 0889-8529/08/$–seefrontmatterª2009ElsevierInc.Allrightsreserved. 2 Lau&Smith oftheUnitedStatessuchastheNationalHealthandNutritionExaminationSurveyIII (NHANES III)6 ortheMulti-Ethnic Study of Atherosclerosis (MESA) populations7 and determinewhereequivalentpercentilegoalsfortheseparametersmightlie.Lacking results from clinical trials to set target goals for these newer parameters, one only canhypothesizethatincertainsubgroupsofthepopulationattainingsuchpopulation percentile–based goals may reduce risk more effectively than simply attaining the moreevidence-basedLDLcholesterolgoals. MEASURESOFLIPIDTESTING Someofthetestsavailabletocliniciansformeasuringatherogeniclipoproteinsare 1. Non–high-densitylipoprotein(non-HDL)cholesterol(fromastandardlipidprofile) 2. ApoB 3. Verticaldensitygradientultracentrifugation(VerticalAutoProfile[VAP];Atherotech) 4. Segmentedgradientgelelectrophoresis(S-GGE;BerkeleyHeartLab) 5. Nuclearmagneticresonance(NMR;Lipoprofile;Liposcience) RefertoTable1forapartiallistoflaboratoriesthatofferadvancedlipidtestswith theirassociatedcosts. LOW-DENSITYLIPOPROTEINCHOLESTEROLLEVELSFROMTHESTANDARDLIPIDPROFILE Inthestandardlipidprofile,theLDLcholesterolleveliscalculatedfromtheFriedewald equation,8which,inthefastingstateandthuswithoutchylomicrons,isasfollows: Total cholesterol level 5 LDLcholesterol level 1 HDL cholesterol level 1 VLDLcholesterol level Thus LDLcholesterol level 5 total cholesterol level(cid:3)HDL cholesterol level (cid:3) VLDLcholesterol level Because VLDL cholesterol level 5 triglyceride level=5 (a good approximation when fasting triglycerides levels are < 400 mg/dL and in the absenceoftypeIII,ordysbetalipoproteinemia),then LDLcholesterol level 5 total cholesterol level(cid:3)HDL cholesterol level (cid:3)triglycerides level=5 Thiscalculationallowsthetotalcholesterolandtotaltriglyceridelevelstobemeasured enzymaticallyandrapidlyinserum,followedbyprecipitationofallapoBlipoproteinsand enzymaticmeasurementofcholesterolinthesupernatetogivetheHDLcholesterollevel. TheLDLcholesterolleveltheniscalculatedbytheFriedewaldequation. NON^HIGH-DENSITYLIPOPROTEINCHOLESTEROL Thenon-HDLcholesterollevel,thedifferencebetweentheHDLcholesterolconcentra- tionandthetotalcholesterolconcentration,isameasureofcholesterolinallpotential atherogenic lipoproteins including IDL, VLDL, lipoprotein (a), and LDL. It was sug- gestedbytheNationalCholesterolEducationProgram(NCEP)asasecondarytarget AdvancedLipoproteinTesting 3 Table1 PricesoflipidandlipoproteintestsbyvariouslaboratoriesasofSeptember2008 Laboratory Cost($) QuestDiagnostics(800-631-1390–NewYorkCity) Lipidprofile(standard) 75 ApoB 59 VerticalAutoProfile(VAP) 154 BerkeleyHeartLab(800-432-7889) Lipidprofile 27 LDLgradientgelelectrophoresis(S -GGE) 51 3 ApoB 28 LipoScience(877-547-6837) Lipoproteinsubparticlesbynuclearmagneticresonance(NMR) 80 Withstandardlipidprofile 99 inpatientswhohavetriglycerideslevelsof200mg/dLorhigher,withgoallevelsbeing 30 mg/dL greater than those for LDL cholesterol.3 This target assumes triglyceride levels of 150 mg/dL or lower, and thus a calculated VLDL cholesterol level of 30 mg/dL or less (ie, a triglyceride level of 150 divided by 5) is a reasonable goal. ForpatientswhohaveCHD,especiallythoseathighestrisk,4thenon-HDLcholesterol goal is less than 100 mg/dL. The Framingham Offspring population percentiles for NCEP III LDL cholesterol and calculated non-HDL cholesterol goals are listed in Table2. Table2 SuggestedLDLandnon-HDLcholesterolandapoBgoalsbasedonthreedifferentpopulations LDLParticle Population LDL-C Non-HDL-C ApoB Number Percentile (mg/dL) (mg/dL) (mg/dL) (nmol/L) RiskCategory 