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2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

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TheSteamRollerisNotJoking
Disclaimer
Ioncehadaconversation
withacardiologistfriendof
mineinwhichIcasually
mentionedtheLinus
PaulingTheoryofheart
disease,andthe
subsequentideathata
nontoxicnutritional
supplementprogramwith
vitaminCandafewamino
acidscouldpreventand
reverseheartdisease.The
responsefrommycardiologistfriendwasheartylaughterthat
anyonewouldevensuggestsuchanonsensicalidea,andsurely
youmustbejoking?

leftimage:courtesywikimedia,roadroller

Mycardiologistfriendandtherestofthemainstreammedical
systemhasnoclueaboutthesteamroller(aboveimage)coming
tohealthcareaimingrightatthehugeprofitsfromdiagnosis
andtreatmentofheartdisease,amultibilliondollarindustryin
theUS.

TheCardiacCathLabandCardiacBypassSurgeryProgramwill
beflattened,thefirstcasualtiesoftheinternetmedical
informationrevolutionprovidinginformationaboutasafeand
cheapsupplementprogramtoreverseheartdiseasecalledthe
LinusPaulingProtocol.Timehascomefortheolddinosaursto
go.Inthenearfuture,thankstoLinusPauling,heart
diseasewillbecomeacuriosityofthepast,likethe
disappearanceofgastriculcersaftertheinventionofantacids
andantibiotics.

TheLinusPaulingProtocolVitaminC

http://www.drdach.com/Heart_Disease.html 1/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

VitaminCDeficiencyHasMajor
ImpactonCollagenProduction

VitaminCisrequiredtomakeaprotein
calledcollagenwhichisthemajor
componentofconnectivetissues.The
lackofVitaminCisadeficiencydisease
calledScurvy.

WhyisCollagenImportant?

Collagenisthemostabundantproteinin
thebody.Itisthestructuralprotein
usedtomakeconnectivetissues,bones,
teeth,hair,andarteries.Strong
collagenisimportantforastrongbody.

Leftimage:"UnravelingCollagen",StainlessSteel,
height:11feetJulianVossAndreae,Orange
MemorialParkSculptureGarden,CityofSouthSan
Francisco,CA.5/10/2006.CourtesyofWikimedia
Commons

VitaminCDeficiencyResultsin
AbsentLysineCrosslinkingon
Collagen

VitaminCisrequiredforstrongcollagen.Howdoesthiswork?
VitaminCisrequiredforlysylhydroxylase,anenzyme
responsibleforattachingthelysineresiduestogetheron
adjacentcollagenstrands.(seediagrambelow)VitaminC
deficiencyresultsinweakenedcollagenstrandscausedby
disruptedlysinecrosslinking.Theresultingweakened
collagenresultsinawidespreadproblemsintheconnective
tissues,bones,teeth,skin,hair,arteries,etc.

StepsinCollagenSynthesis(seediagrambelowCourtesyof
Wikimedia)

http://www.drdach.com/Heart_Disease.html 2/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

Howarethefibrilscrosslinked?ThisisdonewithLysine
residues(seebelowdiagram)

FibrilCrossLinkingwithLysineandLysylOxydase(see
diagrambelow)

http://www.drdach.com/Heart_Disease.html 3/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

Aboveimagecourtesyofwikimediacommonslysyloxidase.

Aboveimageshowsthreestepsinattachmentoftwofibrils
(collagenstrands)bycombiningtwolysinemoleculeswiththe
helpofanenzymelysinehydroxylasewhichrequiresvitaminC.

FullBlownScurvyCollagenFallsApart

InthefullblownVitaminCdeficiencydiseasecalledScurvy,the
structuralelementsofthebodyliterallyfallapart.Collagenis
brokendownandnotreplaced.Thejointswearout,thesmall
arteriesbegintocrackanddegenerate,theskinshowseasy
bruisingandbleedingassmallvesselsrupturethroughoutthe
body,andtheteethmayloosenandfallout.

LinusPauling:HeartDiseaseisaChronicScurvyCondition

http://www.drdach.com/Heart_Disease.html 4/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

LinusPaulingwasunquestionably
thegreatestscientistofthe
twentiethcentury.Allofmodern
biochemistryandmolecularbiology
chemistryisbasedonLinus
Pauling'swork,especiallyhis
discoveryandelucidationof
thechemicalbond.Paulingisthe
onlyscientisttobeawardedtwo
unsharedNobelprizes.

Pauling'slateryearsweredevoted
toheartdisease,andin1989he
published"AUnifiedTheoryof
HumanCardiovascularDisease,"in
whichhestatesthatatherosclerotic
plaquesinheartdisease
areactuallypartofarepair
process,torepairthearterial
damagecausedbychronicvitaminCdeficiency.

LeftImage:LinusPaulingCourtesyofWikimedia

Inessence,Paulingsaidthatheartdiseaseisamanifestation
ofchronicscurvy,andatheroscleroticplaqueisamechanism
evolvedtorepairorpatchbloodvesselsandarteriesdamaged
bychronicvitaminCdeficiency.LinusPaulingalsosaidthat
atheroscleroticplaqueformationcanbepreventedorreversed
withvitaminC,lysineandproline.Thesearenutritional
supplementsavailableatanyhealthfoodstoreforafewdollars.

AtheroscleroticPlaquesContainLipoProtein(a)

Plaquedepositsfoundinhumanaortasaremadeupofaformof
cholesterolcalledlipoprotein(a)alsocalledLp(a).

AtheroscleroticPlaquesAreFoundatMaximalMechanical
Stress

Atheroscleroticplaquesarenotfoundrandomlydistributed
throughoutthearterialtree,ratherdistributionisrestrictedto
sitesofhighmechanicalstresssuchasbifurcations,andareasof
motionsuchasthesurfaceoftheheart(coronaryarteries).In
theearly1950's,aCanadian,G.C.Willis,MD,madethesesame
observations,andtheyhavebeenconfirmedby60years
ofcoronaryandperipheralarteriographyatmajormedical
centers.

ExposedLysineCrosslinksfromDamagedCollagenisSiteof
LipoProtein(a)attachmentandPlaqueFormation

http://www.drdach.com/Heart_Disease.html 5/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

Imaginesteppingonyourgardenhosea
thousandtimesaday.Youwillsoonnotice
cracksinthewallofthegardenhose.This
isthesameprocessthathappensinthe
artery.Asthesecracksopenup,the
collagenstrandsinthewallofthearteryare
teasedapart.Thetriplehelixcollagen
strandsarenormallyboundtogetherwith
lysinecrosslinkswhicharenowteasedapart
andexposedtothecirculatingbloodstream.

leftImage:LysinecourtesyofWIkimedia

TheLysineresidueslooklikelittleflags
wavingfromthedamagedcollagen
strand.TheexposedLysinestrandsareavailableforbinding
tocirculatingLipoprotein(a),aspecialformofcholesterolthat
haslysinereceptors,andisknowntoincreaseheartdisease
risk.Thisattachmentoflipoprotein(a)tothefreelysine
residuesofdamagedcollageninitiatestheatherosclerotic
process.Overtime,thisprocessbuildslargerplaquedeposits
whicheventuallynarrowtheinnerdiameterofthearterycausing
ablockage,orleadstoplaqueruptureandthrombosis,a
catastrophiceventwhichmaycauseheartattackor
suddendeath.

Animalexperimentsingeneticallymodifiedmicewhichhave
"knockedout"thelysinebindingsitesonlipoprotein(a)showa
fivefoldreductioninatheroscleroticplaqueformation.

CanYouMakeVitaminC?NoYouCan't

WehumanscannotmakevitaminCinour
liverasallotheranimalsdo.Wehumans
hadageneticmutationinourancestry50
millionyearsagowhich"knockedout"the
finalenzymeinthehepaticsynthesisof
vitaminC.Themissingenzymeiscalled
GLO(gulanolactoneoxidase).Primates
suchasgorillas,chimpanzeesand
orangutansalsosharethissameGLO
mutationandcannotmakevitaminC.Inaddditionallprimates
sharewithhumanssusceptibilitytoheartdisease.
AboveImageVitaminC,asimpleringstructuresimikartoglucose,Ascorbate
CourtesyofWikimedia

AllAnimalsCanMakeVitaminC,buttheGuineaPigCan't

Exceptforhumansandprimates,allotheranimalshavethe
threeenzymesintheliverwhichcansynthesizevitaminCfrom
glucose(asimplesugar).Onemajorexceptionistheguineapig,
whichisreallyarodentandnotapig,Theguineapig,forsome
unexplainedreason,shareswithhumanstheidenticalGLO
geneticmutationandalsolackstheGLOenzymejustlikewe
do.Thismakestheguineapiganidealexperimentalmodelfor
humandiseases.Bytheway,althoughanimalsthatmake
vitaminCnevergetheartdisease,theguineapigwhichlacks
theabilitytosynthesizevitaminC,alsogetsheartdisease.

AnimalsThatMakeVitaminC,Don'tGetAtherosclerotic
HeartDisease
http://www.drdach.com/Heart_Disease.html 6/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

Ithoughthiswasworthrepeating.

(note:hereIamreferringtoatheroscleroticvascularheart
diseaseinanimals.DogsandCatsDOsuccumbtoother
commontypesofheartdiseasesuchascardiomyopathyand
heartwormetc.)

AnimalsThatDon'tMakeVitaminC,DoGetAtherosclerotic
HeartDisease

Thisshouldbestartingtobecomeclearnow.

AnimalScientificSupportforthePaulingUnifiedTheory

Asmentionedabove,guinea
pigsareespeciallywellsuited
tostudyatherosclerosis
becauseguineapigsare
unabletomaketheirown
vitaminC,andinaddition,
theydevelopatherosclerotic
plaquessimilartothosefound
inhumans.

LeftImageGuineaPigCourtesyof
Wikimedia

G.C.Willis,aCanadiandoctor,conductedresearchwithguinea
pigsinthe1950'sshowingthatguineapigsdeprivedofdietary
vitaminCdevelopedatheroscleroticplaques,whileguineapigs
givenplentifulvitaminCwereprotected.Inaddition,guineapigs
fedavitaminCdeficientdiethadelevatedLipoprotein(a)levels
alongwiththeincreasedatheroscleroticplaqueformationinthe
arteries.(link)(link)

Similarfindingsweredemonstratedingeneticallyengineered
micelackingtheGLOenzyme.TheGLOdeficientmicefeda
vitaminCdeficientdietdevelopedatheroscleroticplaquesinthe
aortawithcharacteristicderangedcollagencrosslinking.GLO
deficientmicefedvitaminCwereprotected.(link)

HumanStudiesSuportingtheLinusPaulingTheory

Optometrist,Dr.SydneyBush'sretinalartery
observationssupportthePaulingtheory.Usingmodern
equipmenttononinvasivelyphotographtheretinalarteriesof
theeyebeforeandafterVitaminCsupplementationinhumans,
Dr.Bushhasdocumentedreversalofatheroscleroticplaquewith
VitaminCsupplementation.(link)

CoronaryCalciumScorestudiesalsosupportthePaulingTheory
withfavorableresultsaftertreatmentwithVitaminCandLysine.
(link)

Anecdotalcaseevidenceofreversalofheartdiseasecanbe
foundinthemedicalliteratureanddocumentedinOwen
Fonorow'sbook(seeimagebelow).Inthesecases,advanced
heartdiseaseregressesaftersupplementionwiththe
LinusPaulingProtocol.Thisishighlysignificantbecausethe
naturalcourseofheartdiseaseisprogression,andany

http://www.drdach.com/Heart_Disease.html 7/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

intervetionthataltersthenaturalcourseofadiseaeprocessis
highlysignificant.

