Table Of ContentTherapeutic Lipidology
Contemporary Cardiology
Christopher P. Cannon, md
SERIESEDITOR
TherapeuticLipidology,editedbyMichaelH. SurgicalManagementofCongestiveHeart
DavidsonMD,FACC,FACP,PeterP.TothMD,PhD, Failure,editedbyJamesC.Fang,MDand
FAAP,FICA,FAHA,FCCP,FACC,andKevinC. GregoryS.Couper,MD(cid:2)2005
Maki,PhD,2007 CardiopulmonaryResuscitation,editedbyJoseph
CurrentConceptsinCardiology:Cardiac P.Ornato,MD,FACP,FACC,FACEPandMaryAnn
Rehabilitation,editedbyWilliamE.Kraus,MD, Peberdy,MD,FACC(cid:2)2005
FACC,FACSM,andStavenJ.Keteyian,PhD,2007 CToftheHeart:PrinciplesandApplications,
ManagementofAcutePulmonaryEmbolism, editedbyU.JosephSchoepf,MD(cid:2)2005
editedbyStavrosV.Konstantinides,MD,2007 CoronaryDiseaseinWomen:Evidence-Based
StemCellsandMyocardialRegeneration,edited DiagnosisandTreatment,editedbyLesleeJ.
byMarcS.Penn,MD,PhD,2007 Shaw,PhDandRitaF.Redberg,MD,FACC(cid:2)2004
EssentialEchocardiography:APractical CardiacTransplantation:TheColumbia
HandbookWithDVD,editedbyScottD. UniversityMedicalCenter/New
Solomon,MD,2006 York-PresbyterianHospitalManual,edited
PreventiveCardiology:InsightsIntothe byNilooM.Edwards,MD,JonathanM.Chen,
PreventionandTreatmentofCardiovascular MD,andPamelaA.Mazzeo,
Disease,SecondEdition,editedbyJoAnne 2004
MicaleFoody,MD(cid:2)2006 HeartDiseaseandErectileDysfunction,edited
TheArtandScienceofCardiacPhysical byRobertA.Kloner,MD,PhD(cid:2)2004
Examination:WithHeartSoundsandPulse ComplementaryandAlternativeCardiovascular
WaveFormsonCD,byNarasimhan Medicine,editedbyRichardA.Stein,MDand
Ranganathan,MD,VaheSivaciyan,MD,and MehmetC.Oz,MD(cid:2)2004
FranklinB.Saksena,MD(cid:2)2006 NuclearCardiology,TheBasics:HowtoSetUp
CardiovascularBiomarkers:Pathophysiologyand andMaintainaLaboratory,byFransJ.Th.
DiseaseManagement,editedbyDavidA. Wackers,MD,PhD,WendyBruni,BS,CNMT,and
Morrow,MD(cid:2)2006 BarryL.Zaret,MD,2004
CardiovascularDiseaseintheElderly,editedby MinimallyInvasiveCardiacSurgery,Second
GaryGerstenblith,MD(cid:2)2005 Edition,editedbyDanielJ.Goldstein,MD,
PlateletFunction:Assessment,Diagnosis,and andMehmetC.Oz,MD2004
Treatment,editedbyMartinQuinn,MBBCh CardiovascularHealthCareEconomics,edited
BAO,PhD,andDesmondFitzgerald,MD,FRCPI, byWilliamS.Weintraub,MD(cid:2)2003
FESC,APP(cid:2)2005 PlateletGlycoproteinIIb/IIIaInhibitorsin
DiabetesandCardiovascularDisease,Second CardiovascularDisease,SecondEdition,
Edition,editedbyMichaelT.Johnstone,MD, editedbyA.MichaelLincoff,MD(cid:2)2003
CM,FRCP(C),andAristidisVeves,MD,DSc,2005 HeartFailure:AClinician’sGuidetoAmbulatory
AngiogenesisandDirectMyocardial DiagnosisandTreatment,editedbyMariell
Revascularization,editedbyRogerJ. L.Jessup,MDandEvanLoh,MD(cid:2)
Laham,MD,andDonaldS.Baim,MD(cid:2)2005 2003
InterventionalCardiology:Percutaneous ManagementofAcuteCoronarySyndromes,
NoncoronaryIntervention,editedbyHoward SecondEdition,editedbyChristopherP.
