4) Risk Factors

Definition ofDefinition ofHypercholesterolemiaHypercholesterolemia

Total cholesterol by age and sexTotal cholesterol by age and sexAverage distribution of plasma total cholesterol (means and selected percentiles)

Pla

sm

a to

tal c

ho

les

tero

l (m

g/d

L)

Age (years) Age (years)

320

280

240

200

160

120

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

White males White females

90th

Mean

50th

10th

90th

Mean

50th

10th

Risk Factors:Risk Factors: Serum CholesterolSerum Cholesterol(carried by LDL particles)(carried by LDL particles)

How do we know who is at risk?

ALSO Implicated:Family History

Smoking why?

Hypertension why?

Death rate per 1000 men

Percentilemmol/l

18

161412

10

86

4

2

05 15 25 35 45 55 65 75 85 954.1 4.8 5.3 5.8 6.5 7.8

Top 15% cholesterol = 43/1000

N = 100/1000 50%

Serum Cholesterol in N = 360,000 men over 6 years

CHD Risk FactorsCHD Risk Factors

0

5

10

15

20

25

30

35

40

4.5 5 5.5 6 6.5 7 7.5 8 8.5 9

Low HDLCholesterol

Smoking

Hyperglycemia

Hypertension

No other riskfactors

Plasma Cholesterol (mmol/l)

%

Note – those countries with risk also have serum cholesterol dietary fat & cholesterol intake

FinlandUSA

New ZeelandAustralia

UKIreland

CanadaNorway

Belgium-Lux.Yugoslavia

DenmarkNetherlands

West GermanyAustria

SwedenItaly

SwitzerlandPortugal

SpainFranceGreeceJapan

IsochemicHeart disease

Other possiblecoronary deaths

0 100 200 300 400 500 600Mortality rates per 100,000

Mortality rates due to coronary heart diseaseMortality rates due to coronary heart disease

2

1

0.5

100 200 300

Relative Risk of Death From CHD by blood cholesterolRelative Risk of Death From CHD by blood cholesterol (mg/dl)(mg/dl) 6 prospective studies6 prospective studies

100 200 300 100 200 300

2

1

0.5

Finland347 CHD

MRFIT (US)3,243 CHD

Whitehall (UK)455 CHD

Framingham (US)216 CHD

Israel615 CHD

Hawaii242 CHD

Ideal, Feasible And Existing Total Ideal, Feasible And Existing Total Serum Cholesterol Levels in AdultsSerum Cholesterol Levels in Adults

Ideal Mean 4.3 mMl

2.7 4.0 5.4 6.7 8.1

Feasible Mean 5.1 mM

Present Mean 5.7 mM

Total Serum Cholesterol mmol/L

CANADIAN HEART HEALTH SURVEYCANADIAN HEART HEALTH SURVEYPREVALENCE OF TOTAL CHOLESTEROL LEVELSPREVALENCE OF TOTAL CHOLESTEROL LEVELS

0

10

20

30

40

50

60

70

<5.2mmol/l

5.2-6.1mmol/l

>6.2mmol/l

MENWOMENTOTAL

%

52%57% 55%

30% 27%29%

18%16%17%

Classification Based on Total Blood CholesterolClassification Based on Total Blood Cholesterol mg/dl (mmol/L=mM)

Men & Women

Age

Desirable Moderate Risk

High Risk

18-30 <180

(4.6)

180-220

(4.6-5.7)

220+

(5.7)

30+ <200

(5.2)

200-240

(5.2-6.2)

240+

(6.2)

What is the risk of coronary heart disease in the next 6 years What is the risk of coronary heart disease in the next 6 years in these individuals?in these individuals? [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, 90% ]