Messageboardsareasourceofanecdotalcasesreports
supportingtheLinusPaulingProtocol.TheTrackYourPlaque
MessageBoardshavedocumentedmanycasesofregressionof
atheroscleroticdiseasewithprotocolswhichincludevitaminC
aswellasothernutritionalsupplements.(Thereisamodest
membershipfeeforTYP)

Whynodrugcompanysponsoreddoubleblindplacebocontrolled
studies?Sincetherearenopatentsinvolvedfornatural
supplements,andnodrugsinvolved,nodrugcompanywould
everinvestthe250milliondollarstofundsuchastudywithno
potentialforfinancialreturn.

ThePhysician'sHealthStudyDon'tWasteYourMoneyOn
Vitamins!!

Usingpublicfunds,theNIH(NationalInstituteof
Health)fundedalargestudycalledThePhysicians'HealthStudy
IIwhichevaluatedVitaminsCandEinheartdiseaseand
waspublishedNov.9,2008inJAMAbyHowardD.Sesso.The
studyfoundthatVitaminCandEdidnotpreventmortalityfrom
heartdisease,resultswhicharecompletelyopposite
tomassivepreviouslypublishedresearchandanecdotalcase
reports.

Acloserlookshowsafewglaringerrorsinstudydesign.
TheLinusPauliingProtocolwasnotfollowed.Thedosageof
vitaminCwassettoolow,atonetenththedosage
recommendedbytheLinusPaulingprotocol,andlysinewasnot
provided.WhiletheSessostudyshowednomortalitybenefit,
manypreviousstudiessuchastheEnstromStudyshoweda
striking40%reductioninallcausemortalityover6yearsfrom
thesame500mgdailyvitaminCdosage.ThePaulKnechtstudy
showeda25%reductioninHeartDiseaseriskwithdaily700mg
VitaminC.TwopreviousstudiesfromJapanandFinland
showedthatVitaminCreducesriskforstroke,another
atheroscleroticdisease.Therearemanymorelikethese.

Sincefavorableresultswouldbefinanciallydestructivetothe
drugandhospitalindustries,acynicmightsuggestthatvested
interestswereatworkinSesso'sstudyintendingtodiscredit
vitaminC(asdocumentedmanytimesinthepastwithexamples
ofcorporateinfluenceinmedicalresearch).Itisnotdifficult
todesignamedicalstudytofail.Iregardthisasmerely
anotherexampleoftheinformationwarwagedbycorporate
mainstreammedicineagainstnaturalmedicine.

EnstromStudy,500mgVitaminCReducesMortality40%
over6years

EnstromshowedthatincreasingvitaminCintakehadadramatic
40%reductioninmortalitybenefitwhichexceedsanystatindrug
studyeverconducted.

LinusPaulingProtocolForPreventionandReversalof
Plaque

Ifheartdiseaseischronicscurvy,causedbychronicvitamin
http://www.drdach.com/Heart_Disease.html 8/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

Cdeficiency,thenitmakessensetosupplementwithvitaminC
intheamountsneededtomakestrongcollagenandprevent
arterialdamagefrommechanicalstress.

Inaddition,Paulingdevisedacleveryetsimplemethod
toaddresstheissueofLipoprotein(a)attachingtothelysine
residuesonthedamagedcollagenfibersinthearterialwall.He
recommendedsupplementingwith24gramsoflysineperday.
Theadditionallysineinthebloodstreamattachestothe
receptorsitesonthelipoprotein(a)molecules,inactivatingthe
lipoprotein(a)andpreventingitfromattachingtothearterial
wall.Thispreventstheinitiationoftheatheroscleroticprocess.
Inaddition,VitaminCandLysinearebothimportantprecursors
forbuildingstrongcollagenwhichmakesstrongarteries.

InadditiontoLysine,someofthecollagencrosslinkingisdone
withanotheraminoacidcalledProline,soprolinewasalso
addedtothetreatmentprotocol.

WheretoReadAbouttheLinusPauling
Protocol:

Aboveimage,CoverofLinusPaulingProtocolBookcourtesyofOwen
Fonorow.

ReadmoreabouttheLinusPaulingProtocolinthisnewbook
(aboveimage):
PracticingMedicineWithoutaLicensebyOwenFonorow.
(link)(link)

OwenFonorowisperhapsthesinglemostdedicatedperson
devotedtothe1992LinusPaulingProtocolforpreventionand
reversalofheartdisease.(link)ApatentfortheLinusPauling
Protocolwasissuedin1994.(link)In1996,aCATscancoronary
calciumscorestudyvalidatedtheprotocolshowinga15%
reversalofcalcificationindicatingreversalofcoronaryartery
disease.(link)AnotherexcellentbookonthesubjectofVitamin
Candheartdiseaseis,StopAmerica's#1KillerbyThomasLevy
MD,JD.2006(link).ToreadmoreontheLinusPaulingProtocol,
seethisshortfourpagebookletbyOwenFonorow.(link)Or,
readthisexcellentarticlebyEnglishandCass.(link)

WhatistheLinusPaulingProtocol?

Lascorbate(VitaminC)56gramsadayindivideddoses
LLysine5gramsadayindivideddoses
http://www.drdach.com/Heart_Disease.html 9/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

LProline23gramsadayindivideddoses

Thesesupplementscanbeobtainedatanythehealthfoodstore
astabletsorcapsulesfor40to50dollarsamonth.A
convenientpowderformcanbeobtainedatTowerLaboratories.
TheyhaveaproductcalledHeartTechwhichprovidestheLinus
PaulingProtocolinpowderform.ThereisalsotheVitaminC
FoundationCardioCwhichprovides2500mgvitaminCand2500
mglysineperservingplus500mgproline.(link).

VitaminE,GoodorBad,YesorNo,BlessingorCurse?

SteveHickeyandHilaryRobertscomerightoutonpage167of
theirbook,andmakethestatement,"VitaminCandTocotrienols
canreversecoronaryarterydisease".Theywouldadd
theTocotrienolformofVitaminEtotheLinusPaulingProtocol.
Regardingheartdisease,andatheroscleroticvasculardisease,
theauthorsstatethat"ontheavailableevidence,the
combinationofVitaminCandTocotrienolscouldbecurativewith
noknownharmfuleffects."Foramorecompletediscussionof
VitaminE,seemyarticle,VitaminE,CurseorBlessing?by
JeffreyDachMD.

OppositiontotheLinusPaulingProtocolbyMainstream
Medicine

Ifyouarefacingthe
prospectsofcoronary
arterybypasssurgery(left
image),youmightaskthe
obviousquestion:Why
hasn'tmycardiologisttold
meaboutthisinformation
andstartedmeonthe
LinusPaulingProtocol?

Mostcardiologistseither
don'tknowaboutitor
ignoreitbecauseofthe
informationwargoingon
betweenmainstreammedicineandnaturalmedicine.
Cardiologistsreadmedicaljournalswhichregularlyrunincorrect
andbiasedarticlessayingVitaminCisuselessforprevention
andreversalofheartdisease,suchastheNov92008Sesso
study.(link).
Aboveimage:coronaryarterybypassoperationcourtesywikimedia.

Diagnosingandtreatingheartdiseasewithexpensivetestsand
proceduressuchascoronaryangiography,angioplasty,stenting
andbypassoperationsisthemostprofitablepartofhospitalbig
business.That'swhyhospitalscompeteandfightwitheach
otherovertherightstoexpandandbuildlargercardiaccathlabs
andcardiacbypassoperationprograms.Theseprogramsare
hugemoneymakersforthenationalhospitalsystem.

Whatwouldhappeniftherewasacheapandeffectivewayto
reverseandpreventheartdisease,(ie.theLinusPauling
Protocol)?Heartdiseasewouldbecomeanuncommon
illness.Withfewerheartpatientstotreat,themultimillion
dollarcathlabsandcardiacbypassprogramsatyourlocal
hospitalwouldbecomeobsoleteanddisappear.Thiswouldbea
http://www.drdach.com/Heart_Disease.html 10/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

financialcatastropheformainstreammedicine.

NoMoreConstructionCranes?

Withsomuchmoneyandvested
interestatstake,youcanimagine
whyitisnotprudentfora
cardiologisttobringupthe
benefitsoftheLinusPauling
Protocolinfriendly
conversationwhilelunchinginthe
Doctor'sDiningHall.Thatwould
beaninstantticketoffthe
medicalstaffrosterandoutthe
hospitaldoor,andtheendofalucrativecardiologypractice.
Whatcardiologistintheirrightmindwoulddothat?Itiseasier
forthemainstreamcardiologiststosimplylaughitoffasajoke
andgobacktothecathlab,domoreproceduresandmake
somemoneytopaytheirbills.

Aboveleftimage:Hospitalexpansionprojectfornewcardiaccathlabandcardiac
surgerytheater.Courtesywikimedia.

Relatedarticles:

VitaminE,CurseorBlessing?byJeffreyDachMD

Crestor,Jupiter,CRPandHeartAttackbyJeffreyDachMD

CATCoronaryCalciumScoring,ReversingHeartDiseaseby
JeffreyDachMD(PartOne)

HeartDiseasePartTwobyJeffreyDachMD

CholesterolLoweringStatinDrugsforWomen,JustSayNoby
JeffreyDachMD

LipitorandTheDraculaofModernTechnologybyJeffreyDach
MD

VitaminCandStrokePreventionbyJeffreyDachMD

FinancialDisclosure:IhavenofinancialinterestinVitaminC
Foundation,TowerLabororatoriesorLivOnLabs,TrackYour
Plaque,nordoIreceiveincomefromthesaleofanybooks
mentionedhere.

