Risk Factors for Premature Atherosclerotic Heart Disease

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Risk Factors for Premature Atherosclerotic Heart
Disease

• Dyslipidemia (high LDL, low HDL)
• Diabetes
• Hypertension
• Obesity
• Sedentary lifestyle
• Obesity
• Smoking
• Male sex
• Hyperhomocysteinemia

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Homocysteine

• Non-protein-forming, sulfur-containing amino acid
• Formed exclusively by demethylation of methionine
• Eliminated through one of two vitamin-dependent
  pathways, in addition to an alternate
  vitamin-independent pathway in liver

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Hyperhomocystinemia

• Independent risk factor for atherosclerotic and
  thromboembolic disease
• A 5 µM increase in serum level confers a 80
  increased risk to women and a 60 increased risk
  to men for atherosclerotic vascular disease
• In patients with coronary artery disease, serum
  homocysteine levels increase with the number of
  stenosed coronary vessels
• Hyperhomocystinemia may reflect
• Genetic defects
• Folate (most common), pyridoxine (vitamin B6), or
  cobalamin (vitamin B12) deficiencies
• Renal failure
• Serum levels of homocysteine may be lowered by
  supplementation with folate, vitamin B6, and
  vitamin B12

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Homocysteine Metabolism and Vascular Dysfunction
Hajjar KA, J Clin Invest 107663, 2001
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Case 1

• 45 year-old African-American male
• Presents with acute onset of chest pain
• Undergoes cardiac catheterization and is found to
  have blockage in 4 coronary arteries and is
  scheduled for bypass surgery
• Past medical history is unremarkable
• No current medications

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Case 1

• Activity
• Works as a bank teller. Very little vigorous
  physical activity. Walks for 30 min three times
  per week.
• Social
• Divorced, lives alone
• Smokes 1/2 pack cigarettes/day
• Denies alcohol/substance abuse

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Case 1

• Physical Exam
• BP 138/90 mm Hg right arm sitting (normal 140/90)
• Ht 180 cm
• Wt 77 kg
• BMI (wt/ht2) 23.8 (normal lt 25)
• Rest of physical exam normal

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Case 1
62 yo hypertension stroke
54 yo hypertension MI
72 yo hypertension
69 yo cancer
69 yo obese CH 204 TG 204 HDL 42
70 yo hypertension CH 236 TG 120 HDL 42
49 yo stroke
40 yo healthy CH ?
42 yo obese CH 210 TG 201 HDL 38
45 yo borderline hypertension CAD CH 230 TG
120 HDL 40 hyperhomocysteinemia
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Case 1

• Diet
• No breakfast
• Takes lunch meat sandwich and fruit
• Dinner eats alone, usually fast food or frozen
  dinner
• Analysis of 3-day food diary
• Average 2230 kcal/day
• Diet composition ( of total calories)
• Protein 20
• Fat 38 (desirable lt 30)
• Carbohydrate 42
• Cholesterol 340 mg/day (desirable lt 300 mg/day)
• Folic acid 212 mcg/day (desirable gt 240 mcg/day)

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Case 1

• Cardiovascular Risk Profile
• Lipids
• Total cholesterol 230 mg/dL (normal lt 200 mg/dL)
• Triglycerides 120 mg/dL (normal lt 200 mg/dL)
• HDL cholesterol 40 mg/dL (normal gt 35 mg/dL)
• LDL cholesterol 166 mg/dL (normal lt 130 mg/dL)
• Homocysteine 16 µmol/L (normal lt 12 µg/L

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Dietary Sources of Folate and Vitamins B6 and B12

• Foods Rich in Folate
• Leafy vegetables, liver, whole-grain cereals,
  legumes, and some fruits, such as oranges
• Foods Rich in Vitamin B6
• Fish, poultry, meat, and wheat
• Foods Rich in Vitamin B12
• Animal products

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Homocysteine reduction therapy

• 205 patients post-angioplasty
• Double-blind, randomized to placebo or treatment
• Treatment folate (1mg), B12 (400µg), B6 (10mg)
• Homocysteine levels 11.1 to 7.2 (Tx) vs 10.8 to
  9.5 (placebo
• Re-stenosis at 6m follow-up 19.6 (Tx) vs 37.6
  (P)
• All cardiac events (6m) 12.7 (TX) vs 24.5 (P)
• Schnyder et al. NEJM 2001 3451593

