Risk Factors
Definition of Hypercholesterolemia
Total cholesterol by age and sex Average distribution of plasma total cholesterol (means and selected percentiles) Plasma ...
Risk Factors: Serum Cholesterol (carried by LDL particles) How do we know who is at risk? ALSO Implicated: Family History ...
CHD Risk Factors Plasma Cholesterol (mmol/l) %
Note –  those countries with    risk  also have    serum cholesterol    dietary fat & cholesterol intake Finland USA Ne...
2 1 0.5 100   200   300 Relative Risk of Death From CHD by blood cholesterol   (mg/dl) 6 prospective studies 100   200   3...
Ideal, Feasible And Existing Total  Serum Cholesterol Levels in Adults Ideal Mean 4.3 mMl 2.7 4.0 5.4 6.7 8.1 Feasible Mea...
CANADIAN HEART HEALTH SURVEY PREVALENCE OF TOTAL CHOLESTEROL LEVELS % 52% 57% 55% 30% 27% 29% 18% 16% 17%
Classification Based on Total Blood Cholesterol   mg/dl   (mmol/L=mM) 220+ (5.7) 180-220 (4.6-5.7) <180 (4.6) 18-30 240+ (...
What is the risk of coronary heart disease in the next 6 years  in these individuals?  [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, ...
What is the risk of coronary heart disease in the next 6 years  in these individuals?  [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, ...
What is the risk of coronary heart disease in the next 6 years  in these individuals?  [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, ...
What is the risk of coronary heart disease in the next 6 years  in these individuals?  [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, ...
LDLC  =  TC  –  HDL  –  (TG/2) < 3.5 nM  < 5.2 mM  > 1.5 – 2.0  < 2.0 mM ppt Chylo LDL VLDL VLDL VLDL LDL HDL 95% Fasting ...
Calculation of  LDL Cholesterol LDL C = TC – HDL C – (TG/2) 3.0 = 6.0 – 1.0  – (4.0/2) calculated (not direct) apoB =  < 1...
LDL cholesterol and apoB  distribution in CAD patients
Threshold Effect of LDL Cholesterol Frequency 50 LDL Cholesterol 56.5% of CAD had LDL C > 50th percentile,  therefore no t...
Threshold for LDL Particle Number 88% of CAD had LDL apoB > 50th percentile NA population. Frequency 50 LDL apoB N CAD
Lipoprotein Screening <ul><li>Canadian Consensus Conference on  </li></ul><ul><li>Cholesterol </li></ul><ul><li>« As resou...
CCCC recommendations:  Screening priorities <ul><li>Screening for priority groups </li></ul><ul><li>Priority screening for...
Interpretation  of Lipid Values Men and Women Age 18-29 DRUGS? DIETARY MODIFICATION TG >200 HDL <35 LDL >115 39% 19% 180 (...
Coronary Heart Disease Main Risk Factors Non-Modifiable Modifiable Family History of CHD Dyslipidemia Male Sex Hypertensio...
Normal Endothelial Function   EDRF   PC   EDRF   PC   EDRF   PC   EDRF   EDRF   EDRF
B B B B B B In One Door… And Out the Other
Tg Tg Tg Tg Tg Tg Tg Tg  Tg Tg  Tg Tg Tg Tg CE CE CE CE CE B CE CE CE CE Tg B VLDL LDL
B B B B B The Pathogenic Power Of Particle Number B B B B B B B B B B B
B B B B B B B B B B B B Oxidation of LDL Particles within the vessel wall B B
Hypertension  -> Subintimal Thickening
400 350 300 250 200 150 100 50 0 0 2 4 6 8 10 mol Fibrinogen X 10 12 /cm 2 Perfusion Time (MIN) n=17 n=20 n=22 * * * High ...
HyperapoB  -> Hyperthrombogenicity ↑  PAI-1 ↑  Fibrinogen ↑  Factor VII ↑  Factor VII c + ← ↑  FFA ← ↑ CE B Tg CE Tg B CE ...
B B B B B B B Thicker ith Thlower
CAD Mortality in NIDDM 60 50 40 30 20 10 0 Mortality Rate per 1000 0-3  4-7  8-11  13-15  18-19  20-23 0-3  4-7  8-11  13-...
Can Glucose Glycate Glycosaminoglycans which then Grab apoB? B B B B B B B B
Relative odds of developing IHD over a 5-yr follow-up  period in a sample of 91 IHD cases and 91 matched controls   The Qu...