Linktothisarticle:
http://jeffreydach.com/2008/11/27/heartdiseaseascorbatelysineandlinuspauling
byjeffreydachmd.aspx

JeffreyDachMD
7450GriffinRdSuite180/190
Davie,FL33314

Phone:9547924663
Email:drdach@drdach.com
Facebook
Blog

ReferencesandLinks
http://www.drdach.com/Heart_Disease.html 11/33
2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

WillisStudiesonVitaminCGuineaPigModeland
Atherosclerosis

http://www.vitamincfoundation.org/pdfs/WillisGround.pdf
ANEXPERIMENTALSTUDYOFTHEINTIMALGROUNDSUBSTANCE
INATHEROSCLEROSIS,G.C.Willis,Canad.M.A.J.Vol69,1953,
p.1722

http://www.vitamincfoundation.org/pdfs/WillisSerial.pdf
SERIALARTERIOGRAPHYINATHEROSCLEROSIS,G.C.Willis,A.
W.Light,W.S.Cow,Canad.M.A.J.Dec1954,Vol71,1954,p.
562568

http://www.vitamincfoundation.org/pdfs/WillisTissue.pdf
ASCORBICACIDCONTENTOFHUMANARTERIALTISSUE,G.C.
Willis,S.Fishman,Canad.M.A.J.,April1,1955,Vol72,Pg
500503

http://www.vitamincfoundation.org/pdfs/WillisAthero.pdf
THEREVERSIBILITYOFATHEROSCLEROSIS,G.C.Willis,Canad.
M.A.J.,July15,1957,Voll77.,Pg106109

http://www.vitamincfoundation.org/pdfs/
CAPILLARYRUPTUREWITHINTIMALHEMORRHAGEINTHE
CAUSATIONOFCEREBRALVASCULARLESIONS,J.C.Paterson,
ArchPath,Vol29,1940,Pg345354

http://www.vitamincfoundation.org/pdfs/
SOMEFACTORSINTHECAUSATIONOFINTIMALHEMORRHAGES
ANDINTHEPRECIPITATIONOFCORONARYTHROMBI,J.C.
Paterson,Canad.M.A.J.,Feb1941,Pg114120

GuineaPigsareexcellentmodelforatherosclerosis

http://www.pubmedcentral.nih.gov/articlerender.fcgi?
artid=1435897
NutrMetab(Lond).20063:17.
Guineapigs:Asuitableanimalmodeltostudylipoprotein
metabolism,atherosclerosisandinflammationbyMariaLuz
Fernandez1andJeffSVolek2

http://jn.nutrition.org/cgi/content/full/131/1/10
JournalofNutrition.2001131:1020.
GuineaPigsasModelsforCholesterolandLipoprotein
MetabolismMariaLuz

http://ci.nii.ac.jp/naid/110002603577/
JapanesecirculationjournalVol.35,No.12(19711200)pp.1559
1565
EXPERIMENTALATHEROSCLEROSISWITHASCORBICACID
DEFICIENCYbyFUJITANITAKAOetal.

Influenceofascorbicaciddeficiencyonserumandhepaticlipid
andontheaortawerestudied.Twogroupsofascorbicacid
deficientguineapigsweremadebyfeedingwithscorbuticdiet
withorwithout5%coconutoilfortwoweeks(group3and1).

Controlanimalsoftheexperimentalgroupswerefedwiththe
samedietofprevioustwogroupsandreceived25mgof
ascorbicacidsubcutaneouslyforthesameperiod(group2and
4).

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Moderateincreaseoftriglycerideandcholesterolesterandbeta
lipoproteinintheserumofascorbicaciddeficiency(group1),
andmarkedlytoapproximatelytwiceofnormalintheascorbic
aciddeficiencywithcoconutoilfeeding(group3).

Increaseofserumlipidsanddepressionofplasmalipoprotein
lipaseactivitybyascorbicaciddeficiencywaspreventedby
ascorbicacidadministrationasobservedinthecontrolgroups.
Histologicalexaminationoftheaortarevealededematous
swellingofthegroundsubstanceintheintimaandmediain
thescorbutic,andearlyatheromatouslesionsof
accumulatedfoamcellsintheintimaoftheascorbicacid
deficiencywithcoconutoilfeeding.Thesefindingssuggest
thatanyfactorsdisturbingascorbicacidmetabolisminducean
increaseofserumlipidsandalteredvascularwallmetabolism,
andconsequentlyfollowsatherosclerosis.

LandmarkLinusPaulingArticles

http://www.pnas.org/content/87/23/9388.full.pdf
Immunologicalevidencefortheaccumulationoflipoprotein(a)in
theatheroscleroticlesionofthehypoascorbemicguineapig.M
Rath,LPaulingProceedingsoftheNationalAcademyof
Sciences,1990NationalAcadSciences.Vol.87,pp.93889390,
December1990

http://www.pnas.org/content/87/16/6204.full.pdf
Hypothesis:lipoprotein(a)isasurrogateforascorbate.
MRath,LPaulingProceedingsoftheNationalAcademyof
Sciences1990

Anotherlinktosamearticle:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?
tool=pubmed&pubmedid=2143582
ProcNatlAcadSciUSA.1990August87(16):62046207.
PMCID:PMC54501
Hypothesis:lipoprotein(a)isasurrogateforascorbate.MRath
andLPauling

http://faculty.washington.edu/ely/paulinglysine.html
JournalofOrthomolecularMedicine,6(34):14446,1991.
http://www.orthomed.org/jom/jom.htm
CaseReport:Lysine/AscorbateRelatedAmeliorationofAngina
PectorisbyLinusPauling

http://orthomolecular.org/library/jom/1992/pdf/1992v07n01
p005.pdf
AUnifiedTheoryofHumanCardiovascularDiseaseLeadingthe
WaytotheAbolitionofThisDiseaseasaCauseforHuman
MortalityMRath,LPaulingJOrthoMed,1992

http://www.americanhearthealthservices.com/images/Cellular_Essentials.pd
JOURNALOFAPPLIEDNUTRITION,VOLUME48,NUMBER3,1996
ORIGINALREPORTCopyrightInternationalAcademyof
NutritionandPreventiveMedicine

NUTRITIONALSUPPLEMENTPROGRAMHALTSPROGRESSIONOF
EARLYCORONARYATHEROSCLEROSISDOCUMENTEDBY
ULTRAFASTCOMPUTEDTOMOGRAPHY
MatthiasRath,M.D.andAleksandraNiedzwiecki,Ph.D.

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2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

Othersupportivearticles

http://www.ncbi.nlm.nih.gov/pubmed/1588941
MolCellBiochem.1992Apr111(12):417.
Protectiveroleofascorbicacidagainstlipidperoxidationand
myocardialinjury.

ChakrabartyS,NandiA,MukhopadhyayCK,ChatterjeeIB.
DepartmentofBiochemistry,UniversityCollegeofScience,
Calcutta,India.

Ascorbicacid(AH2)isapotentialscavengerofsuperoxide
radicalandsingletoxygen.Intheguineapig,marginalAH2
deficiencyresultsinintracellularoxidativedamageinthecardiac
tissueasevidencedbylipidperoxidation,formationof
fluorescentpigmentandlossofstructuralintegrityofthe
microsomalmembranes.Theoxidativedamagedoesnotoccur
duetolackofenzymaticscavengersofreactiveoxygenspecies
suchassuperoxidedismutase,catalaseandglutathione
peroxidase.Also,glutathionetransferaseactivityisnot
decreasedinAH2deficiency.Lipidperoxidation,fluorescent
pigmentformationandproteinmodificationdisappearafterAH2
therapy.Theseresults,ifextrapolatedtohumanbeings,would
indicatethatchronicsubclinicalAH2(ascorbate)deficiency
mayresultinprogressiveoxidativedamagewhichinthe
longrunmayleadtopermanentdegenerativediseasesin
theheart.

HighBloodsugarworsenseffectofvitaminCDeficiency

http://www.ncbi.nlm.nih.gov/pubmed/11500168
Atherosclerosis.2001Sep158(1):112.
Hyperglycemiainducedascorbicaciddeficiencypromotes
endothelialdysfunctionandthedevelopmentof
atherosclerosis.PriceKD,PriceCS,ReynoldsRD.

Dehydroascorbicacid,theoxidizedformofvitaminC,is
transportedintomammaliancellsviafacilitativeglucose
transportersandhyperglycemiainhibitsthisprocessby
competitiveinhibition.Thisinhibitedtransportmaypromote
oxidativestressandcontributetotheincreaseinatherosclerotic
cardiovasculardiseaseobservedinpatientswithdiabetes
mellitus.

http://www.ajcn.org/cgi/reprint/23/1/27.pdf
AmJClinNutr.1970Jan23(1):2730.
Ascorbicacidandatherosclerosis.ShafferCF.

AntiVitaminCArticles,FailureofVitaminC

http://jama.amaassn.org/cgi/content/full/2008.600

VitaminsEandCinthePreventionofCardiovascularDiseasein
Men
ThePhysicians'HealthStudyIIRandomizedControlledTrial
JAMAEXPRESS

HowardD.Sesso,ScD,MPHJulieE.Buring,ScDWilliamG.
Christen,ScDTobiasKurth,MD,ScDCharleneBelanger,MA
JeanMacFadyen,BAVadimBubes,PhDJoAnnE.Manson,MD,
DrPHRobertJ.Glynn,ScDJ.MichaelGaziano,MD,MPH
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JAMA.2008300(18):21232133.PublishedonlineNovember9,
2008(doi:10.1001/jama.2008.600).

BasicresearchandobservationalstudiessuggestvitaminEor
vitaminCmayreducetheriskofcardiovasculardisease.
However,fewlongtermtrialshaveevaluatedmenatinitially
lowriskofcardiovasculardisease,andnoprevioustrialinmen
hasexaminedvitaminCaloneinthepreventionof
cardiovasculardisease.

ObjectiveToevaluatewhetherlongtermvitaminEorvitaminC
supplementationdecreasestheriskofmajorcardiovascular
eventsamongmen.

Design,Setting,andParticipantsThePhysicians'HealthStudyII
wasarandomized,doubleblind,placebocontrolledfactorialtrial
ofvitaminEandvitaminCthatbeganin1997andcontinued
untilitsscheduledcompletiononAugust31,2007.Therewere
14641USmalephysiciansenrolled,whowereinitiallyaged50
yearsorolder,including754men(5.1%)withprevalent
cardiovasculardiseaseatrandomization.

InterventionIndividualsupplementsof400IUofvitaminE
everyotherdayand500mgofvitaminCdaily.

MainOutcomeMeasuresAcompositeendpointofmajor
cardiovascularevents(nonfatalmyocardialinfarction,nonfatal
stroke,andcardiovasculardiseasedeath).

ResultsDuringameanfollowupof8years,therewere1245
confirmedmajorcardiovascularevents.Comparedwithplacebo,
vitaminEhadnoeffectontheincidenceofmajorcardiovascular
events(bothactiveandplacebovitaminEgroups,10.9events
per1000personyearshazardratio[HR],1.01[95%confidence
interval{CI},0.901.13]P=.86),aswellastotalmyocardial
infarction(HR,0.90[95%CI,0.751.07]P=.22),totalstroke
(HR,1.07[95%CI,0.891.29]P=.45),andcardiovascular
mortality(HR,1.07[95%CI,0.901.28]P=.43).Therealso
wasnosignificanteffectofvitaminConmajorcardiovascular
events(activeandplacebovitaminEgroups,10.8and10.9
eventsper1000personyears,respectivelyHR,0.99[95%CI,
0.891.11]P=.91),aswellastotalmyocardialinfarction(HR,
1.04[95%CI,0.871.24]P=.65),totalstroke(HR,0.89[95%
CI,0.741.07]P=.21),andcardiovascularmortality(HR,1.02
[95%CI,0.851.21]P=.86).NeithervitaminE(HR,1.07[95%
CI,0.971.18]P=.15)norvitaminC(HR,1.07[95%CI,0.97
1.18]P=.16)hadasignificanteffectontotalmortalitybut
vitaminEwasassociatedwithanincreasedriskofhemorrhagic
stroke(HR,1.74[95%CI,1.042.91]P=.04).

