RiskFactorsforPremature

AtheroscleroticHeartDisease

Dyslipidemia(highLDL,lowHDL)
Diabetes
Hypertension
Obesity
Sedentarylifestyle
Obesity
Smoking
Malesex
Hyperhomocysteinemia

Homocysteine
Nonproteinforming,sulfurcontainingamino
acid
Formedexclusivelybydemethylationof
methionine
Eliminatedthroughoneoftwovitamindependent
pathways,inadditiontoanalternatevitamin
independentpathwayinliver

Hyperhomocysteinemia
Independentriskfactorforatheroscleroticandthromboembolicdisease
A5Mincreaseinserumlevelconfersa80%increasedrisktowomenand
a60%increasedrisktomenforatheroscleroticvasculardisease
Inpatientswithcoronaryarterydisease,serumhomocysteinelevelsincrease
withthenumberofstenosedcoronaryvessels
Hyperhomocysteinemiamayreflect:
Geneticdefects
Folate(mostcommon),pyridoxine(vitaminB 6),orcobalamin(vitamin
B12)deficiencies
Renalfailure
Serumlevelsofhomocysteinemaybeloweredbysupplementationwith
folate,vitaminB6,andvitaminB12

HomocysteineMetabolismandVascularDysfunction

QuickTime and a
GIF decompressor
are needed to see this picture.

HajjarKA,JClinInvest107:663,2001

Case#1
45yearoldAfricanAmericanmale
Presentswithacuteonsetofchestpain
Undergoescardiaccatheterizationandisfoundtohave
blockagein4coronaryarteriesandisscheduledfor
bypasssurgery
Pastmedicalhistoryisunremarkable
Nocurrentmedications

Case#1
Activity
Worksasabankteller.Verylittlevigorousphysical
activity.Walksfor30minthreetimesperweek.

Social
Divorced,livesalone
Smokes1/2packcigarettes/day
Deniesalcohol/substanceabuse

Case#1
PhysicalExam

BP138/90mmHgrightarmsitting(normal140/90)
Ht180cm
Wt77kg
BMI(wt/ht2)23.8(normal<25)
Restofphysicalexamnormal

62yo
hypertension
stroke

54yo
hypertension
MI

49yo
stroke

Case#1

69yo
obese
CH204
TG204
HDL42

70yo
hypertension
CH236
TG120
HDL42

40yo
healthy
CH?

72yo
hypertension

42yo
45yo
obese
borderline
CH210 hypertension
TG201
CAD
HDL38
CH230
TG120
HDL40
hyperhomocysteinemia

69yo
cancer

Case#1
Diet

Nobreakfast
Takeslunch:meatsandwichandfruit
Dinner:eatsalone,usuallyfastfoodorfrozendinner
Analysisof3dayfooddiary
Average2230kcal/day
Dietcomposition(%oftotalcalories)
Protein
20%
Fat
38%
Carbohydrate

Cholesterol:
Folicacid:

(desirable<30%)
42%

340mg/day
212mcg/day

(desirable<300mg/day)
(desirable>240mcg/day)

Case#1
CardiovascularRiskProfile
Lipids

Totalcholesterol
Triglycerides
HDLcholesterol
LDLcholesterol

Homocysteine

230mg/dL
120mg/dL
40mg/dL
166mg/dL

(normal<200mg/dL)
(normal<200mg/dL)
(normal>35mg/dL)
(normal<130mg/dL)

16mol/L (normal<12g/L

DietarySourcesofFolateand
VitaminsB6andB12
FoodsRichinFolate
Leafyvegetables,liver,wholegraincereals,legumes,
andsomefruits,suchasoranges

FoodsRichinVitaminB6
Fish,poultry,meat,andwheat

FoodsRichinVitaminB12
Animalproducts

Case#2

4hroldinfantboybornto25yoG1P1Caucasian
PregnancynotableonlyforUTIat5mths
Termbydates
Uncomplicatedvaginaldelivery
Familyhistorynegativeforbirthdefects

FolicAcidandBirthDefects

About2,500neuraltubedefectsperyearinUS
Occurat2628dayspostconception
95%arespontaneouswithnofamilyhistory
1991UKstudyshowed71%riskreduction
inrecurrences(4mgdose)
In1999(NovNEJM)85%reductioninriskfor
primaryprevention(0.4mgdose)
Lifetimecostsestimatedtobe$330.000(1998)

Case#3

38yearoldfemalepediatrician
Normalfastfooddiet,socialdrinker
RoutineOb/Gynvisit
Massnotedinleftbreast
Biopsyc/wbreastcancer(BRCAnegative)

FolateandCancer
Increasedriskforbreastcancerinwomenwho
consume15g/dayofethanoland<300mcg
folate/day(RR=1.32)
Reducedriskforcoloncancerinwomenwho
consumedailyfolatesuplementsfor15yearsor
more(RR=0.25)
Reducedriskforcoloncancerinmenwho
consumedsupplementsfor10years(RR=0.75)

Mechanismsofbenefit
Cardiovasculardisease
thrombogenicfactors,decreasednitricoxide,
increasedinflammation

Neuraltubedefects
????

Cancer
HypomethylationofDNA,lowCH2THFleadingto
uracilforthymidine