~Atherosclerosis (Coronary Artery Disease)

~Atherosclerosis (Coronary Artery Disease)
Reprinted with permission of Life Extension®.

The most common form of heart disease is caused by atherosclerosis. It is generally referred to as coronary heart disease or hardening and/or thickening of the arteries. Atherosclerosis involves the slow buildup of deposits of fatty substances, cholesterol, body cellular waste products, calcium, and fibrin (a clotting material in the blood) in the inside lining of an artery. The buildup that results (referred to as plaque) can partially or totally block the flow of blood through the artery. This can lead to the formation of a blood clot (thrombus) on the surface of the plaque. If either of these events occurs and blocks the entire artery, a heart attack or stroke may result.

Atherosclerosis-related diseases are a leading cause of death and impairment in the United States, affecting over 60 million people. Additionally, 50% of Americans have levels of cholesterol that place them at high risk for developing coronary artery disease. However, cholesterol is only one factor that causes the occlusion of arteries that is technically known as atherosclerosis.

The high mortality of atherosclerosis, the widespread suffering, and the huge economic impact demand integrated medical approaches and therapies. This protocol reflects that demand.


Although the terms are used interchangeably, atherosclerosis (or "hardening of the arteries") is one type of arteriosclerosis. Arteriosclerosis is actually a generic term for a number of diseases in which the arterial wall becomes thickened and loses elasticity. The term atherosclerosis is derived from combining the Greek words athero (paste) and sclerosis (hardness). Atherosclerosis involves a process that causes a build-up of deposits on artery walls called plaque. Typically, the deposits occur in the tunica intima (the innermost layer of a blood vessel) of large and medium-sized arteries. The plaques contain fatty substances, cholesterol, cellular waste products, fibrin found in blood), and calcium.

Plaque can become large enough to partially or totally block the flow of blood through an artery. A build-up of plaque or a rupture occurring within the plaque can result in a blood clot. The dislodged plaque material can travel to other parts of the body (e.g., brain, heart, kidneys, and legs), resulting in serious injury to tissues and organs (AHA 2002b; NIH 2003; Washington University 2003), principally by blocking blood flow through smaller arteries.

Atherosclerosis is a progressive, complex disease often associated with the aging process, but for some it starts much earlier in life. One study found that healthy soldiers returning from World War II already had occluded arteries (22% occlusion) even though their average age was 22.1 years. Early signs of atherosclerosis have been identified in children.

Half of the children and siblings of individuals with diseased coronary arteries had signs of atherosclerosis, even though they had no symptoms of heart or vessel disease (Strong 1986; Pharmabiz 2001; AHA 2002b). This indicates that genetic factors play an important role, but as you will soon read, it is possible to modify many of these hereditary defects.

Atherosclerosis is a factor in several conditions including coronary heart disease (CHD), myocardial infarction (MI), angina pectoris, cerebral vascular disease (CVD), thrombotic stroke, transient ischemic attacks (TIAs), insufficient blood supply to lower limbs and feet (claudication), organ damage, and vascular complications of diabetes (NIH 2003). Because symptoms can be few or minor in the early stages, atherosclerosis is referred to as "the silent killer" because it can progress undetected for years, particularly in individuals who are at high risk for heart disease.

Elevated blood pressure is associated with many factors (obesity, lack of exercise, increased blood sugar, and cholesterol levels), but high blood pressure can also be an indication of atherosclerosis. Increases in blood pressure generally occur gradually, concurrent with signs of advancing atherosclerotic disease. A study of 18,682 healthy American males (age 40-84 years; follow-up of 11.7 years) confirmed that blood pressure readings of 140/90 or higher were a risk factor for cardiovascular disease (including stroke and cardiovascular death). Hypertension is a major cardiovascular risk factor and borderline, isolated, systolic hypertension deserves special attention as a cardiac risk factor. Systolic hypertension has greater prognostic significance than diastolic hypertension. It is now recognized that the effective treatment of systolic hypertension proportionally reduces cardiac risk (O'Donnell et al. 1997; Izzo 2000).