C.Herrmann,MD(cid:2)2005 Cannon,MD2003
PrinciplesofMolecularCardiology,editedby Aging,HeartDisease,andItsManagement:
MarschallS.Runge,MD,andCamPatterson, FactsandControversies,editedbyNilooM.
MD(cid:2)2005 Edwards,MD,MathewS.Maurer,MD,and
HeartDiseaseDiagnosisandTherapy:A RachelB.Wellner,MPH,2003
PracticalApproach,SecondEdition,byM. PeripheralArterialDisease:Diagnosisand
GabrielKhan,MD,FRCP(cid:3)LONDON)(cid:2)FRCP(C),FACP, Treatment,editedbyJayD.Coffman,MDand
FACC(cid:2)2005 RobertT.Eberhardt,MD(cid:2)2003
CardiovascularGenomics:GeneMiningfor CardiacRepolarization:BridgingBasicand
PharmacogenomicsandGeneTherapy,edited ClinicalScience,editedbyIhorGussak,MD,
byMohanK.Raizada,PhD,JulianF. PhD,CharlesAntzelevitch,PhD,StephenC.
R.Paton,PhD,MichaelJ.Katovich,PhD,and Hammill,MD,WinK.Shen,MD,andPreben
SergeyKasparov,MD,PhD,2005 Bjerregaard,MD,DMSc(cid:2)2003
Therapeutic Lipidology
Edited by
Michael H. Davidson, md, facc, facp
Director of Preventive Cardiology,
Rush University Medical Center,
Radiant Research,
Chicago, IL
Peter P. Toth, md, p d, faap, fica,
h
faha, fccp, facc
Director of Preventive Cardiology,
Sterling Rock Falls Clinic,
Chief of Medicine,
CGH Medical Center
Clinical Associate Professor,
University of Illinois College of Medicine,
Peoria, IL
Southern Illinois University School of Medicine,
Springfield, IL
and
Kevin C. Maki, p d
h
Chief Science Officer, Provident Clinical Research,
Bloomington, IN
Foreword by
Antonio M. Gotto, J ., md, dp
r hil
Weill Cornell Medical College
New York, NY
©2007HumanaPressInc.
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To the memory of my father, Dr. David M. Davidson, who died at age 47 of a
myocardial infarction.
Michael H. Davidson
ToRSM(especiallyMMQ,MMMc,MBA,andMYML)forteachingmethefundamentals
of living my life with faith, fortitude, and ferocity.
Peter P. Toth
To the PCRC team, whose commitment to “doing well while doing good” contributes
everydaytoourmissionofhelpingpeopleacheivegreaterqualityoflifebypreventing
diseases that erode good health and function.
Kevin C. Maki
Preface
Lipids constitute a diverse array of molecules with an astounding range of functions
in biological systems in both health and disease. Many of the greatest scientific minds
of the last century committed their energies to the identification of lipids and sterols
and to characterizing how these molecules are synthesized and metabolized by a
large number of cell types. This led to the identification of many species of lipids,
includingphospholipids,sphingolipids,cerebrosides,triglycerides,fattyacidsandtheir
metabolites (eicosanoids, leukotrienes), and cholesterol/cholesterol esters and other
sterols. Lipids are involved in cell membrane and organelle formation, intracellular
andintercellularsignaling,cellsurfacereceptorfunction,inflammation,andimmunity.
Cholesterolisamodulatorofcellmembranefluidity,isaprecursortosteroidhormones
and bile salts, and, along with many lipid species, is a key modulator of risk for
developing atherosclerotic disease. Cholesterol can also be a source of fatty acid in
its esterified form. Fifteen Nobel Prizes have been awarded to investigators for work
related to the biosynthesis and metabolism of cholesterol, and more are sure to follow.
