Homocysteine: An Update
TRACK YOUR PLAQUE
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?
In the Swiss Heart Study, 553 patients were given 1 mg folic acid, 10 mg B6, and 400 mcg B12 per day or placebo following coronary angioplasty. After six months, 9.9% of the patients receiving B vitamins had to undergo a repeat procedure for re-growth of blockage or a new blockage, while 16.0% of placebo patients required another procedure, a relative reduction of 30%. Overall events, including death, were reduced from 22.8% in placebo to 15.4% in the B vitamin group. Interestingly, both groups started with a homocysteine level of only 11.0 µmol/l, reduced to 7.2 µmol/l with B vitamins.27 Another trial of folic acid, 5 mg, vs. placebo was conducted by a Dutch group in 283 patients, all heart attack survivors, and yielded conflicting results. All participants took a cholesterol-reducing medicine along with folic acid or placebo. This trial revealed no benefit of folic acid in addition to the cholesterol drug over one year.28
The Vitamin Intervention for Stroke Prevention (VISP) study from the Stroke Research Center at Wake Forest University disclosed somewhat conflicting results in that a so-called "high-dose" B vitamin formulation of 2.5 mg folic acid, 25 mg B6, 400 mcg B12 vs. a "low-dose" regimen of 0.2 mg folic acid, 0.2 mg B6, 6 mcg B12 showed no difference in stroke or heart attack over two years. However, when the likelihood of events was examined in light of the treatment homocysteine level, a clear-cut effect of diminishing risks with lower homocysteine levels was seen in both high- and low-dose groups. The investigators suggested that another trial should be conducted, this time by selecting participants with higher starting homocysteine levels.29
Two additional studies have now been conducted and published within the last few months that have tried to examine this question and, surprisingly to most of us following the homocysteine story, showed no benefit.
A closer look at the studies
In the Norwegian Vitamin Trial, or NORVIT, 3749 men and women, all of whom had suffered heart attacks within the preceding week, were enrolled. Four treatment groups were created at random: a "high-dose" group received 0.8 mg folic acid (800 mcg), 0.4 mg vitamin B12 (400 mcg), and 40 mg vitamin B6; a placebo group; one group receiving folic acid and B12; and a group receiving B6 alone.
The groups were then tracked over the ensuing 3 ½ years. The result: An average 27% reduction of homocysteine levels (from 13.1 µmol/l to 9.5 µmol/l) but no reduction in heart attack and stroke among the groups receiving any combination of B vitamins. The study authors also believe that there may have been a slight increase in events in the group receiving all three B vitamins (153 people in the placebo group, 182 in the vitamin group.)
The study authors, including the outspoken Dr. Kaare Bonaa, proclaimed that the combination of B vitamins provided no reduction in heart attack or stroke and, in fact, a harmful effect may be present.30
The Heart Outcomes Prevention Evaluation (HOPE) 2 study followed a somewhat different design. 5522 participants enrolled, all with a history of coronary disease, carotid disease, vascular disease, or diabetes. Participants received B vitamins: 2.5 mg folic acid, vitamin B6 50 mg, and vitamin B12 1 mg, or placebo.
Five years later, homocysteine levels were reduced by 2.4 µmol/l, from 12.2 to 9.8 µmol/l. 18.8% of the B vitamin group experienced heart attack, death or stroke; 19.8% of the placebo group experienced an event. The difference was not statistically significant. There was, however, a trend towards less stroke in the B vitamin treated group (5.3 vs. 4.0%).31
Curiously, despite the lack of any treatment benefit, both trials showed that the higher starting homocysteine levels, the greater the risk of heart and stroke, whether participants were treated or not. Nonetheless, spokesmen for both studies declared the homocysteine hypothesis dead and declared that B vitamin treatment plays no role in heart disease prevention.
What do the studies really tell us?
If we look even closer, what questions do these studies really answer?
* One of the deficiencies of both studies is that participants were not chosen for having high homocysteine levels. Homocysteine levels at the beginning averaged 12µmol/l—not very high at all. If we treat a person with antibiotics but they don't have an infection, no benefit will be obtained. Perhaps that's true here, too. How about performing a trial with high starting homocysteine levels of, say, 18 or even 30? Or, choosing people with specific genetic defects that cause very high levels (e.g., 3',5'-methyltetrahydrofolate reductase deficiency)? Whether B vitamin treatment benefits these specific groups is unknown and has not been answered by the NORVIT or HOPE trials.
* 60–80% of participants in these studies were taking statin cholesterol drugs. We know that this results in a 30% reduction in heart attack and death. It's possible that the benefits of homocysteine reduction were diluted by the use of statin agents in the majority of participants. However, eliminating the use of statin drugs would be probably be criticized as unethical in view of their established track record of preventing heart attack.
* Approximately 30% of the placebo group were taking various nutritional supplements, including B vitamins. In other words, the placebo group was not truly a placebo group. This may have also diluted the differences between placebo and treated groups.
* Perhaps homocysteine is indeed a risk for vascular disease but the treatment regimen of B vitamins is the wrong method to reduce it. Dr. Loscalzo of Harvard Medical School has made this proposal and suggested that we continue to seek other avenues for homocysteine reduction.32
"Clearly, folic acid, vitamin B12, and vitamin B6 are not the therapeutic solution expected, and they do not provide a preventive benefit in patients with mild hyperhomocysteinemia. The straightforward but incorrect view that folic acid can decrease homocysteine levels and, thus, reduce the risk of atherosclerosis effectively may be an unintended consequence of oversimplifying a complicated metabolic network."
Dr. Joseph Loscalzo
Harvard University
Despite the vigor of the epidemiologic association of homocysteine and heart attack and stroke risk, additional treatment trials still need to better define how to best manage vitamin supplementation—or other treatments. Studies that include participants with higher homocysteine levels are needed.
Should we believe Dr. Bonaa's contention that B vitamins increase risk of cardiovascular events? We believe this to be a statistical fluke. It is highly improbable that a simple regimen of B vitamins causes events and it is more likely that the small effect observed was simply a result of the relatively small number of people involved that generated this statistical anomaly.
Conclusion
The homocysteine hypothesis is not dead. We simply cannot dismiss the considerable observations generated over the last 30 years that relate homocysteine and increased risk. But the issues are clearly not fully understood.
The NORVIT and HOPE-2 trials tell us that taking a regimen of folic acid, vitamin B6, and vitamin B12 is likely of no benefit for reduction of cardiovascular events when homocysteine levels are in the range of 12 µmol/l or so.
If you are already taking a regimen of B vitamins to reduced homocysteine, should you toss them in the garbage? No, absolutely not! There are other benefits to B vitamins—increased energy, improvements in memory, a modest reduction in blood pressure, and other non-cardiac effects—that still make them worthwhile. Given the existing body of data in total, we do not believe there's any merit to the concern that B vitamins introduce risk.
What if you have a high homocysteine level of, say, 24 µmol/l? Will you benefit from reduction of homocysteine? This important question remains unanswered. Levels this high predict very heightened risk of events. Given the existing and incomplete clinical data, we continue to advise treatment at these levels. In fact, we still try to reduce homocysteine levels that exceed 14 µmol/l. Though we do this with incomplete validation, the potential risks of having a very high homocysteine are so great, yet the risks of treatment so low or non-existent, that we continue to reduce these levels.
There are still many aspects of homocysteine that need to be explored. There's no avoiding prior observations that this toxic amino acid, even at levels regarded as normal, exaggerate the adverse effects of other atherosclerotic risk factors and heighten long-term risk osteoporosis, depression, blood clot formation, even cancer.
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