5thpercentile 70 100 65 700 Highriskof coronaryheart disease 80(ADA/ ACC)51 20thpercentile 100 130 85 1000 Coronaryheart diseaseequivalent, diabetesmellitus 90(ADA/ ACC)51 50thpercentile 130 160 105 1300 >2cardiovascular riskfactors 80thpercentile 160 190 125 1600 0,1cardiovascular riskfactors DatafromRefs.6,7,55 4 Lau&Smith APOLIPOPROTEINB ApoB,ameasureofallnon-HDLlipoproteins(LDL,IDL,VLDL,lipoprotein(a),andchylo- microns[<1%ofallnon-HDLlipoproteins])9butlargelydeterminedbythenumberof LDLparticles,canbeusedasasurrogatemeasureofLDLorthenumberofatherogenic particlesandmaybeabettermeasureoflipoprotein-associatedatheroscleroticrisk thantheLDLcholesterolconcentration.10Therearemanystandardizedimmunochem- icaltechniquesformeasuringApoBlevelsinclinicallaboratories,butin1994theWorld Health Organization, the International Federation for Clinical Chemistry, and the CentersforDiseaseControlandPreventiondevelopedaninternationalreferencestan- dard,SP3-07,thatreducedtheamong-methodcoefficientofvariationto6%orless, imprecisionto5%orless,andbiascomparedwiththereferenceto6%orless.11Certi- fied laboratories should have this level of accuracy and precision when using this referencestandard. ApproximatepercentilelevelsintheNHANESIIIstudyareshowninTable2.6Thus, apoB goals corresponding to less than 70 mg/dL, less than 100 mg/dL, less than 130 mg/dL, and less than 160 mg/dL of LDL cholesterol in NHANES III population percentiles according to this inspection of the population data would be less than 65mg/dL,lessthan85mg/dL,lessthan105mg/dL,andlessthan125mg/dL,respec- tively.However,oneauthorityhasrecommendedthepreferencefora5mg/dLhigher goalforApoBthanthevaluesestablishedbypopulationpercentiles(ie,agoalof<90 mg/dLforLDL-Cof<100mg/dL;apoBgoalof<110mg/dLforLDL-C<130mg/dL; apoBgoalof<130mg/dLforLDL-C<160mg/dL;seeTable2).12 VERTICALDENSITYGRADIENTULTRACENTRIFUGATION Based on ultracentrifugation studies at the Berkeley National Laboratories of the University of California in 1954, HDL, VLDL,LDL, and IDLparticles were defined by a range of migration rates measured in Svedberg units.13 The original Framingham lipid distributions associated with this technology required 20 hours of sequential ultracentrifugation, thus precluding the use of centrifugation in mass lipoprotein screeningofindividuals.Amorepracticalapproach,verticaldensitygradientultracen- trifugation, is marketed as the VAP test.14 With this method, the major lipoprotein groups can be sorted by density into subcomponents, including four levels of LDL andatleastthreelevelsofeachoftheothermajorlipoproteingroups.TheVAPeval- uationincludesmeasuresofnon-HDLcholesterol,totalLDLcholesterol,anditsthree components:lipoprotein(a)cholesterol,IDLcholesterol,and‘‘real’’LDLcholesterol. ThepositionofthemostprominentpeakofrealLDLcholesterolisshownalongalinear scale defining LDL particle size from large to small as patterns A, A/B, and B. The concentrationsofeachofthefourLDLsubfractionsallowdeterminationoftherelative percentagesofsmall,less-preferableLDL andlargeLDL particles,buttheclin- 314 112 icaluseofthisinformationhasnotbeendetermined.Lipoprotein(a),measuredasthe cholesterolcontentinthelipoprotein(a)densitypeak,haselevatedvalueshigherthan 10mg/dL,ratherthanhigherthan30mg/dL(orhigherthan75nmol/Lusingthemore commonantibodyassaysoflipoprotein(a)mass).15 Goals for LDL cholesterol and non-HDL cholesterol levels in VAP reports are the sameasthegoalsintheNCEPATPIII.Practicallyspeaking,thistestyieldsveryaccu- ratemeasuresofLDLcholesterol,eveninanonfastingstateorinthepresenceofhy- pertriglyceridemia.ItalsoprovidesadeterminationofLDLsize.Forinstance,apatient