This document discusses homocysteine and its relationship to cardiovascular disease. Homocysteine is an amino acid produced during metabolism that can accumulate in high levels due to genetic or nutritional factors. High homocysteine levels are associated with damage to blood vessels and an increased risk of cardiovascular problems like heart attacks and strokes. The document reviews research studies investigating the effects of homocysteine and whether vitamin supplements can help lower levels and reduce cardiovascular risk.

1. Homocysteine and
Cardiovascular Disease
Aharon Roberts
FCSFN 648

2. Homocysteine
 :Sulfur containing nonessential
amino acid that is not found in the
diet. Dietary methionine is
converted to homocysteine.
Methionine Homocysteine
NH3+ H
l |
CH3-S-Ch2-CH2-CH-CO2- → +H3N-C-COO-
|
CH2-CH2-SH

3. Homocysteine
 Varying forms
 1% free
 70-80% bound to albumin via a disulfide link
 20-30% either as a homocysteine dimer or a
cysteine-homocysteine-mixed disulfide.
* The type(s) of species responsible for the CVD
pathology have yet to be determined.

4. Etiology of
Hyperhomocysteinemia
 Causes
 Genetic mutations
 Nutritional deficiencies
 Disease states
 Drugs

5. Etiology of
Hyperhomocysteinemia
 Genetic Mutations
 5-methyleneterahydrofolate reductase
(MTHFR) polymorphism due to a point
mutation on chromosome 1.

6. Etiology of
Hyperhomocysteinemia
 Nutritional deficiencies
 Folate deficiency
 Cobalamine deficiency
 Pyridoxine deficiency

7. Mechanism for
Homocysteine Metabolism

8. Etiology of
Hyperhomocysteinemia
 Disease states
 Cystathione β-synthase deficiency
 Homocysteinuria
 Methionine synthase deficiency
* Both are rare autosomal recessive disorders that are
correlated with hyperhomocysteinemia and vascular
thrombosis.
 Chronic renal failure regardless of etiology, duration, or
type of dialysis
 Severe psoriasis
 Possibly through increased cell turnover
 Pernicious anemia
 Cobalamine deficiency

9. Etiology of
Hyperhomocysteinemia
 Drugs
 Cholestryamine (reduces cholesterol in blood)
 Impairs folate absorption
 Methotrexate (treatment of psoriasis)
 Depletes folate metabolites
 Anti-epileptics (carbemazapine, phenytoin)
 Lower folate concentrations
*Tobacco and caffeinated coffee are also
associated with increased homocysteine
concentrations

10. How Homocysteine
effects CVD
 Homocysteine is one of many damaging
agents to endothelial cells
 LDL and platelets invade
 Platelets secrete chemoattractants for monocytes
 PDGF - Platelet derived growth factor stimulates smooth
muscle proliferation and thickening of the tunica media.
Smooth muscle cells from the tunica media invade the
tunica intima.
 Monocytes invade and are activated to
macrophages/scavenger cells.

11. How Homocysteine
effects CVD
 Smooth muscle cells and macrophages
ingest LDL
 Foam cells/Fatty streaks
 The high amounts of cholesterol ester consumed
will precipitate into crystalline deposits.
 Deposits calcify and become rough stimulating
clot formation creating a fibrous plaque.
 Narrows the lumen of the vessels, restricting blood
flow.

12. Research
 1969 – Dr. Kilmer McCully, M.D.
 Compared an 8 y/o patient with homocysteinuria
who died of a stroke and an infant with an inherited
defect of cobalamine metabolism who died of
cardiac arrest.
 Concluded that elevated homocysteine levels result
in premature atherosclerosis.
 Later expanded to include general populations with
mild hyperhomocysteinemia, typically associated
with dietary deficiencies.

13. Research
 VITATOPS
 Vitamins to Prevent Stroke
 Stated that an adjustment for renal function
eliminated the relationship between total
homocysteine levels and intima media thickness
as well as flow-mediated dilation of the brachial
artery.

14. Research
 VISP
 Vitamin Intervention for Stroke Prevention
 Reduction in total plasma homocysteine
concentration was reported at 21% in participants
after exclusion of those with impaired renal
status, those with malabsorption of B vitamins, or
those taking other B vitamins not associated with
the study.

15. Research
 HOPE
 Heart Outcomes Prevention Evaluation
 For patients with vascular disease, B vitamin
therapy significantly reduced stroke by 25% but
not myocardial infarction or death.

16. Research
 Severe homocysteinuria
 Treatment with high-dose B vitamins in combination
with dietary methionine restriction resulted in
markedly reduced results.
* Results for mild homocysteinuria have not shown
such significant results. Contradictory results may
be due to trial design, adverse effects from vitamin
supplementation, and using homocysteine as a risk
factor or not as a risk factor.

17. Reduction in
Homocysteine Levels
 Supplementation of B vitamins
 Folate, B6, and B12
 Restriction of methionine containing
substances
 Sesame seeds, brazil nuts, fish, meats
 Exercise

18. Bibliography
 Gauthier, G.M., Keevil, J.G., McBride, P.E., The
Association of Homocysteine and Coronary Artery
Disease. Clin. Cardiol. 2003; 26:563-8.
 Gropper, S.S., Groff, J.L., and Smith, J.L., Advanced
Nutrition and Human Metabolism. 5th Edition,
Wadsworth Publishing, 2009.
 Lavie, C.J., Milani, R.V., Homocysteine The Rubik’s
Cube of Cardiovascular Risk Factors. Mayo Clinic
Proceedings. 2008; 83(11):1200-02.
 Scott, J., Weir, D. Homocysteine and cardiovascular
disease. Q J Med. 1996; 89:561-3.