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. Homocysteine. Non-protein-forming, sulfur-containing amino acid

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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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Hyperhomocysteinemia

  • 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

  • Hyperhomocysteinemia 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 107:663, 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 < 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

49 yo

stroke

70 yo

hypertension

CH 236

TG 120

HDL 42

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 < 30%)

        • Carbohydrate 42%

      • Cholesterol: 340 mg/day (desirable < 300 mg/day)

      • Folic acid: 212 mcg/day (desirable > 240 mcg/day)


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Case #1

  • Cardiovascular Risk Profile

    • Lipids

      • Total cholesterol 230 mg/dL (normal < 200 mg/dL)

      • Triglycerides 120 mg/dL (normal < 200 mg/dL)

      • HDL cholesterol 40 mg/dL (normal > 35 mg/dL)

      • LDL cholesterol 166 mg/dL (normal < 130 mg/dL)

    • Homocysteine 16 µmol/L (normal < 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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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 $330.000 (1998)


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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 < 300mcg folate/day (RR=1.32)

  • Reduced risk for colon cancer in women who consume daily folate suplements for 15 years or more (RR=0.25)

  • Reduced risk for colon cancer in men who consumed supplements for 10 years (RR=0.75)


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Mechanisms of benefit

  • Cardiovascular disease

    • -thrombogenic factors, decreased nitric oxide, increased inflammation

  • Neural tube defects

    • ????

  • Cancer

    • Hypomethylation of DNA, low CH2THF leading to uracil for thymidine