ConclusionsInthislarge,longtermtrialofmalephysicians,
neithervitaminEnorvitaminCsupplementationreduced
theriskofmajorcardiovascularevents.Thesedataprovide
nosupportfortheuseofthesesupplementsfortheprevention
ofcardiovasculardiseaseinmiddleagedandoldermen.

TrialRegistrationclinicaltrials.govIdentifier:NCT00270647

http://circ.ahajournals.org/cgi/content/full/105/12/1396
VitaminC,Collagen,andCracksinthePlaque,byPeterLibby,
MDMasanoriAikawa,MDPhD

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Mostfatalacutemyocardialinfarctionsresultfromafractureof
theplaquesfibrouscap.Weproposedthehypothesissome
yearsagothatthelevelofcollageninthefibrouscapdepends
onadynamicbalanceofsynthesisanddegradation.1Wefurther
showedthatinflammatorycytokinescanregulateboththe
expressionofgenesthatdirectinterstitialcollagensynthesisin
vascularsmoothmusclecellsandtheinterstitialcollagenases
(matrixmetalloproteinases1,8,and13)requiredtoinitiatethe
breakdownofcollagenfibrils.25Giventhecapitalimportanceof
collageninprotectingtheplaquefromruptureandhence
thrombosis,themetabolismofthiscomplexmoleculemerits
considerationindepth.Seep1485

Theformationofmaturefibrillarcollageninvolvesmanysteps
beyondgenetranscription(Figure).Theinitialtranslation
product,theprocollagenpeptidechain,undergoesextensive
posttranslationalmodification:anespeciallynoteworthypoint
duringthisperiodofexplorationoftheproteome.Collagen
containsunusualaminoacids,hydroxyprolineandhydroxylysine,
formedbyavitaminCdependentprocessthatentailsenzymatic
transferofhydroxylgroupstoselectedprolineandlysine
residuesinthenascentprocollagenchains.Glycosyltransferases
thenaddsugarmoietiestotheprocollagenchains.The
hydroxylatedandglycosylatedmonomersthenselfassemble
intohelicaltrimersastheytraverseseveralintracellular
compartments.Trimmingthenonhelicaltails(thetelopeptides)
frombothendsoftheprocollagenmoleculebyproteinases
yieldsthematureinterstitialcollagentriplehelixsecretedby
smoothmusclecellsinarteries.Thesebuildingblocksthen
furtherselfaggregateintomultimersandforminterstitial
collagenfibrils,linearstructuresasstrongassteelwires.

Theascorbatedependentadditionofpolarhydroxylgroupsto
thesidechainsofprolineandlysinemayaidtheselfassembly
andstabilityofthecollagenfibrilbyforminginterchainhydrogen
bonds.Theabsenceofsufficientascorbicacid(vitaminC),a
requiredcofactorforprolylhydroxylase,thusimpairsthe
formationofstablecollagen.ThehumanphenotypeofvitaminC
deficiency,scurvy,classicallyinvolvesfragilityofbloodvessels.
In1753,JamesLinddescribedtheskinofscorbuticsas
"...coveredwithseveralreddish,bluish...spots...resemblingan
effusionofblood."6LindsdiscoverythatfoodrichinvitaminC
providedacureforscurvyspurredEnglandssubsequentnaval
supremacyandputativelychangedthecourseofhistory.Of
course,chemicalcharacterizationofvitaminCasthe
antiscorbuticfactordidnotoccuruntilthe1930s.(Interested
readersmayfindAlbertSzentGyrgisdisputewiththeeditorof
theBiochemicalJournalregardingpublicationofthestructureof
vitaminCamusing.7CardiologistsknowSzentGyrgibetterfor
hislaterdiscoveryofthebiochemicalbasisofmuscle
contraction).

StudyofvitaminCsroleinvivohasprovenchallenging.Unlike
humans,usualexperimentalanimalscansynthesizevitaminC
andthuscannotbemadescorbutic.Maedasgrouphasrecently
introducedatargetedmutationthatmakesmicedependenton
dietaryvitaminC,allowingmanipulationofascorbatelevels.In
thisissueofCirculation,Nakataetal8studiedatheromain
hypercholesterolemicandscorbuticmice.Theyfindnochangein
lesionsize,buttheyobservedecreasedcollagencontentinthe
lesions.Suchchangesshouldimpairthebiomechanicalstrength

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oftheplaqueandmakeitmorepronetorupture.Thisfinding
extendstheburgeoningevidencethatchangesincollagen
metabolismcaninfluencecrucialcharacteristicsofthe
atheroscleroticplaque.Ourrecentinvivostudiesalsoshowed
thatalterationsincollagensynthesisandcatabolisminducedby
lipidloweringorstatintreatmentinfluencethecollagenous
structureofatheromainrabbits.911Itwouldhavebeenof
interesttoevaluateoverallproteincontentintheselesions,as
weshowedalmost2decadesagothatascorbatecanaugment
noncollagenproteinsynthesisbyculturedarterialsmoothmuscle
cells.12

Wedonotknowwhetherscorbutichumanswithatherosclerosis
wouldexperienceincreasedplaquerupture,acuriousbut
currentlyclinicallyirrelevantquestion.Inadditiontoits
antiscorbuticaction,vitaminChaspotentantioxidantproperties.
Physiologicalconcentrationsofascorbicacidcaninhibitinvitro
oxidativemodificationofLDL,acriticaleventduring
atherogenesis.13Forthisreason,manyindividualstakethisand
otherantioxidantvitaminsinhopethatcombatingoxidative
stresscanforestallatherosclerosisanditscomplications.
VitaminChasotherantiinflammatoryeffectsaswell,including
decreasedleukocyteadhesiontotheendotheliumandincreased
bioavailabilityofatheroprotectivenitricoxide(NO).
AdministrationofvitaminCfor10days(2g/d)reducesadhesion
ofmonocytesobtainedfromcigarettesmokerstocultured
endothelialcells.14VitaminCspotencygenerallyexceedsthat
ofvitaminEasanantiinflammatoryandantiatherogenicagent.
Forexample,intakeofvitaminC,butnotvitaminE,inhibits
oxidizedLDLinducedleukocyteadhesiontoendotheliumin
hamsters.15Physiologicalconcentrationsofascorbicacidalso
increasesynthesisandactivityofNOinvitro.16VitaminCalso
inhibitsactivationofnuclearfactorB(NF ,akeyregulatorof
inflammatorygeneexpression.17AdministrationofvitaminC
canimproveendothelialdysfunctioninhypercholesterolemic
patients.18Ascorbateseffectonplaquecollagencontentadds
anothertheoreticalrationaleforusingvitaminCinpatientsat
riskforatheroscleroticevents.

Unfortunately,welackclinicalevidencethatwouldpermit
ustotranslatethisbasicscienceintopractice.Therecently
reported(butasyetunpublished)HeartProtectionStudy(HPS)
administeredacocktailofantioxidantvitamins(vitaminC250
mg,vitaminE600mg,betacarotene20mg/d)toalargegroup
ofindividualsathighriskforatheroscleroticeventsforaperiod
of5years.Thevitaminshadabsolutelynoeffectonavariety
ofendpoints,includingcoronaryevents19(seealsoThe
HeartProtectionStudyInvestigatorsat
http://www.hpsinfo.org/).Brownandcolleaguesrecently
reportedaccelerationofcoronaryatherosclerosisinpatients
treatedwithacombinationofstatinsandacocktailof
antioxidantvitamins(vitaminC1000mg,vitaminE800IU,
betacarotene25mg/d)intheHDLAtherosclerosisTreatment
Study(HATS).20

Towhatmayweattributethisapparentfailureofaplausible
andwidelyusedtherapeuticapproach?First,thesestudies
mayhaveemployedsuboptimaldosesofthevitaminsused,or
interactionsamongthemmayhavemitigatedabeneficialeffect
ofoneortheothersupplements.Inthisregard,vitaminE
monotherapyshowednobenefitonatheroscleroticeventsin

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boththeHeartOutcomesPreventionEvaluation(HOPE)and
GISSIstudies.21,22Inthesevariousstudies,thedegreeof
preexistingdiseaseorinadequatedurationoftreatmentmight
havelimitedthebenefitoftheantioxidants.Yet,thestriking
beneficialeffectsobservedinthestatintreatmentarmsofboth
theHPSandHATS20andoftheangiotensinconvertingenzyme
inhibitorintheHOPEstudy21establishthemutabilityof
outcomesmeasuredinthesepatientpopulationsinthesame
trials.PartitionoffatsolublevitaminEintothelipidphaseof
plaqueorlipoproteinsmightshielditfromthecooperative
antioxidanteffectofwatersolubleascorbate,excludedfrom
theselipidmilieux.Thus,morepotentoramphipathic
antioxidantsmightinterruptoxidativestressduring
atherogenesismoreeffectivelythanthevitamins.Although
vitamindeficienciesleadtodisease,consumptionof
pharmacologicalamountsofthesesubstancesinindividualswho
maintainvitaminsufficientdietsmaynotpreventdisease.
Indeed,malnutritionhardlyappliestoourpatientswith
atherosclerosis.Contemporarydevelopedsocietiesseemat
muchhigherriskofdietarysurfeitthanlack.

Itiscuriousindeedthatmanyremainsuspiciousof
pharmacologicallipidlowering,astrategynowproven
unequivocallytopreventmyocardialinfarctionandstrokeandto
prolonglifeaswell.Yet,manyindividualsreadilyconsume
costlyvitaminsupplementsdevoidofbenefitinclinicaltrials.
Thissituationmayreflectinpartafailureofthemedical
communitytocommunicateeffectivelywiththepublicregarding
evidencebasedmedicineandthelifesavingbenefitsof
preventivestrategies.ThepresentresultsofNakataetal8
reinforcetheimportanceofcollagenmetabolismindetermining
thestructureofatheroscleroticplaques.However,current
clinicalandexperimentalevidencesuggeststhatthebestwayto
influencefavorablythebalanceofcollagensynthesisand
degradationinatheromaathandtodayremainslipidlowering,
notvitaminC.

EnstromStudy500mgVitaminCReducesMortality40%
over6years

http://www.ncbi.nlm.nih.gov/pubmed/1591317
Epidemiology.1992May3(3):194202

VitaminCintakeandmortalityamongasampleoftheUnited
Statespopulation.EnstromJE,KanimLE,KleinMA.Schoolof
PublicHealth,UniversityofCalifornia,LosAngeles90024.