Note: On May 21, 2003 the Journal of the American Medical Association provided new guidelines for hypertension management: (1) in individuals over 50 years of age, systolic blood pressure over 140 mmHg is a greater risk factor for cardiovascular disease than diastolic blood pressure; (2) beginning at 115/75 mmHg, risk of cardiovascular disease doubles with each increment of 20/10 mmHg; (3) individuals who have normal blood pressure at age 55 have a 90% lifetime risk for developing hypertension; (4) individuals with a systolic blood pressure 120 to 139 mmHg or a diastolic blood pressure 80 to 89 mmHg should be considered pre-hypertensive. To prevent cardiovascular disease, these individuals require lifestyle changes that promote health (Chobanian et al. 2003).

Precisely what causes atherosclerosis is not known, but several theories have been proposed. Scientists think atherosclerosis begins with damage to the endothelium (the inner layer of an artery). Possible causes of damage to the arterial wall are free-radical reactions; elevated levels of oxidized serum cholesterol, triglycerides, fibrinogen, homocysteine, insulin; high blood pressure; obesity; chronic inflammation, lifestyle factors (physical inactivity and tobacco smoking); and diabetes (AHA 2002b).


Some controllable mechanisms that are involved in the development of atherosclerosis are: (1) homocysteine overload, (2) oxidation of low density lipoprotein-cholesterol (LDL-C), and (3) abnormal platelet aggregation; and (4) inflammation. This protocol will empower individuals, enabling them to positively impact the factors contributing to atherosclerosis.

There is evidence that dietary supplementation, combined with appropriate changes in lifestyle, diet, and an exercise program, can prevent or reverse cardiovascular disease (Oakley 1998). The conventional medical establishment has long questioned the benefits of vitamin supplementation, but now even the American Medical Association encourages the use of homocysteine-lowering vitamin supplements to reduce the risks of cardiovascular disease (McCully 1998).

The Life Extension Foundation recommends using four different approaches to reduce elevated homocysteine levels. One approach is to supply supplements such as folic acid, vitamin B12, and trimethylglycine (TMG) to increase the remethylation of homocysteine back to methionine The second approach employs the detoxification method using vitamin B6 to enhance the transsulfuration pathway to convert homocysteine into cysteine, which can be used to synthesize such beneficial amino acids such as glutathione and taurine. The third approach entails addition to the diet of ‘methylated nutrients', such as creatine and various choline-containing supplements. More than half of the body's S-adenosylmethionine (SAMe) is used to synthesize creatine alone (Devlin 2002), which generates most of the homocysteine that must be either remethylated or detoxified. The fourth approach is to cut down or eliminate ingestion of foods containing high amounts of methionine such as red meat.

  • Overview of Metabolic Pathways
  • Food Sources of Methionine and Homocysteine
  • How Does Homocysteine Contribute to Atherosclerosis
  • The Homocysteine/Atherosclerosis Link is not Novel
  • Homocysteine Testing: A Measurement of Risk
  • Do Not Be Misled
  • Oxidized LDL
  • Abnormal Platelet Aggregation
  • Fibrinogen
  • Inflammation
  • Low Testosterone = Increased Heart Attack Risk

Overview of Metabolic Pathways

All homocysteine is derived from the essential amino acid methionine. Homocysteine is converted into cysteine, methionine, or SAMe (Bottiglieri 1996). SAMe donates methyl groups to form creatine, phosphatidylcholine, carnitine, and other compounds (Devlin 2002). These methylation reactions create homocysteine that must be (1) remethylated to methionine or (2) catabolized into cysteine, glutathione, and taurine. Homocysteine is mostly remethylated (Jacobs et al. 2001; Ratnam et al. 2002) with new methyl carbons supplied by folic acid.

Elevated homocysteine occurs in man with nutritional deficiencies in folic acid, vitamin B12 and vitamin B6, particularly in the elderly or in those with these genetic defects. The prevalence of these genetic defects, associated with marginal B vitamin intake, indicates that homocysteine is a risk factor in cardiovascular disease (Guilland et al. 2003; Haynes 2002).

Elevated homocysteine is predominantly remethylated by 5-methyltetrahydrofolic acid (5-MTHF) to resynthesize methionine (Finkelstein et al. 1984) using the enzyme methionine synthase. High levels of methionine decrease methionine synthase, the primary enzyme for remethylation of homocysteine.