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Case 2

• 4 hr old infant boy born to 25 yo G1P1 Caucasian
• Pregnancy notable only for UTI at 5mths
• Term by dates
• Uncomplicated vaginal delivery
• Family history negative for birth defects

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Folic Acid and Birth Defects

• About 2,500 neural tube defects per year in US
• Occur at 26-28 days post-conception
• 95 are spontaneous with no family history
• 1991 UK study showed 71 risk reduction
  
  in recurrences (4mg dose)
• In 1999 (Nov NEJM) 85 reduction in risk for
  primary
  prevention (0.4mg dose)
• Lifetime costs estimated to be 532.000 (2001,
  MOD)

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• What per cent of cases of spina bifida are
  preventable today?
• What is the lifetime cost of medical expenses for
  this problem?
• What is the average cost of prevention of this
  problem?
• How many women in the audience are taking folate
  supplements at this time? (yes or no)

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Folic Acid and Birth Defects

• About 4000 neural tube defects per year
• Occur at 26-28 days post-conception
• 95 are spontaneous with no family history
• 1991 UK study showed 71 risk reduction
  
  in recurrences (4mg dose)
• In 1999 (Nov NEJM) 85 reduction in risk for
  primary
  prevention (0.4mg dose)

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Folic Acid and Birth Defects Federal Responses

• 1992-USPHS recommended all women of childbearing
  age receive 400mcg of folate daily
• 1996-FDA required 150mcg supplement of folate in
  all grains
• Multiple agencies/organizations in August 1999
• All childbearing age women-400mcg (MVI or
  fortified foods)
• All women with prior NTD-4mg (by supplements)

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Folic Acid and Birth Defects Knowledge

• 1998 MOD/Gallup poll
• 68 of women have heard of the relationship of
  folate and birth defects
• 13 knew folate prevents birth defects, 7 knew
  that was required before before conception
• 32 took a daily vitamin supplement
• Lowest among young and poorly educated

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Folic Acid Dietary Sources

• Dark, leafy vegetables, citrus fruits, liver and
  organ meats, fortified cerials and legumes.
• 8oz of OJ and bowl of fortified cereal 200mcg of
  folic acid
• Cant rely on diet for pregnancy

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Folate Public Health Strategies

• Advertising- TV, General Mills, Kelloggs and
  others
• Florists-Mothers day flowers
• Folic acid awareness week may 7-14
• Teach doctors only 1/3 of OB residents knew
  correct dose of folate

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Case 3

• 38 year old female pediatrician
• Normal fast food diet, social drinker
• Routine Ob/Gyn visit
• Mass noted in left breast
• Biopsy c/w breast cancer (BRCA negative)

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Folate and Cancer

• Increased risk for breast cancer in women who
  consume 15g/day of ethanol and lt 300mcg
  folate/day (RR1.32)
• Reduced risk for colon cancer in women who
  consume daily folate suplements for 15 years or
  more (RR0.25)
• Reduced risk for colon cancer in men who consumed
  supplements for 10 years (RR0.75)
• Reduced risk for childs ALL for moms on folate
  (RR.4, lancet 20013581935)

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Case 4

• 71 year old healthy female
• Lost spouse 6mths previously
• Mild depression
• Found by police 100 miles from home in car
• Has neurobehavioral testing consistent with
  Alzheimers disease
• Elevated homoscyseine level (16µmol/L)

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Homocysteine and Dementia

• 1092 subjects without dementia (Framingham)
• Mean age 76 (61 female)
• 111 subjects developed dementia (83 Alzheimers)
• For subjects in highest quartile of levels, RR of
  dementia was approximately 50 higher with follow
  up as long as 11 years.
• Seshadri S et al NEJM 2002346476-83

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Mechanisms of benefit

• Cardiovascular disease
• -thrombogenic factors, decreased nitric oxide,
  increased inflammation (B12 as cofactor)
• Neural tube defect(????)
• Alzheimers (???)
• Excitotoxicity, apoptosis, amyloid interaction,
  vascular oxidative stress leading to hypoxia
• Cancer
• Hypomethylation of DNA, low CH2THF leading to
  uracil for thymidine

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