Homocysteine: An Update

Study after study has confirmed that, the higher your homocysteine blood level,
the greater your risk for heart attack and stroke.

But two recent studies have been recently released that cast serious doubt on whether reducing homocysteine using B vitamins has any beneficial effect on heart disease.

What now?

“…it’s a revolution in thinking about the origin of heart disease. The cholesterol hypothesis has been that eating an excess of either cholesterol or high fat in the diet somehow causes the elevation of blood cholesterol and somehow damages the arteries. The homocysteine approach attributes the process of arteriosclerosis to a deficiency of B vitamins.”

Dr. Kilmer McCully

Two credible studies recently reported that there’s no benefit to reducing homocysteine by using B vitamins. Yet hundreds of previous studies have demonstrated that increased homocysteine escalates heart attack and stroke risk.

Is it time to discard Dr. McCully’s hypothesis of homocysteine’s role in causing heart disease?

The issues have indeed become murkier. Let’s try to sort through them.

Homocysteine: a 60-second history

Back in 1969, Dr. Kilmer McCully of Harvard hypothesized that advanced atherosclerosis observed in teenagers suffering from heart attacks and strokes was due to an excess of a sulfur-containing amino acid, homocysteine. Blood levels of homocysteine in these children ranged as high as 300 μmol/l, high enough to be detected in the urine, thus the misnomer “homocystinuria”.

McCully later expanded his theory to adults with lower blood levels of homocysteine. Homocysteine in this group can be due to deficiencies of B vitamins or to specific genetic defects.

In experimental preparations, homocysteine displays an impressive catalog of adverse effects. Homocysteine has been implicated in multiple steps of the process leading to coronary and arterial plaque growth and activity. Among the most damaging effects are:

• Homocysteine induces growth of vascular muscle cells, an important component of atherosclerotic plaque.
• Elevated homocysteine levels stimulate production of inflammatory mediators interleukin-8 and monocyte chemoattractant protein-1, both responsible for drawing inflammatory cells into the arterial wall. Inflammation drives injury and plaque rupture, causing heart attack.
• Superoxide dismutase activity is increased, yielding excess hydroxyl radicals. This leads to oxidation of LDL cholesterol particles, a more damaging form of LDL.
• Homocysteine encourages blood clot formation by increasing clotting factors XII and V, tissue factor expression, platelet aggregation, and reduction of anti-coagulants protein C and thrombomodulin. Blood clot formation is the final step in heart attack after a plaque ruptures.
• Homocysteine increases levels of asymmetric dimethylarginine, the natural blocker of l-arginine and nitric oxide, natural dilators of arteries. This causes abnormal arterial constriction and injury. ¹

Yes, but does homocysteine cause heart attack in humans?

A substantial body of epidemiologic observations shows that the higher your homocysteine level, the greater your risk of heart attack. A Norwegian study reported in the New England Journal of Medicine in 1997, for instance, tracked 587 people with coronary disease, many of whom had undergone bypass surgery or angioplasty. Over the ensuing five years, the mortality rate of those with homocysteine levels below 9 μmol/l was 3.8%. The mortality rate for those with homocysteine levels of 15 μmol or greater was 24.7%—a dramatic difference.²  Similar observations have been made in several other large studies.^3–4

There’s more to homocysteine than heart disease

Elevated homocysteine levels magnify the dangers of other risk factors for vascular disease. In persons with diabetes, for instance, an increase of 5 μmol/l in homocysteine confers a 38% increased risk for vascular disease, but the same 5 μmol increase in diabetics confers a 233% increased risk.⁵

People who smoke have tremendously magnified risk in the presence of higher homocysteine levels. The European Concerted Action Project showing a 12-fold (1200%!) heightened risk for cardiovascular disease in smokers with homocysteine levels above 12 μmol/l.⁶  High homocysteine with high cholesterol multiplies risk several-fold.⁷ A particularly lethal combination of risk factors is found when a high homocysteine (>12 μmol/l for females, >15 μmol/l for males in this study) is combined with lipoprotein(a) >40 mg/dl, with risk increased 31-fold.⁸

The higher your homocysteine, the greater the extent of plaque in the aorta (the large artery that emerges from the heart).^9,10  The European Concerted Action Project reported more than a doubling of stroke when homocysteine levels exceeded 12 mol/l.⁶  Homocysteine levels of 20 μmol/l or higher predict risk for stroke and heart attack a startling 10-fold higher over that at a level of 9 μmol/l.¹¹

The Canadian group at the Stroke Prevention and Atherosclerosis Research Centre in Ontario reported that a homocysteine level >14 mmol/l identified a group that showed much more rapid growth of carotid plaque. Treatment with folic acid 2.5 mg, B6 25 mg, and B12 250 mcg per day completely eliminated any further plaque growth.¹²

Homocysteine plays an important role in depression. Poor response to antidepressant medication, dysthymia (a lesser form of depression), and full depression have all been linked to low folic acid levels and high homocysteine levels.¹³  Depressed, hostile, or angry people have higher homocysteine levels, and higher levels are very prevalent among the depressed, with up to 50% of people showing homocysteine levels >10 μmol/l.^14,15 Anti-depressant medication may have diminished effectiveness in this variety of depression, but it may respond to folic acid. Studies have firmly established that folic acid replacement, resulting in reduced homocysteine blood levels, is an important treatment for depression. In a 1993 University of Parma, Italy, study of 96 patients, folic acid supplementation yielded improvements in mood similar to conventional anti-depressants.¹⁶  Several studies have shown that response to prescription anti-depressants like fluoxetine is substantially improved by taking as little as 500 mcg of folic acid per day. ^17-18

A growing appreciation for the role of folic acid, vitamins B6 and B12, and homocysteine in the cognitive decline of aging is developing. It’s well established that diminished memory and functioning are associated with deficiency of these B vitamins and higher homocysteine levels.^{19, 20} An MRI study showed that lower folic acid blood levels were associated with deficient volumes of brain white matter, the portion of the brain responsible for higher mental function.²¹

Emerging research relates deficient folate and high homocysteine levels with such disparate conditions as osteoporosis, hip fractures, complications of pregnancy (e.g., eclampsia), inflammatory bowel disease, and several forms of cancer.^22–26

Does treatment reduce risk?

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