Why is smoking atherogenic? Tg B CE Tg B CE Tg B CE
A Dysfunctional Artery ↓ EDRF ↑ TF ↓ t-PA  ↑PAI-1 ↓ EDRF  ↓PC  ↑TF Tg B CE Tg B CE Tg B CE
Risk Factor – Obesity! <ul><li>Although excess obesity is a risk factor, so is  moderate   </li></ul><ul><li>obesity espec...
   BMI    age    men CORONARY MORBIDITY AND MORTALITY ASSOCIATED WITH RELATIVE WEIGHT Metropolitan relative weight Age-...
Alcohol Obesity  Diet Saturated Fat Salt Genetic Susceptibility Kidney  Damage Diabetes High Blood Pressure OC’s (female) ...
<ul><li>RISK FACTORS FOR CORONARY ARTERY DISEASE           </li></ul><ul><li>Modifiable </li></ul><ul><li>Smoking (> 10 ci...
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4) Risk Factors

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4) Risk Factors

  1. 1. Risk Factors
  2. 2. Definition of Hypercholesterolemia
  3. 3. Total cholesterol by age and sex Average distribution of plasma total cholesterol (means and selected percentiles) Plasma total cholesterol (mg/dL) 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
  4. 4. Risk Factors: Serum Cholesterol (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 Percentile mmol/l 18 16 14 12 10 8 6 4 2 0 5 15 25 35 45 55 65 75 85 95 4.1 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
  5. 5. CHD Risk Factors Plasma Cholesterol (mmol/l) %
  6. 6. Note – those countries with  risk also have  serum cholesterol  dietary fat & cholesterol intake Finland USA New Zeeland Australia UK Ireland Canada Norway Belgium-Lux. Yugoslavia Denmark Netherlands West Germany Austria Sweden Italy Switzerland Portugal Spain France Greece Japan Isochemic Heart disease Other possible coronary deaths 0 100 200 300 400 500 600 Mortality rates per 100,000 Mortality rates due to coronary heart disease
  7. 7. 2 1 0.5 100 200 300 Relative Risk of Death From CHD by blood cholesterol (mg/dl) 6 prospective studies 100 200 300 100 200 300 2 1 0.5 Finland 347 CHD MRFIT (US) 3,243 CHD Whitehall (UK) 455 CHD Framingham (US) 216 CHD Israel 615 CHD Hawaii 242 CHD
  8. 8. Ideal, Feasible And Existing Total Serum 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
  9. 9. CANADIAN HEART HEALTH SURVEY PREVALENCE OF TOTAL CHOLESTEROL LEVELS % 52% 57% 55% 30% 27% 29% 18% 16% 17%
  10. 10. Classification Based on Total Blood Cholesterol mg/dl (mmol/L=mM) 220+ (5.7) 180-220 (4.6-5.7) <180 (4.6) 18-30 240+ (6.2) 200-240 (5.2-6.2) <200 (5.2) 30+ High Risk Moderate Risk Desirable Men & Women Age
  11. 11. What is the risk of coronary heart disease in the next 6 years in these individuals? [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, 90% ] <ul><li>« WORST » SYSTOLIC </li></ul><ul><li>BLOOD </li></ul><ul><li>AGE SEX TOTAL HDL PRESSURE DIABETES SMOKING </li></ul><ul><li>55 M 7.2 0.8 150 NO YES </li></ul><ul><li>55 F 7.2 0.8 150 NO YES </li></ul><ul><li>55 M 7.2 0.8 150 NO NO </li></ul><ul><li>55 M 5.2 1.1 150 NO YES </li></ul><ul><li>55 M 5.2 1.1 120 NO NO </li></ul><ul><li>55 M 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 10.0 0.8 170 YES YES </li></ul><ul><li>55 F 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 7.2 0.8 150 NO YES </li></ul>
  12. 12. What is the risk of coronary heart disease in the next 6 years in these individuals? [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, 90% ] <ul><li>« LEAST LIKELY » SYSTOLIC </li></ul><ul><li>BLOOD </li></ul><ul><li>AGE SEX TOTAL HDL PRESSURE DIABETES SMOKING </li></ul><ul><li>55 M 7.2 0.8 150 NO YES </li></ul><ul><li>55 F 7.2 0.8 150 NO YES </li></ul><ul><li>55 M 7.2 0.8 150 NO NO </li></ul><ul><li>55 M 5.2 1.1 150 NO YES </li></ul><ul><li>55 M 5.2 1.1 120 NO NO </li></ul><ul><li>55 M 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 10.0 0.8 170 YES YES </li></ul><ul><li>55 F 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 7.2 0.8 150 NO YES </li></ul>