WeexaminedtherelationbetweenvitaminCintakeand
mortalityintheFirstNationalHealthandNutritionExamination
Survey(NHANESI)EpidemiologicFollowupStudycohort.This
cohortisbasedonarepresentativesampleof11,348
noninstitutionalizedU.S.adultsage2574yearswhowere
nutritionallyexaminedduring19711974andfollowedupfor
mortality(1,809deaths)through1984,amedianof10years.An
indexofvitaminCintakehasbeenformedfromdetaileddietary
measurementsanduseofvitaminsupplements.Therelationof
thestandardizedmortalityratio(SMR)forallcausesofdeathto
increasingvitaminCintakeisstronglyinverseformalesand
weaklyinverseforfemales.

AmongthosewiththehighestvitaminCintake,maleshavean
SMR(95%confidenceinterval)of0.65(0.520.80)forall
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causes,0.78(0.501.17)forallcancers,and0.58(0.410.78)for
allcardiovasculardiseasesfemaleshaveanSMRof0.90(0.74
1.09)forallcauses,0.86(0.551.27)forallcancers,and0.75
(0.550.99)forallcardiovasculardiseases.

ComparisonsaremaderelativetoallU.S.whites,forwhomthe
SMRisdefinedtobe1.00.Thereisnoclearrelationfor
individualcancersites,exceptpossiblyaninverserelationfor
esophagusandstomachcanceramongmales.Therelationwith
allcausesofdeathamongmalesremainsafteradjustmentfor
age,sex,and10potentiallyconfoundingvariables(including
cigarettesmoking,education,race,anddiseasehistory).

25%reductioninHeartDiseaseRiskwith700mgVitC

http://www.ajcn.org/cgi/content/full/80/6/1508
AmericanJournalofClinicalNutrition,Vol.80,No.6,15081520,
December2004

Antioxidantvitaminsandcoronaryheartdiseaserisk:apooled
analysisof9cohorts
PaulKnektetal.

Epidemiologicstudieshavesuggestedalowerriskofcoronary
heartdisease(CHD)athigherintakesoffruit,vegetables,and
wholegrain.Whetherthisassociationisduetoantioxidant
vitaminsorsomeotherfactorsremainsunclear.

Objective:Westudiedtherelationbetweentheintakeof
antioxidantvitaminsandCHDrisk.

Design:Acohortstudypooling9prospectivestudiesthatincluded
informationonintakesofvitaminE,carotenoids,andvitaminC
andthatmetspecificcriteriawascarriedout.Duringa10y
followup,4647majorincidentCHDeventsoccurredin293172
subjectswhowerefreeofCHDatbaseline.

Results ietaryintakeofantioxidantvitaminswasonlyweakly
relatedtoareducedCHDriskafteradjustmentforpotential
nondietaryanddietaryconfoundingfactors.Comparedwith
subjectsinthelowestdietaryintakequintilesforvitaminsEand
C,thoseinthehighestintakequintileshadrelativerisksofCHD
incidenceof0.84(95%CI:0.71,1.00P=0.17)and1.23(1.04,
1.45P=0.07),respectively,andtherelativerisksforsubjects
inthehighestintakequintilesforthevariouscarotenoidsvaried
from0.90to0.99.SubjectswithhighersupplementalvitaminC
intakehadalowerCHDincidence.Comparedwithsubjectswho
didnottakesupplementalvitaminC,thosewhotook>700mg
supplementalvitaminC/dhadarelativeriskofCHD
incidenceof0.75(0.60,0.93Pfortrend<0.001).

Conclusions:Theresultssuggestareducedincidenceofmajor
CHDeventsathighsupplementalvitaminCintakes.

VitaminCDeficiencyIntheUS

http://www.pubmedcentral.nih.gov/articlerender.fcgi?
tool=pubmed&pubmedid=15117714
AmJPublicHealth.2004May94(5):870875.PMCID:
PMC1448351

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VitaminCDeficiencyandDepletionintheUnitedStates:The
ThirdNationalHealthandNutritionExaminationSurvey,1988to
1994JeffreySHampl,etal.Inconclusion,ourdataindicate
thataconsiderablenumberofchildrenandadultsinthe
UnitedStatesarevitaminCdeficientordepleted.

OwenFonorowArticlesonVitaminC

http://www.internetwks.com/owen/TheoryPaper.htm

TheUnifiedTheory,TheLongNeglectedTheoryof
CardiovascularandHeartDiseaseByOwenRichard
Fonorow2002

1)CVMortalitydeclinesafterVitaminCConsumptionincreases
afterpublicationofLinusPAulingBookpublished1970.USis
onlyindustrializedcountrytoexperiencea40%dropinCV
disease.

2)MosthighordermammalsmaketheirownvitaminC(311g
daily)donothaveCV(cardiovascular)diseaseasseenin
humans.

3)AnimalssuchastheGuineapigwhichcannotmaketheirown
vitaminC,alsohavecardiovasculardisease,sameashumansif
theyarefedaVitaminCdeficientdiet.

4)TheWillisGuineaPigExperimentsinthe1950'sshowthat
deprivingtheanimalofvitaminCcausesatherosclerosiswhich
isquitesimilartothehumanlesion.Noplaqueformsinthe
controlgroupgettingadequatevitaminC.(Source:The
ReversibilityofAtherosclerosis,G.C.Willis,CanadM.A.J,July
15,1957,Vol77)

5)PaulingandRathshowedtheapo(a)/Lp(a)increasedinthe
animalsdeprivedofvitaminC,butnotinthecontrols.(Source:
ImmunologicalevidencefortheaccumulationofLp(a)inthe
Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD
atheroscleroticlesionofthehypoascorbemicguineapig,
Pauling/Rath,Pro.Nat.Acad.SciUSA,Vol87,pp93889390,
Dec1990,Biochem)

6)Theheartdiseaseprocessbeginswithalesionintheartery.
(Source:BrownGoldsteinScientificAmerican1982,andLinus
PaulingHeartDiseaseVideo)

7)Veins,ingeneral,donotsufferplaquedeposits.(Source:
CommonknowledgefromthemedicalLiterature)

8)Plaquesareoftenlocalizedtoareasofmechanicalstress,at
bifurcations,andthesurfaceoftheheart(coronaryarteriesor
carotidarteries).(Source:AnExperimentalStudyoftheIntimal
GroundSubstanceinAtherosclerosis,G.C.Willis,CanadM.A.
J.,July1953,Vol69,pg17)

9)VitaminCisrequired(andusedup)makingcollagenthe
mostabundantproteininthehumanbody.(Source:RogerJ.
Williams,NutritionAgainstDisease,1971,LinusPaulingHOWTO
LIVELONGERANDFEELBETTER,1986)

10)Scurvyiscausedbyadeficiencyinmakingcollagenwhichis
inturncausedbyalackofvitaminC.(Source:JamesLind,
1753,LinusPaulingHOWTOLIVELONGERANDFEELBETTER
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1986)

11)TheBeisiegelstudiesinGermanyofpostmortemhuman
aortasin1989determinedthatplaqueconsistsofLp(a)andonly
Lp(a)noordinaryLDL.(Source:Morphologicaldetectionand
quantificationoflipoprotein(a)depositioninatheromatous
lesionsofhumanaortaandcoronaryarteriesinVirchowsArchA
PatholAnatHistopathol1990417(2):10511,NiendorfADietel
MBeisiegelUArpsHPetersS,WolfKRathMand
Lipoprotein(a)inthearterialwall.BeisiegelURathMReblinT
WolfKNiendorfA,EurHeartJ1990Aug11SupplE:17483)

12)ElevatedcholesterolhasbeencorrelatedwithCVD,butmany
studieswereconductedbeforeLp(a)wasknown,Lp(a)was
lumpedinwithLDL.InSeptember,2000,anOxfordmeta
analysisof27largestudiesshowedthatpeoplewithelevated
Lp(a)are70%moreliketosufferaheartattackorstroke.
(Source:CirculationSep2000)

RadioInterviews
mms://rense.gsradio.net/rense/windows_media/
WMHigh/May2008/kx2u91/rense_052208_hr2.wma

OwenFonorowFirstInterviewMAy2008onJeffRense

1/2to1millioncardiovasculardeathsperyearcanbeprevented
withvitaminC.Thereareaboutamillioncardiacprocedures
(angioplasty,stent,bypass)peryear.Wehaveageneticdefect
intheinabilitytomakevitaminC.WehaveadefectinGLO
enzymewhichhappened50millionyearsago.Highlevel
primates,guineaspigandfruitbatcannotmakevitaminC.
Peoplewithanginaandchestpainusuallygetbetterin10days
onVitaminCandLysine.WHentheystopthesupplements,they
mayhavearecurrenceofpain.Casereportofapatient:Unique
EandHighVitaminC(6grams),Lysine(6grams)revertsEKG
backtonormal.About6monthsafterstopping,heartproblems
recurr.50millionyearsago,Lipoprotein(a)evolvedwithLysine
bindingsitetoallowustoevolve.Lipoportein(a)forms
cholesterolplaqueinabsenceofVitaminC.MedicalStudy:
Examinationofaortas,lipoprotein(a)foundinplaque.Most
peoplelivewithchroniclowlevelsofvitaminC.CardioCdrink
mixwithPaulingrecommendation.Contains23gramsof
Lysine,3gramsofVitaminC.After12yearsofexperience:it
doesreverseatherosclerosiswhichisasymptomofchronic
scurvywhichbuildsplaqueinthearteries.

(Bush)Whiteatheromascanbeseeninretinalarteries.Inthe
VitaminCgroup,theseplaquesreverse,Thisworkwas
published.With10gramsofVitaminCaday,andittakesa
monthtoreversesoftatheromas.Calcifiedatheromastakes
longer.Oncecasetook2yearstoreverse.CardioRetinometry:
Weseeamazingreversalsinaveryshorttime.Notnoticedby
cardiologists.VitaminCissafewithnoadverseeffects.
TherapeuticDosage:take500mg1000mgVitaminCevery4
hours.NonChineseVitaminCmadeinEuropeVitaminC
Foundation.
Costis:24dollarsamonthautoshipCardioC.Liposomal
VitaminCisavailableforpeoplewithgasanddiarrhea.More
expensive.