Humans with cardiovascular disease showed a significantly higher plasma homocysteine and reduced TMG levels (Schwahn et al. 2003). Scientists have found that mice deficient in remethylation enzymes had high levels in liver of homocysteine with low levels of phosphocholine and TMG. These levels were restored to normal by supplemental TMG (Schwahn et al. 2003).

About 11% of Caucasians possess gene mutations of a key enzyme involved in remethylation of homocysteine and express mild homocysteine elevation that is normalized by folic acid (Wilcken et al. 1998). Additional genetic mutations to this enzyme and to methionine synthase occur in man (Rozen 2000). Hyperhomocysteinemia is common when any of three different enzymes are defective in man (Selhub 1999). A genetic deficiency of the enzyme that irreversibly catabolizes homocysteine that was found in 32 patients with endothelial cell and smooth muscle cell dysfunction and increased thrombogenesis was treated with high folic acid, vitamin B6, and vitamin B12 (Wilcken et al. 1998). Fifteen of the patients were unresponsive to vitamin B6 but were successfully treated with TMG. TMG is most effective if taken regularly (Dudman et al. 1996).

What is considered to be normal levels of homocysteine (5-15 micromoles/L) is subject to debate because there is a proportional relationship between the development of cardiovascular disease and homocysteine (Robinson et al. 1995). Specifically, all levels over 6.3 mcmol/L proportionally increased cardiovascular disease.

Methionine generates SAMe (Bottiglieri 1996), the principal provider of methyl groups for biosynthetic reactions. Half of SAMe is used to biosynthesize creatine (Finkelstein et al. 1984) predominantly in kidney, liver (Stead et al. 2001; Lee 1998), and perhaps brain (Silveri et al. 2003). Humans excrete 1.4 grams of creatinine in urine per day, mostly derived from creatine (Devlin 2002). Animals fed (0.3%) creatine showed inhibition of creatine biosynthesis at the gene level (McGuire et al. 1984). A human consuming 400 grams of food per day may only require 1 gram of creatine to inhibit creatine biosynthesis and cut in half production of homocysteine. Supplemental creatine diminishes the need for SAMe, reduces formation of homocysteine, and the need to remethylate homocysteine. Supplemental creatine for two weeks lowered homocysteine by 25% in rats (Stead et al. 2001). Human subjects taking 1600 mg of SAMe per day increased phosphocreatine in brain (Silveri et al. 2003). This increase of phosphocreatine suggests creatine biosynthesis was enhanced by SAMe.

The liver biosynthesizes phosphatidylcholine for export as lipoproteins. This is a major use of SAMe in liver for the biosynthesis of choline via methylation of phosphatidylethanolamine (Devlin 2002). This is a primary source of homocysteine and a therapeutic target for hyperhomocysteinemia (Noga et al. 2003). Animals showed "significant depression of [homocysteine remethylation] when choline plus creatine were infused" (Lobley et al. 1996).

Food Sources of Methionine and Homocysteine

Methionine is the only amino acid that creates homocysteine, therefore, individuals who eat foods high in methionine (red meat) and develop high serum levels of homocysteine might benefit from intake of additional vitamins that enhance remethylation of homocysteine including folate, vitamin B12, and TMG, which detoxify dietary homocysteine (and methionine). Dietary intake of supplements containing creatine and phosphatidylcholine, CDP-choline, a-glycerylphosphorylcholine, and choline, reduces the demand for methylation reactions and lower levels of homocysteine. Vitamin B6 facilitates homocysteine detoxification via the transsulfuration pathway.

Elevated homocysteine can be very pronounced if there is a genetic defect in the transsulfuration pathway that affects the activity of the B6-dependent enzyme, cystathionine-ß-synthase (Perry 1999; Guilland et al. 2003). High doses of vitamin B6 are often required to suppress excessive homocysteine accumulation. Cofactors derived from vitamin B6 catalyze the catabolism of homocysteine via pathways of transsulfuration. During transsulfuration, homocysteine is converted to cysteine, taurine, and eventually, sulfate. The amount of vitamin B6 required to lower homocysteine varies considerably among individuals, and varies according to the severity of certain clinical (and subclinical) genetic disorders related to the metabolism of this amino acid. Some of the enzyme mutations alter the binding coefficients for B6, thus increasing the requirement of the enzyme for vitamin B6.