  13. 13. What is the risk of coronary heart disease in the next 6 years in these individuals? [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, 90% ] <ul><li>SYSTOLIC </li></ul><ul><li>BLOOD </li></ul><ul><li>AGE SEX TOTAL HDL PRESSURE DIABETES SMOKING </li></ul><ul><li>55 M 7.2 0.8 150 NO YES </li></ul><ul><li>55 F 7.2 0.8 150 NO YES </li></ul><ul><li>55 M 7.2 0.8 150 NO NO </li></ul><ul><li>55 M 5.2 1.1 150 NO YES </li></ul><ul><li>55 M 5.2 1.1 120 NO NO </li></ul><ul><li>55 M 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 10.0 0.8 170 YES YES </li></ul><ul><li>55 F 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 7.2 0.8 150 NO YES </li></ul>26% 35%
  14. 14. What is the risk of coronary heart disease in the next 6 years in these individuals? [ 1%, 5%, 10%, 15%, 25%, 35%, 60%, 90% ] <ul><li>SYSTOLIC </li></ul><ul><li>BLOOD </li></ul><ul><li>AGE SEX TOTAL HDL PRESSURE DIABETES SMOKING </li></ul><ul><li>55 M 7.2 0.8 150 NO YES </li></ul><ul><li>55 F 7.2 0.8 150 NO YES </li></ul><ul><li>55 M 7.2 0.8 150 NO NO </li></ul><ul><li>55 M 5.2 1.1 150 NO YES </li></ul><ul><li>55 M 5.2 1.1 120 NO NO </li></ul><ul><li>55 M 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 10.0 0.8 170 YES YES </li></ul><ul><li>55 F 10.0 0.8 170 YES YES </li></ul><ul><li>25 M 7.2 0.8 150 NO YES </li></ul>10% 15% 10% 5% 10%
  15. 15. LDLC = TC – HDL – (TG/2) < 3.5 nM < 5.2 mM > 1.5 – 2.0 < 2.0 mM ppt Chylo LDL VLDL VLDL VLDL LDL HDL 95% Fasting NO Apo B Chylos no apoB very little Particles apoB in VLDL 80-120 mg/dL Calculation of LDL Cholesterol
  16. 16. Calculation of LDL Cholesterol LDL C = TC – HDL C – (TG/2) 3.0 = 6.0 – 1.0 – (4.0/2) calculated (not direct) apoB = < 120 (direct)
  17. 17. LDL cholesterol and apoB distribution in CAD patients
  18. 18. Threshold Effect of LDL Cholesterol Frequency 50 LDL Cholesterol 56.5% of CAD had LDL C > 50th percentile, therefore no threshold for LDL C. N CAD
  19. 19. Threshold for LDL Particle Number 88% of CAD had LDL apoB > 50th percentile NA population. Frequency 50 LDL apoB N CAD
  20. 20. Lipoprotein Screening <ul><li>Canadian Consensus Conference on </li></ul><ul><li>Cholesterol </li></ul><ul><li>« As resources permit » </li></ul><ul><li>A priority for those with risk factors and established CHD </li></ul><ul><li>U.S. National Cholesterol Education Program </li></ul><ul><li>At least every five years for all adults aged 20 and over </li></ul><ul><li>More often as follow-up for those with elevated serum </li></ul><ul><li>cholesterol </li></ul><ul><li>Canadian Cardiovascular Society </li></ul><ul><li>Within 24 hours of myocardial infraction, </li></ul><ul><li>repeated 6-12 weeks after hospital discharge </li></ul>
  21. 21. CCCC recommendations: Screening priorities <ul><li>Screening for priority groups </li></ul><ul><li>Priority screening for individuals with: </li></ul><ul><ul><li>Coronary heart disease </li></ul></ul><ul><ul><li>Family history of hyperlipidemia or CHD at an </li></ul></ul><ul><ul><li>early age </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>Renal failure </li></ul></ul><ul><ul><li>Abdominal obesity </li></ul></ul><ul><li>Screening for all Canadians </li></ul><ul><li>As part of a periodic health examination </li></ul>
  22. 22. Interpretation of Lipid Values Men and Women Age 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