SecondRadioInterview
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mms://rense.gsradio.net/rense/windows_media/WMHigh/Aug2008/r8r10x/
rense_081408_hr2.wma
RadioInterviewonVitaminCandHeartDiseasewithOwen
FonorowAug2008

HeartDiseaseandVitaminC,LinusPaulingGeniusdiscovereda
waytostopandreverseheartdiseaseinhumans.Owen
Fonorow,VitmainCFoundation.Sosimple,yetsocrucial.
Remarkablebreakthroughinhumanhealthandwellness.Book:
PracticingMedicineWithoutALicense,thestoryofLinusPauling
andHeartDiseasebyOwenFonorow.CarolSmithexperience
relaseandrecoveryonthreeocassions.Basictheoryisthat
mostofanimalspeciesproduceownbitaminCintheliver.
HumanscannotmakevitaminC,andwesuffercardiovascular
disease.
ThespeciesthatmakevitaminCcanmakecollagenwhichkeeps
artieriesstrong.IntheabsenceofvitaminCproductionwehave
evolvedcholesterolplaquestorepairthearteriescausing
occludedarteriesandheartattacks.Wecannolongerproduce
vitaminCduetoageneticdefect.Lysinebindingsite.Lysineis
thesecondcomponent.Highdose,needspowserandavoid
pills.Collagenisthemajorproteinofconnectivetissueand
arteries.LackofvitaminCcausesweakcollagen.

http://www.internetwks.com/owen/
HealthArticlesbyOwenFonorow,OrthomolecularNaturopath
(Orthomopath)
(c)19962008OwenFonorow.

http://practicingmedicinewithoutalicense.com/protocol/excerpt_chp7.pdf
Chapter7PracticingMedicineWIthoutaLicensesummaryof
Paulingtherapytoreverseheartdisease

http://www.vitamincfoundation.org/VitaminCFoundation,
OwenFonorow

ArticleSummarizingLinusPaulingTheoryofHeartDIsease

http://www.nutritionreview.org/library/collagen.connection.html
LinusPauling'sUnifiedTheoryofHumanCardiovascularDisease
TheCollagenConnectionJimEnglishandHylaCass,MD

PaulingTherapyfortheReversalofHeartDisease

1.VitaminC:toboweltoleranceasmuchasyoucantake
withoutdiarrhea.Formostpeoplethiswillbeintherangeof
fivetotengrams(5,00010,000mg.)eachday.Spreadthis
amountintotwoequaldoses12hoursapart.(VitaminC
preventsfurthercrackingofthebloodvesselwallthe
beginningofthedisease.)

2.LProline:3gramstwiceperday(actstorelease
lipoprotein(a)fromplaqueformationandpreventfurther
depositionofsame).

3.LLysine:3gramstwiceeachday(actstorelease
lipoprotein(a)fromplaqueformationandpreventfurther
depositionofsame).

4.CoenzymeQ10:90180mg.twiceperday(strengthensthe
heartmuscle).

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2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

5.LCarnitine:3gramstwiceperday(alsostrengthensthe
heartmuscle).

6.Niacin:Decreasesproductionoflipoprotein(a)intheliver.
Inositolhexanicotinateisaformofniacinwhichgiveslessofa
problemwithflushingandthereforeallowsforlargertherapeutic
doses.Beginwith250mg.atlunch,500mg.atdinnerand500
mg.atbedtimethefirstdaythenincreasegraduallyoverafew
daysuntilyoureachfourgramsperday,orthehighestdose
underfourgramsyoucantolerate.Besuretoaskyourdoctor
forliverenzymeleveltestseverytwomonthsorlesstobesure
yourliverisabletohandlethedoseyouaretaking.

7.VitaminE:8002400IUperday.(Inhibitsproliferationof
smoothmusclecellsinthewallsofarteriesundergoingthe
atheroscleroticchanges.)

ReferencesforCassarticle:

1.MarcouxCLussierCacanSDavignonJCohnJS.
AssociationofLp(a)ratherthanintegrallyboundapo(a)with
triglyceriderichlipoproteinsofhumansubjects.
BiochimBiophysActa1997Jun231346(3):26174.

2.EnsenatD,HassanS,ReynaSV,SchaferAI,DuranteW.
Transforminggrowthfactorb1stimulatesvascularsmooth
musclecellLprolinetransportby
inducingsystemAaminoacidtransporter2(SAT2)gene
expression.Biochem.J.(2001)360,(507512)

3.WhiteALLanfordRE.Cellsurfaceassemblyoflipoprotein(a)
inprimaryculturesofbaboonhepatocytes.
JBiolChem1994Nov18269(46):2871623.

4.KlezovitchOEdelsteinCScanuAM.Evidencethatthe
fibrinogenbindingdomainof
Apo(a)isoutsidethelysinebindingsiteofkringleIV10:
astudyinvolvingnaturallyoccurringlysinebindingdefective
lipoprotein(a)phenotypes.
JClinInvest1996Jul198(1):18591.

5.BoonmarkNWLouXJYangZJSchwartzKZhangJLRubin
EMLawnRM.
Modificationofapolipoprotein(a)lysinebindingsitereduces
atherosclerosisintransgenicmice.
JClinInvest1997Aug1100(3):55864.

6.PhillipsJRobertsGBolgerCelBaghdadyABouchier
HayesDFarrellMCollinsP.
Lipoprotein(a):apotentialbiologicalmarkerforunruptured
intracranialaneurysms.
Neurosurgery1997May40(5):11125discussion11157.

7.StubbsPSeedMMoseleyDO'ConnorBCollinsonPNoble
M.
Aprospectivestudyoftheroleoflipoprotein(a)inthe
pathogenesisofunstableangina.
EurHeartJ1997Apr18(4):6037.

8.ShinozakiKKambayashiJKawasakiTUemuraYSakonM
ShibaEShibuyaTNakamuraTMoriT.
Thelongtermeffectofeicosapentaenoicacidonserumlevelsof
lipoprotein(a)andlipidsinpatientswithvasculardisease.J
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2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

AtherosclerThromb19962(2):1079.

9.McCullyKS,Homocysteinemetabolisminscurvy,growthand
arteriosclerosis.Nature1971231:391392.

10.PaulingL,RathM.Pro.Nat.Acad.SciUSA,Vol87,pp9388
9390,Dec1990.

11.CarrAC,FreiB.Towardanewrecommendeddietary
allowanceforvitaminCbasedonantioxidantandhealtheffects
inhumans.AmericanJournalofClinicalNutrition
199969(6):10861107.

12.SimonJA,HudesES.Serumascorbicacidandgallbladder
diseaseprevalenceamongUSadults:theThirdNationalHealth
andNutritionExaminationSurvey(NHANESIII).ArchIntern
Med.2000160(7):931936.

13.StephenR,UtechtT.Scurvyidentifiedintheemergency
department:acasereport.JournalofEmergMed.
200121(3):235237.

14.CameronE,PaulingL.Supplementalascorbateinthe
supportivetreatmentofcancer:Prolongationofsurvivaltimesin
terminalhumancancer.ProcNatlAcadSciUSA.
197673(10):36853689.

http://www.orthomolecular.org/library/jom/1992/pdf/1992
v07n03p153.pdf
[PDF]ReducingtheRiskforCardiovascularDiseasewith
NutritionalSupplementsMRath.Niacinandascorbatehave
beenreportedtolowerplasmalipoproteinalevels....withthe
bindingoflipoproteinatocollagenandothermatrix
components....

LipoProtein(a)isindependentmarkerofatherosclerosis

http://www.chestjournal.org/cgi/content/abstract/121/5/1589
Chest.2002121:15891594.
ElevatedSerumLipoprotein(a)LevelIsanIndependentMarker
ofSeverityofThoracicAorticAtherosclerosisMarcelPeltier,MD
etal.

Conclusion:ThisprospectivestudyindicatesthatserumLp(a)
levelisanindependentmarkerofseverityofthoracicaortic
atherosclerosisdetectedbymultiplaneTEE.Thesefindings
emphasizetheroleofLp(a)asamarkerofatherosclerotic
lesionsinthemajorarteriallocations.

Lipoprtein(a)detectedinarterialwallcontributingto
plaqueformation

http://www.ncbi.nlm.nih.gov/pubmed/2528948
Arteriosclerosis.1989SepOct9(5):57992.Links

Detectionandquantificationoflipoprotein(a)inthearterialwall
of107coronarybypasspatients.RathM,NiendorfA,ReblinT,
DietelM,KrebberHJ,BeisiegelU.
MedizinischeKernundPoliklinik,UniversittsKrankenhaus
Eppendorf,Hamburg,FRG.

Theaimofthisstudywastodeterminetheextentof

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accumulationoflipoprotein(a)[Lp(a)]inhumanarterialwalland
todefineitspotentialroleinatherogenesis.Biopsiesroutinely
takenfromtheascendingaortaof107patientsundergoing
aortocoronarybypasssurgerywereanalyzedforlipidand
lipoproteinparameters,whichwerethencorrelatedtoserum
values.Asignificantpositivecorrelationwasestablished
betweenserumLp(a)andarterialwallapolipoprotein(apo)(a)
byenzymelinkedimmunosorbentassay.HighserumLp(a)also
ledtoasignificantincreaseofapoBinthearterialwall.No
significantcorrelationwasfoundbetweenapoBinserumand
aortictissue.ApoBwasfoundtobepartiallylinkedtoapo(a)in
theaorticextract.Furthermore,apo(a)wasfoundtobeintact,
asdeterminedbyitsmolecularweightinsodiumdodecylsulfate
electrophoresis.Thistechniquealsorevealedthattheapo(a)
isoformpatternofaortichomogenatewascomparabletothe
individualserumpattern.Immunohistochemicalmethods
demonstratedastrikingcolocalizationofapo(a)andapoBinthe
arterialwall,predominantlylocatedextracellularly.Both
proteinswereincreasedinatheroscleroticplaques.Withdensity
gradientultracentrifugation,Lp(a)likeparticlescouldbeisolated
fromplaquetissue.ThisinitialstudyshowedthatLp(a)
accumulatesinthearterialwall,partlyintheformof
lipoproteinlikeparticles,thereforecontributingtoplaque
formationandcoronaryheartdisease.

http://www.ncbi.nlm.nih.gov/pubmed/7605357
Atherosclerosis.1995Mar113(2):17988.
Extractionoflipoprotein(a),apoB,andapoEfromfreshhuman
arterialwallandatheroscleroticplaques.ReblinT,MeyerN,
LabeurC,HenneBrunsD,BeisiegelU.MedizinischeKernklinik
undPoliklinik,UniversittskrankenhausEppendorf(UKE),
Hamburg,Germany.

Severalstudieshaveanalysedapo(a)quantitativelyinarterial
walltissuederivedfrompostmortemsamples.Thepurposeof
thisstudywasaqualitativeanalysisofLp(a)infreshhuman
arterialwalltissue.ItwasevaluatedwhetherLp(a)existsasan
intactlipoproteinorwhetheritisdegraded.Additionallyitwas
analysedwhethertherearedifferencesintheapolipoprotein
compositionbetweenlesionfreeanddiseasedhumanarterial
walltissue.Serumandintimaltissuesamplestakenfromthe
abdominalaortaandtheinferiorcavalveinof18organdonors
wereanalysedforlipids,Lp(a),andapolipoproteinsapoBand
apoE.Serumandtissueparameterswerecorrelated.Inthe
aortictissue,higherLp(a)andapolipoproteinlevelswere
observedinthediseasedsamples.ThetotalamountofLp(a)
recoveredduringthreedifferentextractionprocedureswas5
micrograms/gwetweightintissuefreeofplaqueand11.8
micrograms/gwetweightinatherosclerotictissue.The
correspondingvaluesforapoBandapoEwere4.3and6.1
micrograms/gwetweightvs.5.0and9.1micrograms/gwet
weight.Afterdensitygradientcentrifugationoftheaortictissue
extracts,itwasshownthatthemajorpartsofapo(a)andapoB
detectedinthelesionfreevesselwallwerepresentasLp(a)like
particles.InthediseasedtissueLp(a)waspartlydissociatedinto
LDLlikeparticlesandfreeapo(a).Withthisstudyweconfirm
thatLp(a)accumulatesinthearterialwall,preferentiallyin
diseasedtissue,andthatLp(a)particles,depositedin
atheroscleroticplaques,arepartlydegradedtoLDLlike
particlesandfreeapo(a)inatheroscleroticplaques.

