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 Formed exclusively by demethylation of methionine Eliminated through one of two vitamin-dependent pathways, in addition to an alternate vitamin- independent pathway in liver

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 B 6 ), or cobalamin (vitamin B 12 ) deficiencies –Renal failure Serum levels of homocysteine may be lowered by supplementation with folate, vitamin B 6, and vitamin B 12

Hajjar KA, J Clin Invest 107:663, 2001 Homocysteine Metabolism and Vascular Dysfunction

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

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

Case #1 Physical Exam –BP 138/90 mm Hg right arm sitting (normal 140/90) –Ht 180 cm –Wt 77 kg –BMI (wt/ht 2 ) 23.8 (normal < 25) –Rest of physical exam normal

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

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) –Protein20% –Fat38%(desirable < 30%) –Carbohydrate42% Cholesterol:340 mg/day(desirable < 300 mg/day) Folic acid:212 mcg/day(desirable > 240 mcg/day)

Case #1 Cardiovascular Risk Profile –Lipids Total cholesterol230 mg/dL(normal < 200 mg/dL) Triglycerides120 mg/dL(normal < 200 mg/dL) HDL cholesterol40 mg/dL(normal > 35 mg/dL) LDL cholesterol166 mg/dL(normal < 130 mg/dL) –Homocysteine16 µmol/L(normal < 12 µg/L

Dietary Sources of Folate and Vitamins B 6 and B 12 Foods Rich in Folate –Leafy vegetables, liver, whole-grain cereals, legumes, and some fruits, such as oranges Foods Rich in Vitamin B 6 –Fish, poultry, meat, and wheat Foods Rich in Vitamin B 12 –Animal products

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

Folic Acid and Birth Defects About 2,500 neural tube defects per year in US Occur at 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 $ (1998)

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)

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)

Mechanisms of benefit Cardiovascular disease –-thrombogenic factors, decreased nitric oxide, increased inflammation Neural tube defects –???? Cancer –Hypomethylation of DNA, low CH 2 THF leading to uracil for thymidine