The identification of the enzymes and intermediates of the cholesterol biosynthetic
pathway will forever be a milestone in human creativity and investigative ingenuity.
The regulatory circuitry of lipid and cholesterol metabolism is understandably of
enormous complexity, and many areas of uncertainty and gaps in knowledge remain.
In the clinical arena, the last 30 years have seen tremendous advances in the fields
oflipidologyandcardiovascularmedicine.TheFraminghamStudyandotherepidemi-
ologic investigations conducted around the world unequivocally demonstrated strong
relationships between lipoproteins and risk for cardiovascular events. Seminal work
by Fredrickson and colleagues classified dyslipidemias according to derangements in
specific classes of lipoproteins. Goldstein and Brown ushered in the modern era of
“therapeuticlipidology”bydiscoveringthelow-densitylipoprotein(LDL)receptorand
subsequently showing that (1) mutations in this receptor were etiologic for familial
hypercholesterolemia and (2) inhibitors of the (cid:4)-hydroxymethylglutaryl coenzyme A
reductase upregulated this receptor and facilitated the clearance of LDL from the
circulation. Gotto and coworkers subsequently sequenced the amino acid structure of
apoprotein B100. Other apoproteins were identified and sequenced and their three-
dimensional conformations and cell surface receptors elucidated. Mutations in these
apoproteins were correlated with both gain and loss of function, yielding many identi-
fiableandcharacteristicchangesinlipoproteindistributions.Morerecently,theroleof
membrane cassette transport proteins in lipid trafficking between the gastrointestinal
tract,liver,andbloodvesselwallshasbeencharacterized.Mutationsinthesemembrane
cassette transport proteins have provided mechanistic insights into such lipid disorders
as Tangier’s disease and (cid:4)-sitosterolemia. The role of lipolytic enzymes (lipoprotein
lipase, hepatic lipase, endothelial lipase, phospholipase A2, and hormone-sensitive
lipase) and their various mutant forms in lipid metabolism have also been elucidated
and remain foci of intensive investigation. Polymorphisms from around the world
continue to be identified and catalogued. The number of nuclear transcription factors
vii
viii Preface
(e.g., peroxisomal proliferator-activated receptors, liver X receptor, and farnesoid X
receptor) involved in lipid metabolism continues to expand. In the next few years,
the areas of lipidomics, isoprenoid metabolism, and vascular biology will continue to
provide us with more expansive vistas from which to view the relationship between
lipid dynamics and atherogenesis.
Until the mid-1980s, serum LDL cholesterol (LDL-C) was recognized as a critical
risk factor for atherosclerotic disease. However, prospective, placebo-controlled data
showingthattherapeuticallyreducingtheburdenofthislipoproteininserumdecreases
riskforcardiovascularmorbidityandmortalitywerelacking.Thefirstproofofbenefit
fromthisapproachcamefromtheLipidResearchClinicsCoronaryPrimaryPrevention
Trial. In this trial, the bile acid binding resin cholestyramine was used to treat men at
high risk for coronary artery disease. Patients experienced a 19% reduction in major
coronary events with a 9% reduction in LDL-C. In its Adult Treatment Panel I, the
National Cholesterol Education Program (NCEP) made its initial attempt to provide
evidence-based guidelines for dyslipidemia management. The first statin, lovastatin,
was approved in 1987. Over the course of the last 20 years, we have observed
a remarkable evolution in our understanding of lipid metabolism and have greatly
expandedthetherapeuticarmamentariumwithwhichtodecreasetheburdenofathero-
geniclipoproteins.Wehavealargenumberofprospectiveclinicaltrialswhichdemon-
strate that lipid lowering with statins, fibrates, and niacin beneficially impacts risk for
cardiovascular morbidity and mortality. Millions of patients have benefited from these
therapies.