  23. 23. Coronary Heart Disease Main Risk Factors Non-Modifiable Modifiable Family History of CHD Dyslipidemia Male Sex Hypertension Age Diabetes Smoking Obesity
  24. 24. Normal Endothelial Function  EDRF  PC  EDRF  PC  EDRF  PC  EDRF  EDRF  EDRF
  25. 25. B B B B B B In One Door… And Out the Other
  26. 26. Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg CE CE CE CE CE B CE CE CE CE Tg B VLDL LDL
  27. 27. B B B B B The Pathogenic Power Of Particle Number B B B B B B B B B B B
  28. 28. B B B B B B B B B B B B Oxidation of LDL Particles within the vessel wall B B
  29. 29. Hypertension -> Subintimal Thickening
  30. 30. 400 350 300 250 200 150 100 50 0 0 2 4 6 8 10 mol Fibrinogen X 10 12 /cm 2 Perfusion Time (MIN) n=17 n=20 n=22 * * * High Shear, Non-Parallel Sreamlines Low Shear, Parallel Sreamlines Effect of Shear Rate and Flow Condition on Fibrinogen Deposition
  31. 31. HyperapoB -> Hyperthrombogenicity ↑ PAI-1 ↑ Fibrinogen ↑ Factor VII ↑ Factor VII c + ← ↑ FFA ← ↑ CE B Tg CE Tg B CE Tg B CE Tg B CE Tg B CE Tg B CE Tg B
  32. 32. B B B B B B B Thicker ith Thlower
  33. 33. CAD Mortality in NIDDM 60 50 40 30 20 10 0 Mortality Rate 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 Diabetes Diabetes No Diabetes No Diabetes
  34. 34. Can Glucose Glycate Glycosaminoglycans which then Grab apoB? B B B B B B B B
  35. 35. Relative odds of developing IHD over a 5-yr follow-up period in a sample of 91 IHD cases and 91 matched controls The Quebec Cardiovascular Study 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
  36. 36. Why is smoking atherogenic? Tg B CE Tg B CE Tg B CE
  37. 37. A Dysfunctional Artery ↓ EDRF ↑ TF ↓ t-PA ↑PAI-1 ↓ EDRF ↓PC ↑TF Tg B CE Tg B CE Tg B CE
  38. 38. Risk Factor – Obesity! <ul><li>Although excess obesity is a risk factor, so is moderate </li></ul><ul><li>obesity especially abdominal android obesity: </li></ul><ul><ul><ul><ul><li>“ beer belly” -Men </li></ul></ul></ul></ul><ul><ul><ul><ul><li> diabetes  hypertension </li></ul></ul></ul></ul>
  39. 39.  BMI  age  men CORONARY MORBIDITY AND MORTALITY ASSOCIATED WITH RELATIVE WEIGHT Metropolitan relative weight Age-adjusted annual rate per 1,000 35 - 30 - 25 - 20 - 15 - 10 - 5 - 54-104 105-114 115-124 125-134 135-272 Men aged 65-94 years (p<0.01) Women aged 65-94 years (p<0.05) Men aged 35-64 years (p<0.001) Women aged 35-64 years (p<0.001)
  40. 40. Alcohol Obesity Diet Saturated Fat Salt Genetic Susceptibility Kidney Damage Diabetes High Blood Pressure OC’s (female) Smoking Psycho-Social Factors Family History of CVD Dietary Cholesterol Physical Activity Blood Lipids Age Sex (male) Lower S/E CVD IHD Stroke
  41. 41. <ul><li>RISK FACTORS FOR CORONARY ARTERY DISEASE         </li></ul><ul><li>Modifiable </li></ul><ul><li>Smoking (> 10 cigarettes / day) </li></ul><ul><li>Obesity, especially Android Obesity </li></ul><ul><li>Hypercholesterolemia and/or Low HDL cholesterol (< 1 mM) *: </li></ul><ul><li>A high HDL cholesterol (>1.6 mM) is a negative risk factor </li></ul><ul><li>(i.e. protective) </li></ul><ul><li>Hypertension (> 140/90 or treated) </li></ul><ul><li>Diabetes Mellitus </li></ul><ul><ul><ul><ul><ul><li>*** MODIFIABLE BY DIET </li></ul></ul></ul></ul></ul><ul><li>Non Modifiable </li></ul><ul><li>Age (>45 in men, >55 in women) </li></ul><ul><li>Family history of premature coronary artery disease: </li></ul><ul><li>Myocardial infarct or sudden death in a 1st degree </li></ul><ul><li>parent < 55 years of age. </li></ul><ul><li>Gender (males are at increased risk </li></ul>

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