« WORST » SYSTOLICBLOOD

AGE SEX TOTAL HDL PRESSURE DIABETES SMOKING

1. 55 M 7.2 0.8 150 NO YES

2. 55 F 7.2 0.8 150 NO YES

3. 55 M 7.2 0.8 150 NO NO

4. 55 M 5.2 1.1 150 NO YES

5. 55 M 5.2 1.1 120 NO NO

6. 55 M 10.0 0.8 170 YES YES

7. 25 M 10.0 0.8 170 YES YES

8. 55 F 10.0 0.8 170 YES YES

9. 25 M 7.2 0.8 150 NO YES


« LEAST LIKELY » SYSTOLICBLOOD


1. 55 M 7.2 0.8 150 NO YES

2. 55 F 7.2 0.8 150 NO YES

3. 55 M 7.2 0.8 150 NO NO

4. 55 M 5.2 1.1 150 NO YES

5. 55 M 5.2 1.1 120 NO NO

6. 55 M 10.0 0.8 170 YES YES

7. 25 M 10.0 0.8 170 YES YES

8. 55 F 10.0 0.8 170 YES YES

9. 25 M 7.2 0.8 150 NO YES


SYSTOLICBLOOD


1. 55 M 7.2 0.8 150 NO YES

2. 55 F 7.2 0.8 150 NO YES

3. 55 M 7.2 0.8 150 NO NO

4. 55 M 5.2 1.1 150 NO YES

5. 55 M 5.2 1.1 120 NO NO

6. 55 M 10.0 0.8 170 YES YES

7. 25 M 10.0 0.8 170 YES YES

8. 55 F 10.0 0.8 170 YES YES

9. 25 M 7.2 0.8 150 NO YES

26%

35%


SYSTOLICBLOOD


1. 55 M 7.2 0.8 150 NO YES

2. 55 F 7.2 0.8 150 NO YES

3. 55 M 7.2 0.8 150 NO NO

4. 55 M 5.2 1.1 150 NO YES

5. 55 M 5.2 1.1 120 NO NO

6. 55 M 10.0 0.8 170 YES YES

7. 25 M 10.0 0.8 170 YES YES

8. 55 F 10.0 0.8 170 YES YES

9. 25 M 7.2 0.8 150 NO YES

10%

15%

10%

5%

10%

LDLC = TC – HDL – (TG/2)

< 3.5 nM < 5.2 mM > 1.5 – 2.0 < 2.0 mM

ppt

Chylo LDL VLDLVLDL VLDLLDLHDL

95% Fasting NOApo B Chylos no apoB very littleParticles apoB in VLDL80-120 mg/dL

Calculation of LDL CholesterolCalculation of LDL Cholesterol

Calculation of Calculation of LDL CholesterolLDL Cholesterol

LDL C = TC – HDL C – (TG/2)

3.0 = 6.0 – 1.0 – (4.0/2)calculated(not direct)

apoB = < 120(direct)

LDL cholesterol and apoB LDL cholesterol and apoB distribution in CAD patientsdistribution in CAD patients

Threshold Effect of LDL CholesterolThreshold Effect of LDL CholesterolF

req

uen

cy

50LDL Cholesterol

56.5% of CAD had LDL C > 50th percentile, therefore no threshold for LDL C.

N

CAD

Threshold for LDL Particle NumberThreshold for LDL Particle Number

88% of CAD had LDL apoB > 50th percentile NA population.

Fre

qu

ency

50LDL apoB

N

CAD

Lipoprotein ScreeningLipoprotein Screening

Canadian Consensus Conference on Cholesterol• « As resources permit »• A priority for those with risk factors and established CHD

U.S. National Cholesterol Education Program• At least every five years for all adults aged 20 and over• More often as follow-up for those with elevated serum cholesterol

Canadian Cardiovascular Society• Within 24 hours of myocardial infraction, repeated 6-12 weeks after hospital discharge

CCCC recommendations: CCCC recommendations: Screening prioritiesScreening priorities

Screening for priority groups• Priority screening for individuals with:

•Coronary heart disease•Family history of hyperlipidemia or CHD at an early age•Hypertension•Diabetes•Renal failure•Abdominal obesity

Screening for all Canadians• As part of a periodic health examination

Interpretation Interpretation of Lipid Valuesof Lipid Values

Men and WomenAge 18-29

DRUGS?

DIETARY MODIFICATION

TG>200

HDL<35

LDL>115

39%

19%

180(4.6)

220(5.7)

Other risk factors

mg/dl(mM/L)

Other risk factors

Coronary Heart DiseaseCoronary Heart DiseaseMain Risk FactorsMain Risk Factors

Non-Modifiable Modifiable

Family History of CHD Dyslipidemia

Male Sex Hypertension

Age Diabetes

Smoking

Obesity

Normal Endothelial FunctionNormal Endothelial Function

EDRF

PC

EDRF

PC EDRF

PC

EDRF

EDRF EDRF

B

B

B

B

B

B

In One Door…In One Door…And Out the OtherAnd Out the Other

Tg Tg Tg TgTg Tg Tg Tg Tg Tg Tg Tg Tg Tg

CE CECE CE CE

B

CE CE CE CETg

B

VLDL

LDL

B

B

B

B

B

The Pathogenic PowerThe Pathogenic PowerOf Particle NumberOf Particle Number

B

BB

BB

B

B

B

B

B

B

B

B

B

BB

B

B

B

B

B

B

B

Oxidation of LDL ParticlesOxidation of LDL Particleswithin the vessel wallwithin the vessel wall

