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Mainstream Doctors Still Confused About Homocysteine

June 2006

By William Faloon

Other Cardiac Risk Factors Ignored

The design of these studies took into account conventional risk factors for vascular disease such as cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, glucose, body mass index, and blood pressure. For example, the average fasting glucose level at baseline was 128.8 mg/dL in one group receiving the B vitamins and 125.7 mg/dL in the placebo group. Both groups clearly had poor glucose control (pre-diabetic, at a minimum).

The independent vascular disease risk factors that were ignored include C-reactive protein, fibrinogen, fasting insulin, hemoglobin A1C, and free testosterone. Imbalances of any one of these “other” risk factors would have almost certainly negated the benefit that would be expected from a modest reduction in homocysteine.

The evidence linking C-reactive protein to vascular disease risk is overwhelming.65-82 In one scientific study after another, elevated levels of C-reactive protein are shown to be strong independent markers for determining who is likely to suffer a heart attack or stroke. Without factoring in proven risk factors such as C-reactive protein (along with fibrinogen,83-93 free testosterone,94-97 and others), it is difficult to know whether more subjects in the B-vitamin group required additional therapies beyond modest homocysteine reduction.

Other than the most basic conventional medical interventions, study subjects continued following the unhealthy lifestyles that may have induced their vascular disease, including cigarette smoking and poor eating habits. It is quite a leap of faith for the designers of these studies to have expected that modest homocysteine reduction would overcome dangerous lifestyles that are proven to cause cardiovascular diseases.

10 Daggers of Arterial Disease

The 10 Daggers: Elevated C-reactive Protein, Excess LDL, Excess Insulin, Low HDL, High Glucose, Excess Triglycerides, Low Free Testosterone, Excess Fibrinogen, Excess Homocysteine, Hypertension.

Because unhealthy lifestyle choices and normal aging can damage arteries, the arterial system serves as an Achilles heel of health for millions of adults in modern Western societies.

In rare cases, arterial disease may have just one cause. An example is the severe atherosclerosis observed in children who suffer from a genetic defect that causes severe hyperhomocysteinemia. In these children, blood homocysteine levels can exceed 100 µmol/L, and they can die in early life from advanced systemic atherosclerosis.

For typical heart attack victims, however, multiple factors cause arterial disease. To elucidate this point, the image above depicts daggers aimed at a healthy heart. Any one of these daggers would kill if thrust deep into the heart. In the real world, however, aging humans suffer small pricks from the point of many of these daggers over a lifetime. Although none of the pricks by itself is enough to cause a heart attack, the cumulative effect of these dagger pricks (risk factors) is arterial occlusion and, far too often, angina or acute heart attack.

This Study Has Nothing to Do with Healthy People

Despite the media proclaiming that the homocysteine theory of vascular disease has been discredited, the fact is that the authors of the studies themselves state that the findings pertain only to those with existing vascular disease.

Nowhere in the studies do they suggest that healthy people seeking to prevent atherosclerosis may not benefit from reducing their homocysteine levels. The authors of all of the studies went to great length in explaining why homocysteine is such a dangerous amino acid.

In today’s world of sound bites, the message from a study of people with serious disease somehow is distorted into a news story that is supposed to pertain to those who do not even have the disease. For instance, we know that selenium does not cure cancer, but it certainly appears that it prevents certain cancers.98 The fact that selenium is not an effective cancer treatment does not mean that those seeking to prevent cancer should not take it.

These two studies showed that modest homocysteine reduction by itself did not prevent cardiac events in those with pre-existing disease. This has no relevance for those seeking to maintain healthy arterial function by keeping their homocysteine in the lower ranges before they develop severe arterial disease.

In fact, one of these same groups of researchers is initiating a five-year study of healthy individuals to ascertain whether modest homocysteine reduction lowers vascular disease risk. The headline-hungry media ignored the fact that homocysteine-lowering therapies are still being researched when proclaiming the homocysteine theory of arterial disease to be “dead.”

Cross-section of an artery demonstrating plaque.

Lethal Misconceptions About Atherosclerosis

The hottest buzzword in cardiovascular research today is endothelial dysfunction, a term that describes the structural and functional damage to the inner arterial wall that so often results in athero-sclerosis.

Atherosclerosis is the cause of most heart attacks and strokes, yet many doctors still do not understand that this artery-blocking process is both initiated and accelerated via the destructive endothelial dysfunction process.