Genetic deficiency of cystathionine-ß-synthase in 32 patients (with adversely affected endothelial cell and smooth muscle cell function, and increased thrombogenesis) was effectively treated with high dietary levels of vitamin B6, vitamin B12, and folic acid. Half of the patients, apparently with minimal enzyme function even at high levels of vitamin B6, benefited by additional supplementation with TMG (Wilcken et al. 1998). This genetic deficiency is particularly troublesome because if residual function of the enzyme cannot be restored by vitamin B6, then the elimination of excess homocysteine and methionine through the normal catabolic route is difficult. Dietary intake of methionine must be carefully controlled and excess amounts of methylating vitamins are needed to remethylate homocysteine.

Excessive doses of vitamin B6 should not be taken if peripheral neuropathy results (following chronic dosages of 300–500 mg daily) (IM 1998; NIH 2001). Homocysteinemia can be monitored through blood tests to determine if supplemental B6 is maintaining safe levels in homocysteine. Some individuals lack the enzyme pyridoxine phosphokinase that converts vitamin B6 into its biologically active cofactor form, pyridoxal-5-phosphate (Ubbink et al. 1993). If low-cost vitamin B6 (pyridoxine) supplements do not sufficiently lower homocysteine levels, then a higher-cost pyridoxal-5-phosphate supplement may be required. (Supplement recommendations are in the Summary section at the end of this protocol.)

How Does Homocysteine Contribute to Atherosclerosis?

Homocysteine often causes the initial lesions on arterial walls that enable accumulated LDL and fibrinogen to eventually obstruct blood flow. Homocysteine contributes to the oxidation of LDL, accumulation of arterial plaque, and subsequent vascular blockage. Homocysteine directly damages cells by promoting oxidative stress. Homocysteine also can cause abnormal arterial blood clots (thrombosis) that can completely block an artery. Even if cholesterol and triglyceride levels are not significantly elevated, homocysteine alone promotes atherosclerosis and thrombosis.

Consumption of remethylation-enhancing nutrients such as folic acid, TMG, and vitamin B12 provides one of the most readily available and effective anti-aging therapies presently known. Provision of methylated nutrients such as creatine and several choline derivatives might effectively diminish the formation of homocysteine in vivo, thereby reducing homocysteine levels by reducing its formation. Useful choline-containing supplements include phosphatidylcholine (lecithin), cytidine-5-diphosphocholine (CDP-choline), choline, and a-glycerolphosphorylcholine (a-GPC).

However, it is important to tailor the intake of remethylation-enhancing and methylated nutrients to each individual's biochemistry. The most effective method to assess your rate of remethylation is to measure homocysteine blood levels. Elevated serum homocysteine is a classic sign of deficient remethylation and/or the over-production of methylated biochemical intermediates, which is correctable by ensuring the proper intake of remethylation-enhancing and methylated nutrients such as folic acid, vitamin B12, TMG; and creatine, CDP-phosphatidylcholine, phosphatidylcholine, a-glycerylphosphorylcholine, and choline.

Note: Recommendations for lowering homocysteine levels have been published by the Journal of the American Medical Association (Tucker et al. 1996) and in the New England Journal of Medicine (Malinow et al. 1998). Conventional physicians have begun to recognize the etiology of homocysteine in heart attack and stroke. Many now recommend folic acid to lower homocysteine levels in patients with coronary artery disease (Verhoef et al. 1996). However, in most instances it requires more than just folic acid to adequately suppress elevated blood levels of homocysteine.

The Homocysteine/Atherosclerosis Link is not Novel

The dangers of homocysteine were recognized in the 1950s (McCully et al. 1999). The Foundation identified a role for homocysteine in cardiovascular disease in its November 1981 issue of Life Extension Magazine (pp. 85–86). Life Extension's position has been confirmed by numerous studies showing that homocysteine, like cholesterol, is strongly associated with risk of heart disease (Haynes 2002; Guilland et al. 2003). Findings suggest there is no safe "normal range" for homocysteine. While commercial laboratories state that normal homocysteine can range from 5–15 micromoles/L of plasma, epidemiological data has revealed that homocysteine levels above 6.3 cause a steep, progressive risk of heart attack. The risk for coronary artery disease rises with increasing plasma homocysteine regardless of age and sex (Robinson et al. 1995).

