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CHRONICLES IN CHOLESTEROLAn Insiders Guide to State of The Art Cardiovascular

Prevention Laboratory Testing Available FromNumerous studies suggest that homocysteine may be a modifiable

risk factor for cardiovascular disease. In experimental studies,

homocysteine causes oxidative stress, damages endothelium, and

enhances thrombogenicity. In general, epidemiologic studies

show an independent and graded association between

homocysteine levels and cardiovascular risk. The observational

data suggest that even mild-to-moderate elevations in

homocysteine increase cardiovascular risk.. Folic acid is the most

important dietary determinant of homocysteine; daily

supplementation with 0.5 to 5.0 mg typically lowers plasma

homocysteine levels by about 25 percent. Vitamin

B12 supplementation of at least 0.4 mg daily further lowers levels

by about 7 percent, and vitamin B6 supplements may be

particularly important in lowering homocysteine after methionine

loading. The problem is that several studies have shown no

benefit to lowering homocysteine levels with B vitamins. It is

possible that elevated homocysteine levels may be a risk marker

for cardiovascular disease and should not necessarily be the target

of therapy.

In 1969, a connection between homocysteine and cardiovascular

disease was proposed when it was observed that people with a

rare hereditary condition called homocystinuria are prone to

develop severe cardiovascular disease as young adults. In this

condition, an enzyme deficiency causes homocysteine to

accumulate in the blood and to be excreted in the urine. Abnormal

homocysteine elevation also occurs among people whose diet

contains inadequate amounts of folic acid, vitamin B6, or vitamin

B12. Regardless of the cause of the elevation, supplementation

with one or more of these vitamins can lower plasma

homocysteine levels.

Studies done in the 1980s and 1990s linked elevated blood levels

of homocysteine to increased risk of premature coronary artery

disease, stroke, and venous blood clots, even among people with

normal cholesterol levels. These studies led to speculations that

high homocysteine levels could contribute to atherosclerosis in at

least three ways: (a) a direct toxic effect that damages the cellslining the inside of the arteries, (b) interference with clotting

factors, and (c) oxidation of low-density lipoproteins (LDL).

Lowering the serum concentration of homocysteine has been

proven to reduce the risk of adverse cardiovascular events among

people with homocystinuria. Without clinical trials, however, it was

impossible to know whether abnormal homocysteine levels among

the general population cause atherosclerosis or are merely a

"marker"a non-causative finding that often occurs in people with

atherosclerosis.

October, 2011 VOL 1 ISSUE 3

In This Issue: Homocysteine

Although there is acorrelation between

cardiovascular disease andelevated homocysteine levels,

the necessity forhomocysteine loweringtreatment is not clear.

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Lowering Homcysteine Levels

Homocysteine elevation is an independent, modifiable

risk factor for cardiovascular disease. It is an

intermediate amino acid formed during the metabolism

of methionine. Plasma homocysteine is normally 12

mol/L, but when elevated has many deleterious

cardiovascular effects.

Supplements combining folic acid and vitamins B6 and

B12 did not reduce the risk of major cardiovascular

events in patients with vascular disease.

The HOPE-2 and NORVIT trials showed no reduction in

cardiovascular events despite impressive homocysteine

lowering with vitamin therapy.

It is possible that the mechanism for lowering

homocysteine needs to be evaluated in light of negative

results associated with B vitamins.

The homocysteine concentration in the blood is an

important reflection of the status of intracellular

methionine metabolism. The metabolic pathway that

homocysteine takes can be influenced by alterations in

the concentrations of folic acid, vitamin B6, and vitamin

B12, and by activities of the various enzymes that

participate in metabolic processes.

Homocysteine concentration is influenced by age, gender, and

medication and by genetic, nutritional, and pathologic factors.Plasma homocysteine increases with age, possibly due to renal

impairment: There is a positive correlation between creatinine

levels and plasma homocysteine. In general, men have higher

levels of homocysteine than women, most likely due to higher

creatinine values and greater muscle mass. Women, before

menopause, have lower levels of homocysteine than do

postmenopausal women.

Use of some medications raises homocysteine levels.

Methotrexate, nitrous oxide, phenytoin (Dilantin), and

carbamazepine (Tegretol) all increase homocysteine levels.

Usually, women taking oral contraceptives have lower

homocysteine. The lipid-lowering agents colestipol and niacin, in

combination with thiazide diuretics, may raise homocysteine levels.

A total plasma homocysteine level of 12 mol/L is considered

optimal. A concentration above 15 mol/L is associated with a

high risk of occlusive vascular disease. If the homocysteine level

is 100 mol/L, the patient should be referred to a geneticist,

especially if several members of the same family have

By Spencer Kroll MD PhD

National Lipid Association Board Certified

Board of Directors, Northeast Lipid Association

October, 2011 VOL 1 ISSUE 3