The inner lining of the arterial wall is made up of a thin layer of cells called the endothelium. The endothelium protects the smooth muscle in the middle wall of the artery from direct contact with the blood. The endothelial barrier is important to arterial health because many blood components are highly toxic to the artery’s smooth muscle (that lies directly beneath the endothelium). When these damaging blood components attack the artery’s smooth muscle, the process of atherosclerosis is initiated.

Among the blood components that are damaging to the inner lining of arteries are glucose,99,100 homocysteine,101-122 low-density lipoprotein (LDL),123-131 free radicals,109,132-136 and pro-inflammatory cytokines.4,137-147

To protect the artery’s elastic smooth muscle against these damaging agents, it is critical to maintain an intact and properly functioning endothelium.

The endothelium can be disrupted at an early age because of poor health habits such as cigarette smoking, poor diet, and nutrient deficiencies. The aging process itself results in endothelial dysfunction that can be caused by a number of known risk factors.

The inner wall of diseased arteries is a battleground where multiple pathological reactions take place. Endothelial dysfunction occurring in damaged arteries provides fertile soil for the seeds of atherosclerosis. To expect a modest reduction of homocysteine to reverse this devastating process—especially after cardiac disease has already manifested—flies in the face of all that has been learned about the underlying causes of heart attack, stroke, and other vascular diseases.

What Causes Endothelial Dysfunction?

High blood pressure,148-153 elevated LDL,123-31 low HDL,154-156 cigarette smoking,157-163 diabetes,164-169 obesity,170-172 and lack of exercise173-175 all contribute to endothelial dysfunction and the subsequent development of atherosclerosis.

Additional endothelial-damaging factors include excess glucose,99,100 insulin,176 iron,177-179 homocysteine,103-122 fibrinogen,85-93 and C-reactive protein,65-82 as well as low free testosterone (in men).94-97

Homocysteine is dangerous because it can induce initial injury to the endothelium, then facilitate the oxidation of the fat/LDL that accumulates beneath the damaged endothelium, and finally contribute to the abnormal accumulation of blood components around the atherosclerotic lesion.

Fibrinogen is a clotting factor that accumulates at the site of the endothelial lesion, contributing to plaque buildup or participating in the blockage of an artery by a blood clot after an unstable atherosclerotic plaque ruptures.

Glucose at even high-normal levels may accelerate the glycation process that causes arterial stiffening, while high-normal fasting insulin inflicts direct damage to the endothelium.

High levels of iron promote LDL oxidation in the damaged endothelium, while low levels of testosterone appear to interfere with normal endothelial function.

C-reactive protein not only is an inflammatory marker, but also directly damages the endothelium. Chronic inflammation, as evidenced by persistent high levels of C-reactive protein, causes initial injuries to the endothelium and also accelerates the progression of existing atherosclerotic lesions.

Clearly, then, the degenerative process of endothelial dysfunction has multiple underlying causes. A modest reduction of homocysteine alone is not going to overcome all of the other risk factors involved in arterial degeneration. Nor is modest homocysteine reduction going to reverse a lifetime of cumulative damage to the arterial wall. Yet that is what these two recent studies were designed to demonstrate.

How Atherosclerosis Develops

Atherosclerosis begins with changes in endothelial cell function that cause white blood cells moving through the blood to stick to the endothelium instead of flowing by it normally. This weakens the endothelium, which allows blood cells and toxic substances circulating in the blood to pass through the endothelium and enter the sub-endothelial compartment. Lipid or fat-cell-like substances such as LDL, cholesterol, and triglycerides in the blood then accumulate in this sub-endothelial compartment that separates the endothelium from the smooth muscle middle arterial wall.

The lipids that accumulate in the broken endothelium become oxidized. This causes them to signal the endothelial cells, which then alert smooth muscle cells to begin a “repair” process that eventually results in an atherosclerotic lesion. Depending on an individual’s risk factors (poor diet, lack of exercise, smoking, high blood pressure, and the aging process itself), fat accumulation continues and the atherosclerotic process accelerates.

White blood cells called macrophages then invade the area to digest the fat. Smooth muscle cells that have migrated to the area have already changed their nature to also scavenge fat. These fat-laden white blood cells and smooth muscle cells are called “foam cells.”

Foam cells induce chronic inflammatory attack by various immune components. Smooth muscle cells try to curtail the injury to the endothelium by producing collagen, which forms a cap over the injury site. Then calcium accumulates and forms a material resembling bone. This is why atherosclerosis used to be called “hardening of the arteries.”