Based on results of very large, long-term studies, elevated levels of homocysteine are associated with cardiovascular disease risks including male gender, age, smoking, high blood pressure, elevated cholesterol levels, and lack of exercise (Nygard et al. 1995). The overall risk of coronary and other vascular disease was 2.2 times higher in subjects with plasma total homocysteine levels in the top fifth of the normal range compared to those in the bottom four-fifths. Overall risk was independent of other risk factors, but was notably higher in subjects who smoked or had high blood pressure (Graham et al. 1997). The risk of death after 4–5 years was proportional to the level of plasma total homocysteine (Nygard et al. 1997). 3.8% of the subjects in the group with the lowest levels (< 9 micromoles/L) had died compared to 25% in the group with the highest levels (> 15 micromoles/L).

The American Heart Association recognized the role of homocysteine in atherosclerosis by issuing an advisory statement emphasizing the importance of reducing homocysteine blood levels and screening high-risk individuals (e.g., senior subjects, individuals diagnosed with chronic renal failure, thromboembolic disease or hypothyroidism, and patients taking drugs such as L-dopa, methotrexate, and theophylline) (Malinow et al. 1999).

Homocysteine Testing: A Measurement of Risk for Atherosclerosis and Cardiovascular Disease

Plasma homocysteine levels were 11% higher in cases of myocardial infarction (MI), whereas dietary and plasma levels of vitamin B6 and folate were lower (Verhoef et al. 1996). This is further evidence that plasma homocysteine is an independent risk factor for MI and that folate was the most important determinant of plasma homocysteine, even in subjects with apparently adequate folate intake. Fasting total plasma homocysteine levels were a strong predictor of severe coronary artery atherosclerosis. These researchers found a significant correlation of homocysteine levels with increasing numbers of occluded arteries. This showed a positive association between plasma homocysteine levels and the risk of coronary atherosclerosis. This association existed over such a wide range of homocysteine levels that no level could be established below which the risk was not related to homocysteine levels (Verhoef et al. 1997).

(Note: "Post-load" blood levels of homocysteine can be measured after giving a "load" of oral methionine, the precursor of homocysteine. Each 10% increase in homocysteine levels carried with it a 10% increase in the risk of developing heart disease. A similar percentage increase in cholesterol levels represents a 20% increased risk for heart disease. A 1999 study by Verhoef et al. was important because of its size and that it showed a positive correlation of risk of atherosclerosis with both "fasting" homocysteine levels and "post-load" homocysteine levels). The study showed that: (1) fasting homocysteine levels were lower in women than in men, (2) homocysteine levels were associated with age in both sexes, including post-menopausal women, (3) homocysteine levels after a methionine load were higher in women than in men, (4) in pre-menopausal women, low circulating levels of vitamin B6 increased the risk of vascular disease by two- to three-fold, independent of homocysteine, and (5) in men, low folate levels increased the risk of cardiovascular disease by 50%. It was concluded that "elevation of plasma total homocysteine appears to be at least as strong a risk for vascular disease in women as men, even before menopause" (Verhoef et al. 1999).

Do Not Be Misled

Individuals taking vitamin supplements often think they are protected from the lethal effects of homocysteine, but supplement users can have homocysteine levels far above the accepted safe level of 6.3–7.0 micromoles/L. The Life Extension Foundation discovered a flaw in conventional homocysteine-reduction therapy back in 1999. The findings of this original study published in Life Extension magazine showed that a significant percentage of people taking vitamin supplements still have dangerously elevated blood homocysteine. Although folic acid, vitamin B12, vitamin B6, and TMG can lower homocysteine levels, it is difficult to know if a safe level of homocysteine is attained unless homocysteine levels are determined by blood testing.

Recommendation: Homocysteine blood testing should be done to establish a baseline as an indicator of present disease risk, and to monitor the effects of homocysteine-lowering supplements.

Continued . . .

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