B

B

Hypertension Hypertension → Subintimal Thickening→ Subintimal Thickening

400

350

300

250

200

150

100

50

0

0 2 4 6 8 10

mo

l F

ibri

no

gen

X 1

012/c

m2

Perfusion Time (MIN)

n=17 n=20 n=22

*

*

*

High Shear,Non-ParallelSreamlines

Low Shear,ParallelSreamlines

Effect of Shear Rate and Flow Effect of Shear Rate and Flow Condition on Fibrinogen DepositionCondition on Fibrinogen Deposition

HyperapoB HyperapoB →→HyperthrombogenicityHyperthrombogenicity

↑ PAI-1↑ Fibrinogen↑ Factor VII↑ Factor VII c

+← ↑ FFA ← ↑

CE

B

TgCETg

B

CETg

B

CETg

B

CETg

B

CETg

B

CETg

B

B

B

B

B

B B B

Thicker ithThlower

CAD Mortality in NIDDMCAD Mortality in NIDDM

60

50

40

30

20

10

0

MortalityRate per

1000

0-3 4-7 8-11 13-15 18-19 20-23 0-3 4-7 8-11 13-15 18-19 20-23

Duration of Follow-up (years)

Men Women

DiabetesDiabetes

No Diabetes

No Diabetes

Can Glucose Glycate Glycosaminoglycans

which then Grab apoB?

B

B

B

B

BB B

B

Relative odds of developing IHD over a 5-yr follow-up Relative odds of developing IHD over a 5-yr follow-up period in a sample of 91 IHD cases and 91 matched controlsperiod in a sample of 91 IHD cases and 91 matched controls

The Quebec Cardiovascular Study

0

3

6

9

12

15

<72 72< <91 >91

Relative Odds

>50th<50th

Total HDL-C

Fasting Insulin (pmol/l)

1.0

3.8

4.4

8.7

6.3

14.1

RO adjusted for medication, systolic BP, family history of IHD

Why is smoking atherogenic?Why is smoking atherogenic?

Tg

B

CE

Tg

B

CE

Tg

B

CE

A Dysfunctional ArteryA Dysfunctional Artery↓EDRF

↑TF

↓t-PA ↑PAI-1 ↓EDRF ↓PC ↑TF

Tg

B

CE

Tg

B

CE

Tg

B

CE

Risk Factor – Obesity!Risk Factor – Obesity!

Although excess obesity is a risk factor, so is moderate obesity especially abdominal android obesity:

-“beer belly” -Men diabetes hypertension

BMI age men

CORONARY MORBIDITY AND MORTALITYCORONARY MORBIDITY AND MORTALITYASSOCIATED WITH RELATIVE WEIGHTASSOCIATED WITH RELATIVE WEIGHT

Metropolitan relative weight

Ag

e-ad

just

ed a

nn

ual

rat

e p

er 1

,000

35 -30 -25 -20 -15 -10 -

5 -

54-104 105-114 115-124 125-134 135-272

Men aged65-94 years(p<0.01)

Women aged65-94 years(p<0.05)

Men aged35-64 years(p<0.001)

Women aged35-64 years(p<0.001)

Alcohol

Obesity

DietSaturated Fat Salt

GeneticSusceptibility

Kidney Damage

Diabetes

HighBloodPressure

OC’s (female)

Smoking

Psycho-SocialFactorsFamily

History of CVD

DietaryCholesterol

PhysicalActivity

BloodLipids

AgeSex (male)

Lower S/E

CVDIHD

Stroke

RISK FACTORS FOR CORONARY ARTERY DISEASERISK FACTORS FOR CORONARY ARTERY DISEASE

Modifiable•Smoking (> 10 cigarettes / day)•Obesity, especially Android Obesity•Hypercholesterolemia and/or Low HDL cholesterol (< 1 mM) *: A high HDL cholesterol (>1.6 mM) is a negative risk factor (i.e. protective)•Hypertension (> 140/90 or treated)•Diabetes Mellitus

•*** MODIFIABLE BY DIETMODIFIABLE BY DIET

•Non Modifiable•Age (>45 in men, >55 in women)•Family history of premature coronary artery disease: Myocardial infarct or sudden death in a 1st degree parent < 55 years of age.•Gender (males are at increased risk

Documents

4) Risk Factors