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http://www.jlr.org/cgi/reprint/32/2/317
JournalofLipidResearchVolume32,1991317
Quantificationofapo[a]andapoBinhumanatherosclerotic
lesionsbyJudithM.Pepinetal.
ndation,Cleveland,OH44195

LysineBindingSiteinLipoprotein(a)LBSknockoutstudy
http://www.pubmedcentral.nih.gov/articlerender.fcgi?
rendertype=abstract&artid=508329
JClinInvest.1997September15100(6):14931500.

Lipoprotein(a)vascularaccumulationinmice.Invivoanalysisof
theroleoflysinebindingsitesusingrecombinantadenovirusby
SDHughesetal.

Althoughthemechanismbywhichlipoprotein(a)[Lp(a)]
contributestovasculardiseaseremainsunclear,consequences
ofitsbindingtothevesselsurfacearecommonlycitedin
postulatedatherogenicpathways.Becauseofthepresenceof
plasminogenlikelysinebindingsites(LBS)inapo(a),fibrin
bindinghasbeenproposedtoplayanimportantroleinLp(a)'s
vascularaccumulation.Indeed,LBSareknowntofacilitateLp(a)
fibrinbindinginvitro.Toexaminetheimportanceofapo(a)LBS
inLp(a)vascularaccumulationinvivo,wegeneratedthree
differentapo(a)cDNAs:(a)miniapo(a),basedonwildtype
humanapo(a)(b)miniapo(a)containinganaturallyoccurring
LBSdefectassociatedwithapointmutationinkringle410and
(c)humanrhesusmonkeychimericminiapo(a),whichcontains
thesameLBSdefectinthecontextofseveraladditional
changes.Recombinantadenovirusvectorswereconstructedwith
thevariousapo(a)cDNAsandinjectedintohumanapoB
transgenicmice.Attheviraldosageusedintheseexperiments,
allthreeformsofapo(a)werefoundexclusivelywithinthe
lipoproteinfractions,andpeakLp(a)plasmalevelswerenearly
identical(approximately45mg/dl).InvitroanalysisofLp(a)
isolatedfromthevariousgroupsofmiceconfirmedthatputative
LBSdefectiveapo(a)yieldedLp(a)unabletobindlysine
Sepharose.QuantitationofinvivoLp(a)vascularaccumulation
inmicetreatedwiththevariousadenovirusvectorsrevealed
significantlylessaccumulationofbothtypesofLBSdefective
Lp(a),relativetowildtypeLp(a).Theseresultsindicatea
correlationbetweenlysinebindingpropertiesofLp(a)and
vascularaccumulation,supportingthepostulatedroleof
apo(a)LBSinthispotentiallyatherogeniccharacteristicofLp(a).

Collagen,Lysine,Lipoprotein(a)

http://www
personal.umich.edu/~egatenby/collagen%20eyre%20chapter.pdf
collagenandlysinecrosslinkingimages

Basementmembranecollagensareancient(>500millionyears
[50,51]),havingevolvedinprimitivemetazoaasearlyor
earlierthanthefibrilformingcollagens.Hydra,asimple
organismformedfromtwocelllayersthatsecreteandsandwich
themesoglea,anextracellularlayer,hasbeenshowntoexpress
genesforabasementmembranecollagenthatishomologousin
sequencetovertebratetypeIVcollagenandforafibrilforming
collagen.

Collagenlysylhydroxylaseisanascorbatedependentenzyme

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thathydroxylateslysylresiduesoncollagenneopeptides.

RoleofVitaminCinHydroxylationofLysineandProline
CrosslinkinginCollagenFibers

http://en.wikipedia.org/wiki/Ascorbate
AscorbateWIkipedia,FunctionInhumans,
vitaminCisahighlyeffectiveantioxidant,actingtolessen
oxidativestressasubstrateforascorbateperoxidase[4]and
anenzymecofactorforthebiosynthesisofmanyimportant
biochemicals.

VitaminCactsasanelectrondonorforeightdifferentenzymes:
[9]

Threeparticipateincollagenhydroxylation.[10][11][12]
Thesereactionsaddhydroxylgroupstotheaminoacidsproline
orlysineinthecollagenmolecule(viaprolylhydroxylaseand
lysylhydroxylase),therebyallowingthecollagenmoleculeto
assumeitstriplehelixstructureandmakingvitaminC
essentialtothedevelopmentandmaintenanceofscartissue,
bloodvessels,andcartilage.[13]

Twoarenecessaryforsynthesisofcarnitine.[14][15]Carnitine
isessentialforthetransportoffattyacidsintomitochondriafor
ATPgeneration.

Theremainingthreehavethefollowingfunctions:dopaminebeta
hydroxylaseparticipatesinthebiosynthesisofnorepinephrine
fromdopamine.[16][17]anotherenzymeaddsamidegroupsto
peptidehormones,greatlyincreasingtheirstability.[18][19]one
modulatestyrosinemetabolism.[20][21]

Biologicaltissuesthataccumulateover100timesthelevelin
bloodplasmaofvitaminCaretheadrenalglands,pituitary,
thymus,corpusluteum,andretina.[22]Thosewith10to50
timestheconcentrationpresentinbloodplasmaincludethe
brain,spleen,lung,testicle,lymphnodes,liver,thyroid,small
intestinalmucosa,leukocytes,pancreas,kidneyandsalivary
glands.

GLOGulanoLactoneOxidaseGeneticDefect

http://www.ncbi.nlm.nih.gov/pubmed/10572964
BiochimBiophysActa.1999Oct181472(12):40811.

Randomnucleotidesubstitutionsinprimatenonfunctionalgene
forLgulonogammalactoneoxidase,themissingenzymeinL
ascorbicacidbiosynthesis.OhtaY,NishikimiM.

HumansandotherprimateshavenofunctionalgeneforL
gulonogammalactoneoxidasethatcatalyzesthelaststep
ofLascorbicacidbiosynthesis.The164nucleotidesequence
ofexonXofthegenewascomparedamonghuman,
chimpanzee,orangutan,andmacaque,anditwasfoundthat
nucleotidesubstitutionshadoccurredatrandomthroughoutthe
sequencewithasinglenucleotidedeletion,indicatingthatthe
primateLgulonogammalactoneoxidasegenesareatypical
exampleofpseudogene.

http://www.jbc.org/cgi/content/abstract/269/18/13685
J.Biol.Chem.,Vol.269,Issue18,1368513688,05,1994
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Cloningandchromosomalmappingofthehumannonfunctional
geneforLgulonogammalactoneoxidase,theenzymeforL
ascorbicacidbiosynthesismissinginman.byMNishikimietal.

Manisamongtheexceptionalhigheranimalsthatareunableto
synthesizeLascorbicacidbecauseoftheirdeficiencyinL
gulonogammalactoneoxidase,theenzymecatalyzingthe
terminalstepinLascorbicacidbiosynthesis.

GeneticallyEngineeredVitaminCDeficientMouseModel
showsdisruptionofCollagenFibersinAortaandCarotid
Bifurcation.

http://www.pnas.org/content/97/2/841.full
PNASJanuary18,2000vol.97no.2841846
Aorticwalldamageinmiceunabletosynthesizeascorbicacidby
NobuyoMaedaetal.

Byinactivatingthegeneforlgulono?lactoneoxidase,akey
enzymeinascorbicacidsynthesis,wehavegeneratedmicethat,
likehumans,dependondietaryvitaminC.Regularchow,
containingabout110mg/kgofvitaminC,isunabletosupport
thegrowthofthemutantmice,whichrequirelascorbicacid
supplementedintheirdrinkingwater(330mg/liter).Upon
withdrawalofsupplementation,plasmaandtissueascorbicacid
levelsdecreasedto1015%ofnormalwithin2weeks,andafter
5weeksthemutantsbecameanemic,begantoloseweight,and
die.Plasmatotalantioxidativecapacitieswereapproximately
37%normalinhomozygotesafterfeedingtheunsupplemented
dietfor35weeks.Asplasmaascorbicaciddecreased,small,
butsignificant,increasesintotalcholesterolanddecreasesin
highdensitylipoproteincholesterolwereobserved.

ThemoststrikingeffectsofthemarginaldietaryvitaminCwere
alterationsinthewallofaorta,evidencedbythedisruption
ofelasticlaminae,smoothmusclecellproliferation,and
focalendothelialdesquamationoftheluminalsurface.Thus,
marginalvitaminCdeficiencyaffectsthevascularintegrityof
miceunabletosynthesizeascorbicacid,withpotentially
profoundeffectsonthepathogenesisofvasculardiseases.
BreedingthevitaminCdependentmicewithmicecarrying
definedgeneticmutationswillprovidenumerousopportunities
forsystematicstudiesoftheroleofantioxidantsinhealthand
disease.

RuptureofElasticLamina,SmoothMuscleCellProliferation,
andInjuryoftheLuminalSurfaceintheThoracicAorta.

Ascorbicacidisanimportantcofactorforthehydroxylationof
prolineandlysinenecessaryforthecrosslinkingofcollagenand
elastin,importantstructuralcomponentsofvesselwall(18,19).
InspectionunderbothlightmicroscopyandTEMofcrosssections
ofthethoracicaortafromanimalswithlowlevelsofplasmaand
tissueascorbicacidrevealedmarkedalterationsinthe
patternandintegrityoftheelasticlaminae.Prominentbreaks
andfragmentationoftheelasticawerelocatedinboththe
superficialanddeepmedia(Fig.5.Theendothelialcells
overlyingtheareasofinternalelasticlamiadisruptionwere
attenuatedasaresultoftheaccumulationofbasement
membranematerial,collagen/elastictissue,andaggregatesof
smoothmusclecells.Somesmoothmusclecellshadanaltered

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morphology,weredevoidofcytoplasmicfilaments,and
containedmyelinfiguresindicativeofcellulardegeneration(not
shown).Smallclustersofsmoothmusclecells,rangingfroma
fewtoadiffusecollectionsofseveralcells,werepresentwithin
thesubintimabelowthebasementmembraneandabovethe
superficialelasticlamina(Fig.5C).Mostofthesmoothmuscle
cellspresentwithintheintimaweremildlyactivatedasjudged
byaslightincreaseintheirroughendoplasmicreticulum.Small
collectionsofelasticfiberswerelocatedbetweensmoothmuscle
cellsbothintheintimaandinthedeepmedia,suggestingthat
reorganizationoftheelasticlaminaisadynamicprocessin
thesemice.