Despite these great successes, much work remains to be done. Even in the face
of very aggressive lipid lowering with statins, the majority of acute cardiovascular
events are not prevented. Clinicians must keep pace with rapidly changing guidelines,
which call for ever greater reductions in both serum LDL-C and non-high-density
lipoprotein cholesterol levels. The percentage of the population that develops the
metabolic syndrome and diabetes is increasing, a greater percentage of the population
is elderly with increased risk, and more patients are surviving ischemic strokes and
acute coronary syndromes such as myocardial infarction and unstable angina. All of
these patients warrant aggressive management according to updated NCEP guidelines.
Many new drug classes are being developed to help address these challenges. Thera-
peutic approaches to more reliably increase serum levels of high-density lipoproteins,
drugs to reduce appetite and weight gain, and deeper insights into specific dietary
and lifestyle approaches to dyslipidemia are actively being developed and evaluated.
The atherogenicity of novel pathways are burgeoning areas of exploration. Many
new markers of risk have also been introduced into medicine in recent years. These
includeC-reactiveprotein,myeloperoxidase,lipoprotein-associatedphospholipaseA2,
and soluble CD36. Evaluation of lipoprotein particle size and number offer valuable
insights into lipoprotein metabolism and risk for cardiovascular events. Considerable
skill is required to integrate information gleaned from these various modes of patient
testing and to tailor and optimize therapeutic approaches. It is these approaches and
skills that Therapeutic Lipidology addresses.
This book is intended to provide practicing clinicians with a focused and intensive,
but useable, source of information on the identification and management of dyslipi-
demias. The need for a volume such as this has been longstanding. Since the creation
oftheAmericanBoardofClinicalLipidology,manyclinicianshaveaskedustocreate
an up-to-date, comprehensive reference on lipidology. Subsequent editions are certain
Preface ix
toexpandinsizeandscopeasmorespeciesofatherogenicenzymes,lipids,andinflam-
matorymediatorsareidentifiedandnoveltherapeuticinterventionsareintroduced.The
pace of scientific and clinical advances in lipidology is astounding. It is our sincerest
wish that this reference will serve as a lifelong stimulus to the reader to continue to
learn about the ever-changing and fascinating field of therapeutic lipidology. We also
hope that this book will empower our readers to improve and extend the lives of the
patients they serve.
Michael H. Davidson, MD,FACC,FACP
Peter P. Toth, MD, PhD,FAAP,FICA,FAHA,FCCP,FACC
Kevin C. Maki, PhD
Contents
Preface.................................................................... vii
Contributors............................................................... xiii
Acknowledgments.......................................................... xv
Foreword.................................................................. xvii
1. Lipoprotein Metabolism and Vascular Biology.............................. 1
BrianG.Choi,JuanJ.Badimon,PedroR.Moreno,andValentinFuster
2. Genetic Disorders of Lipoprotein Metabolism.............................. 23
MarinaCuchel,AtifQasim,andDanielJ.Rader
3. International Guidelines for Dyslipidemia Management..................... 37
CathleenE.Maki
4. Pathophysiology and Management of Dyslipidemias Associated
with Obesity, Type 2 Diabetes, and Other Insulin-Resistant States ......... 55
KevinC.Maki
5. C-Reactive Protein and Other Inflammatory Markers
in Cardiovascular Disease.............................................. 69
NatalieKhuseyinovaandWolfgangKoenig
6. Dietary Prescriptions to Control Dyslipidemias and Coronary Disease Risk....113
MargoA.Denke
7. Pharmacological Therapy for Cardiovascular Disease:
Current and Emerging Therapies.........................................121
MichaelH.Davidson
8. Effects of Thiazolidinediones on Serum Lipoproteins........................149
AnjliMarooandW.H.WilsonTang
9. High-Density Lipoproteins...............................................159
PeterP.Toth
10. Management of Hypertriglyceridemia ..................................... 201
ReginaldLabossiereandIraJ.Goldberg
xi