This complex array of foam cells, calcification, and lipid accumulation is called an atherosclerotic plaque. As the plaque grows, it often becomes unstable and vulnerable to acute rupture that exposes the contents of the plaque to the blood. Platelets can then rapidly accumulate around this ruptured plaque, resulting in a blockade (or blood clot) on the inner surface of the blood vessel wall. This clot can become very large and occlude the vessel. Even small plaques, if they rupture, can interfere with blood flow and cause an acute heart attack. Alternatively, atherosclerotic plaques can enlarge to such a degree as to completely block blood flow.

When reviewing the complex interplay involved in the development and progression of atherosclerosis, it defies scientific principle to take patients with pre-existing endothelial dysfunction and try to prevent future cardiac disease by only modestly reducing homocysteine levels.

Why These Two Studies Were Doomed to Fail

Homocysteine is one of many causes of endothelial dysfunction. Endothelial dysfunction is known to occur in otherwise healthy people with elevations in fasting homocysteine ranging from 15 to 35 µmol/L.180 Furthermore, in otherwise healthy people, impaired endothelial function is seen with small increases in plasma homocysteine (2-3 µmol/L), even when blood homocysteine does not rise above the upper limit of “normal” (15 µmol/L).181 This means that even relatively low circulating levels of homocysteine can damage the arterial wall!

Despite the documented evidence of homocysteine’s adverse effects on normal endothelial function, expecting a significant drop in cardiovascular risk in a group of patients with severe pre-existing endothelial dysfunction with a modest dose of B vitamins is quite a stretch. Yet, that was exactly the assumption made in the two recent studies.

For example, in one of the homocysteine-lowering trials, patients had to have suffered a heart attack within seven days of enrolling in the study. These patients would have already had significant endothelial impairment, and it is well known that the risk of sudden death is greatly increased during the time after a heart attack. For example, a study published in the New England Journal of Medicine evaluated 14,609 patients who suffered heart attacks. The risk of dying was highest in the first 30 days after a heart attack. In fact, 83% of all patients who died suddenly did so in the first 30 days after hospital discharge, and risk persisted for up to two years.182 Clearly, these patients had a high degree of endothelial dysfunction to begin with, and were a very sick group of patients. Assuming that B vitamins alone would have a major impact in this very sick patient population—with severe, pre-existing endothelial dysfunction and at high risk of sudden death—is a major design flaw.

When one steps back and looks at what was done in these studies, it should be no surprise that cardiac risks were not lowered in the B-vitamin groups. Based on everything we know about arterial disease, it would have been impossible to reverse the severe arterial damage in these patients merely by reducing homocysteine levels a few points within the normal mid-range.

The study subjects’ baseline homocysteine levels were not severely high. This means it is likely that their arterial disease was caused by some of the other known risk factors. For instance, compared to the placebo arm, a statistically significantly higher number of people in the B-vitamin group of one study were treated with warfarin (Coumadin®). Could this point to some unknown factor at baseline that increased cardiac risk in the B-vitamin group?

A Windfall for Drug Companies

Pharmaceutical companies profit more from sales of cardiac drugs than from any other class of medication.

With all the media hype about homocysteine not being a cardiac risk factor, many doctors will advise their patients to discontinue their B-vitamin supplements. This is particularly unfortunate for the coronary artery disease patients with homocysteine readings of 15 µmol/L and above. While these two studies do not relate to cardiac patients with these higher homocysteine readings, hurried doctors (who neglected to read the actual studies) may uniformly advise all their cardiac patients to discontinue B-vitamin supplements.

Uninformed consumers will reduce their B-vitamin consumption based on media reports that homocysteine is no longer considered a cardiac risk factor.

All of this adds up to a financial windfall for drug companies, which stand to sell their expensive cardiac drugs to millions of new heart attack patients who become victims of homocysteine-induced atherosclerosis.

Excess homocysteine causes more than just heart attacks. Osteoporosis,183-185 depression,186-189 and Alz-heimer’s disease,190-200 as well as sharply increased risks of stroke,37-50 are linked with elevated homocysteine. If even a small percentage of the American public discontinues its B-vitamin supplements, the demand for prescription antidepressants, anti-Alzheimer’s drugs (acetylcholinesterase inhibitors), and bone-building prescription medications such as the bisphosphonates is likely to skyrocket.

Discrediting low-cost nutrients that have been shown to reduce disease risk is great news for companies that sell drugs to those who fall ill. In a forthcoming issue, we will follow up with a feature article by Dr. William Davis discussing novel nutritional strategies that you can use to lower high homocysteine levels and gain truly effective control of this potentially lethal compound.