Themoststrikingpathologicalfindinginourcurrentstudyisthe
presenceofabnormalitiesintheaorticwallsofthevitaminC
deficientmice.Thesimplestexplanationofthispathologyis
thatthefragmentationofelasticlaminaiscausedbydefects
inthecrosslinkingofcollagenandelastinbecauseofthe
needforvitaminCtogeneratehydroxylysineand
hydroxyproline.

Supportforthisexplanationisprovidedbytheobservationsof
similarfragmentationofelasticfibersinmicewiththeBlotchy
alleleattheXlinkedMottledlocus(33).TheMottledlocuscodes
foracoppertransportingATPase,whichisnecessaryforlysyl
oxidaseactivitytocrosslinkcollagenandelastin(34).

Similaraorticwallchangesalsohavebeenseeninyoungrats
treatedwithaminopropionitrile,aninhibitoroflysyloxidase
(35,36).However,althoughtheaorticwallabnormalitiesin
Blotchymiceprogresstogrossdilatation,aneurysm,andaortic
rupture,theabnormalitiesseeninourvitaminCdeficientmice
appeartobemoresubtle.

ThelesionsintheaorticarchofvitaminCdeficientmiceare
longitudinalandmostfrequentlyareseennearthetakeoffof
thecarotidwherethebloodflowrelatedshearstressis
high.Wedidnotfindplatelets,fibrin,orotherbloodcellsinthe
areaswithendothelialalteration.Butthereisamarkedincrease
intheextravasationofmacromoleculesintotheaorticwallin
theseareasasevidencedbythedistributionofEvansblueinthe
vitaminCdeficientmice.

Inconclusion,wehavegeneratedmicelackinglgulono?
lactoneoxidase,akeyenzymeforascorbicacidsynthesis.The
mutantmice,likehumans,entirelydependondietaryvitaminC,
andtheyshowchangesindicatingthattheintegrityoftheir
vasculatureiscompromised.Whencombinedwiththebatteries
ofmutantmicegeneratedinrecentyears,theGulo/mutant
mouseshouldprovideuniqueopportunitiesforexploringthe
interactionsbetweengeneticdeterminationandenvironmental
factors,suchasoxidativestress,andtheeffectsonthese
interactionsofdifferentlevelsofvitaminCinthediet.

CollagenandAscorbateaReview

http://www.ncbi.nlm.nih.gov/pubmed/3008449
YaleJBiolMed.1985NovDec58(6):5539.RelatedArticles,
Links
Regulationofcollagenbiosynthesisbyascorbicacid:areview.
byPinnellSR.

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Lascorbicacidisanessentialcofactorforlysylhydroxylaseand
prolylhydroxylase,enzymesessentialforcollagenbiosynthesis.
Inaddition,Lascorbicacidpreferentiallystimulatescollagen
synthesisinamannerwhichappearsunrelatedtotheeffectof
Lascorbicacidonhydroxylationreactions.Thisreactionis
stereospecificandunrelatedtointracellulardegradationof
collagen.Theeffectapparentlyoccursatatranscriptionalor
translationallevel,sinceLascorbicacidpreferentiallystimulates
collagenspecificmRNA.Inaddition,itstimulateslysyl
hydroxylaseactivitybutinhibitsprolylhydroxylaseactivityin
humanskinfibroblastsinculture.

LysineBindingSitesonLiporotein(a)Fivefoldreductionin
atherosclerosiswhenLysineBindingSitesEliminatedwith
Mutation.

http://www.jci.org/articles/view/119565
PublishedinVolume100,Issue3J.Clin.Invest.100(3):558564
(1997).

Modificationofapolipoprotein(a)lysinebindingsitereduces
atherosclerosisintransgenicmice.NWBoonmarketal.

Lipoprotein(a)contributestothedevelopmentofatherosclerosis
throughthebindingofitsplasminogenlikeapolipoprotein(a)
componenttofibrinandotherplasminogensubstrates.
Apolipoprotein(a)containsamajorlysinebindingsiteinoneof
itskringledomains.Destructionofthissitebymutagenesis
greatlyreducesthebindingofapolipoprotein(a)tolysineand
fibrin.Transgenicmiceexpressingthismutantformof
apolipoprotein(a)aswellasmiceexpressingwildtype
apolipoprotein(a)havebeencreatedinaninbredmousestrain.
Thewildtypeapolipoprotein(a)transgenicmicehavea
fivefoldincreaseinthedevelopmentoflipidlesions,aswell
asalargeincreaseinthefocaldepositionof
apolipoprotein(a)intheaorta,comparedwiththelysine
bindingsitemutantstrainandtonontransgeniclittermates.
Theresultsdemonstratethekeyroleofthislysinebindingsitein
thepathogenicactivityofapolipoprotein(a)inamurinemodel
system.

http://www.knockoutscience.com/showabstract.php?
pmid=9239402
JClinInvest(1997)100:55864.Modificationof
apolipoprotein(a)lysinebindingsitereducesatherosclerosisin
transgenicmicebyNWBoonmarketal.(additionallinktosame
article)

CollagenTripleHelix

http://www.ohiolink.edu/etd/send
pdf.cgi/Person%20Margaret%20M.pdf?acc_num=ysu1196173663

Collagenconsistsofthreepolypeptidechains,termedalpha
chains,whicharearrangedinaparalleltriplehelix.Thereare
twoa1chainsandonea2chain(Goodsell,2003).Althougheach
chainhasahelicalarrangement,theyonlyhavethis
conformationwhenassociatedwiththetwootheralphachains
andisthenreferredtoaspossessingasuperhelicalconfiguration
(Goodsell,2003).Thissuperhelicalarrangement,consistingof
primarilyCollagenIandIIIfibersformanelaboratenetwork
betweennearlyallcellsandconstitutesthemajorstructural
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elementinbone,tendon,cartilageandteeth.

http://www.cqs.com/cvd.htm
ASimplePreventiveandTherapyforCardiovascularDisease
(CVD)JonathanCampbell,HealthConsultantNaturalTherapies
forChronicIllness&HealthMaintenance

http://www.lef.org/VitaminsSupplements/Item02117/LProline
LLysine.html
LProline,LLysine275mg/275mg,120tabletsItemCatalog
Number:2117$14.16

RETINALPHOTOSCONFIRMVITAMINCPILLSCANREVERSE
ARTERYDISEASE

http://www.hullcontactlensclinic.co.uk/cardior.htm
CardioRetinometryDr.SydneyJBush.PhD.DOpt.(IOSc.
London)Opticnerveheads(Disc)BeforeVitaminC2002,
AfterVitaminC2004,Unretouchedimagesshowingretinal
arteriesopeningandveinscarryingmoreblood..Thewhiteline
downthearteriesislighterandthinnershowinglesscholesterol
inthe2004image.whichalsoshows'lost'vesselsreappearing.
Thisiswhatisnowsaidtohappeninheartmuscleasnew
anastomosesopenwhenarteriesbecomeblocked.

http://www.bmj.com/cgi/eletters/329/7457/79#68348
CardioRetinometry23July2004SydneyJBush,Optometrist.
CardioRetinometrist2022BrookSt.HULLHU28LA

WongTYetal.Prospectivecohortstudyofretinalvessel
diametersandriskofhypertension.BMJ2004329:79(10th
July)pub2ndJne.
BushSJ.CardioretinometryRapidResponseBMJ23rdJuly
BushSJ."Emperor'sNewClothes?"RapidResponse25thNov.
2004
BushSJ.'Optician'Letters9thMay2003andlaterin2004.

GuineaPigandGLOdefect

http://en.wikipedia.org/wiki/Guinea_pig
Likehumans,butunlikemostothermammals,guineapigs
cannotsynthesizetheirownvitaminCandmustobtainthisvital
nutrientfromfood.Ifguineapigsdonotingestenoughvitamin
C,theycansufferfrompotentiallyfatalscurvy.

http://www.ncbi.nlm.nih.gov/pubmed/14703305
InaiYetal.(2003),TheWholeStructureoftheHumanNon
FunctionalLGulunogammaLactoneOxidaseGenetheGene
ResponsibleforScurvyandtheEvolutionofRepetitive
SequencesThereon,JNutrSciVitaminology49:315319.

ThewholestructureofthehumannonfunctionalLgulono
gammalactoneoxidasegenethegeneresponsibleforscurvy
andtheevolutionofrepetitivesequencesthereon.InaiY,Ohta
Y,NishikimiM.

LGulonogammalactoneoxidase(GULO),whichcatalyzesthe
laststepofascorbicacidbiosynthesis,ismissinginhumans.The
wholestructureofthehumangenehomologueforthisenzyme
wasdisclosedbyacomputerassistedsearch.Onlyfiveexons,
ascomparedto12exonsconstitutingthefunctionalratGULO
gene,remaininthehumangenome.Acomparisonofthese
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2/15/2014 Heart Disease, Ascorbate, Lysine and Linus Pauling by Jeffrey Dach MD

exonswiththoseoftheirfunctionalcounterpartsinratshowed
thattherearetwosinglenucleotidedeletions,onetriple
nucleotidedeletion,andonesinglenucleotideinsertioninthe
humansequence.Whencomparedintermsofcodons,the
humansequencehasadeletionofasingleaminoacid,twostop
codons,andtwoaberrantcodonsmissingonenucleotidebesides
manyaminoacidsubstitutions.Acomparisonoftheremaining
humanexonsequenceswiththecorrespondingsequencesofthe
guineapignonfunctionalGULOgenerevealedthatthesame
substitutionsfromratstobothspeciesoccurredatalarge
numberofnucleotidepositions.Fromanalysesofthemolecular
evolutionofAlusequencesinthehumanGULOgenehomologue,
itisthoughtthattwoAlusequenceswereinsertedinthevicinity
ofapresumedpositionoflostexon11duringthesameperiod
asGULOlostitsfunction.ItispredictedthatsixLINE1
sequenceslocatedinandnearthegenehomologuewere
insertednotduringthatperiod.

http://www.jbc.org/cgi/content/abstract/267/30/21967
J.Biol.Chem.,Vol.267,Issue30,2196721972,Oct,1992
GuineapigspossessahighlymutatedgeneforLgulonogamma
lactoneoxidase,thekeyenzymeforLascorbicacidbiosynthesis
missinginthisspecies
MNishikimi,TKawaiandKYagi

HeartDiseaseinUSdeclinedafter1970publicationofLinus
PaulingBookonVitaminC,VitaminCandtheCommonCold.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4830a1.htm
MMWRWeeklyDeclineinCVDDeathRates,Achievementsin
PublicHealth,19001999:DeclineinDeathsfromHeartDisease
andStrokeUnitedStates,19001999

http://www.vitamincfoundation.org/forum/index.php
VitmainCFoundationMessageBoard

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http://jeffreydach.com/2008/11/27/heartdiseaseascorbatelysineandlinuspauling
byjeffreydachmd.aspx

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