whohaspatternB(small)orpatternA/B(intermediate)LDLmayrequireanevenlower LDL cholesterol goal, because the number of such small LDL particles generally is AdvancedLipoproteinTesting 5 higherthantheLDLcholesterolconcentrationmightsuggest.Toobtainameasureof thenumberofLDLparticles,onecouldusenon-HDLcholesterolororderanimmuno- chemical assay of apoB, using population percentiles from Table 2 to obtain acomparativepopulation-basedestimateofLDL-associatedrisk. Usingnon-HDLcholesterolandsubclasslipoproteindatafromfreshserumspeci- menswithtriglycerideslowerthan500mg/dLsenttoAtherotechforverticalultracen- trifugation, VAP reports provide a calculated apoB level that correlates with an immunochemical apoB assay calibrated to the international apoB standard with acorrelationcoefficientof0.961;themeanbiasofthecalculatedvalueis3.8%higher thanthemeasuredvalue.16ThusthisfreecalculatedapoBvaluemaybesufficiently accuratetoavoidtheextraexpenseofanimmunochemicalassayforapoBinaddition totheVAPtestitself. SEGMENTEDGRADIENTGELELECTROPHORESIS Anotherwaytoseparatelipoproteinsinvolveselectrophoresisinnon-denaturingpoly- acrylamide gels, available from Berkeley HeartLab. Such gels form cross-linked matricesthattraplipoproteinsandproteinsastheytraveltowardtheanode.Theoriginal lineargelhadonlyoneconcentrationofpolyacrylamide,limitingitsseparationpower; large lipoproteins could notenter the gel, and smaller lipoproteins traversed thegel withoutentrapmentinthematrix.Thelatestsegmented-gradientgelsconsistofthree gradientsinsequence,providinggreaterlipoproteinseparation ofsevensubclasses ofLDL(LDL-S GGE)and10subclassesofHDL(HDL-S GGE).TheLDLdiameteris 3 10 givenforthetwopredominantLDLpeaks(inAngstromunits),determinedbymigration distancescalibratedusingproteinsandlatexbeadsofknownsizes.Thepercentage goalsgivenonthereportsforfractionforsmallLDLparticles(IIIa1b<15%andIV b < 5%) are based on the values for the lowest coronary plaque progression rates measuredbyquantitativecoronaryangiographyintheStanfordCoronaryRiskInter- vention Project.17 Below-median versus above-median apoB levels of 116 mg/dL addedtotheefficacyofGGE-measuredLDLparticlesizeinpredictingriskforangina, myocardialinfarction(MI),andCHDdeathintheQuebecCardiovascularStudy.18Thus bothinformationaboutthesizeofLDLparticlesobtainedfromGGEandinformation about the number of LDL particles from apoB, which can be ordered through the same laboratory, are important for maximizing preventive information using GGE- measuredLDLparticlesizing.Thislaboratoryalsocanprovideotheradvancedlipopro- teininformationincludingHDLsubclasses,lipoprotein(a),andapoEsubtypes. NUCLEARMAGNETICRESONANCESPECTROSCOPY Amongthelatesttechnologicaldevelopmentsisprotonnuclearmagneticresonance (NMR) spectroscopy.19 A plasma sample is subjected to a microsecond radiofre- quencyNMRpulse,andtheemittedspectrumofinterestreflectstheterminalmethyl groups of the cholesterol, cholesterol esters, triglycerides, and phospholipid mole- cules.PurelipoproteinfractionsobtainedbyGGEhavespecificNMRprofilesbased onsize.TheseprofilesarecombinedtogivethreesizemeasurementsforVLDLand HDL(large,intermediate,andsmall),two forLDL(largeandsmall),andoneforIDL. The clinical report contains the number of LDL particles and levels of risk based on percentilesintheMESApopulations.7Thelowestriskcategory(<1000nmol/L)corre- spondsto an LDL cholesterol level lowerthan 100 mg/dL,which defines thelowest 20%ofthepopulation.Conveniently,dividingthenumberofLDLparticlesby10gives theequivalentpopulationpercentileintheMESApopulation.Thus,onecandetermine
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