While the association between L-arginine and nitric oxide is clear, a few newer studies have suggested that supplemental L-arginine alone may not boost nitric oxide in patients who recently had a heart attack. One study from Johns Hopkins Medical Institutions in Baltimore was stopped after researchers found an increased risk of death in heart attack patients taking L-arginine. There are several possible reasons for this, including the important point that nitric oxide can generate free radicals. Life Extension, however, notes that studies questioning L-arginine’s effectiveness failed to provide the necessary antioxidants to counteract any elevation in free radicals caused by the supplement. Thus, Life Extension believes that any person taking L-arginine to lower blood pressure and improve blood flow should also take antioxidants, such as vitamin C and vitamin E.
Antioxidant and Anti-Inflammatory Nutrients
Interestingly, only about half the people with coronary artery disease have more traditional risk factors, such as elevated cholesterol, smoking, high blood pressure, and obesity. Yet all patients with atherosclerosis suffer from endothelial dysfunction and the damaging effects of oxidized LDL, which provides an important building block for plaque deposits. Antioxidant therapy is therefore important to limit the oxidization of LDL and improve the health of the endothelium by limiting the damage caused by inflammatory cytokines. The following antioxidants are some of the most effective studied in atherosclerosis:
Lipoic acid. This naturally occurring antioxidant serves as a coenzyme in energy metabolism of fats, carbohydrates, and proteins. It can regenerate thioredoxin, vitamin C, and glutathione, which in turn can recycle vitamin E. Lipoic acid also helps manage proper serum glucose levels in diabetic patients (Packer L et al 2001). In animal studies, it has been shown to reduce endothelial dysfunction (Lee WJ et al 2005a). Human studies have found that lipoic acid improves endothelial function among people with metabolic syndrome (Sola S et al 2005). Lipoic acid works best in combination with antioxidants including vitamin E, coenzyme Q10, carnitine, and selenomethionine (Mosca L et al 2002).
Garlic. Aged garlic extract has been studied for its ability to reduce inflammation and the damaging effects of cholesterol in the endothelium (Orekhov AN et al 1995). In one study of 15 men with coronary artery disease who were also being treated with statin drugs and low-dose aspirin, two weeks of supplementation with aged garlic extract significantly improved blood flow by improving endothelial function (Williams MJ et al 2005). Another study examined garlic’s ability to improve exercise capacity in patients with proven coronary artery disease. This study of 30 patients found that garlic oil significantly lowered heart rate during a stress test on a treadmill and otherwise eased the heart’s workload during the exercise (Verma SK et al 2005). Finally, high-dose garlic was studied in 152 people with atherosclerotic plaque. Over 48 months, the study participants experienced significantly less increase in plaque deposits than a control group, and an actual regression of plaque was seen in some participants, leading researchers to conclude that garlic had a “not only preventative but possibly also a curative role in arteriosclerosis therapy” (Koscielny J et al 1999).
Ginkgo biloba. Approximately one-third of Ginkgo biloba extract is made up of the flavone glycoside known as quercetin (Hibatallah J et al 1999). Quercetin has been shown to have antioxidant properties and inhibits LDL oxidation in experimental studies (Janisch KM et al 2004). Daily dosing with 120 mg Ginkgo biloba has been documented to reduce markers of lipid peroxidation in humans (Kudolo GB et al 2003). Higher doses (320 mg daily) have may be beneficial in reducing ischemia in patients with atherosclerosis (Mouren X et al 1994). Life Extension, however, cautions against using doses of ginkgo higher than 120 mg daily. This caution is based on the slight possibility that higher doses of ginkgo could induce too strong an antiplatelet effect, which could result in an internal blood vessel bleed.
Quercetin. The so-called French paradox is the phenomenon of low rates of heart disease in a country known for its high intake of fatty foods. Recent research suggests that some of the reasons French people are protected from heart disease is a high intake of quercetin, a potent antioxidant and polyphenol found in red wine (Kuhlman CR et al 2005). Numerous studies have examined quercetin and found it to be both a powerful antioxidant and a stimulator of nitric oxide, which inhibits endothelial proliferation, a hallmark of atherosclerosis (Kuhlman CR et al 2005). Studies have shown the following:
In spontaneously hypertensive rats, quercetin, along with other bioflavonoids, preserved endothelial function by increasing nitric oxide and reducing blood pressure (Machha A et al 2005).
A porcine study showed that quercetin has potent antioxidative properties and protects endothelial cells against induced dysfunction (Reiterer G et al 2004).
Green tea extract. Green tea extracts, which are rich in natural antioxidants and antiplatelet agents, are routinely used in Asia to lower blood pressure and reduce elevated cholesterol. In studies of smokers, 600 mL green tea (not extract) was shown to decrease markers of inflammation and decrease oxidized cholesterol, both of which are intimately involved in the development of atherosclerosis (Lee W et al 2005b). A Japanese study of 203 patients found that the more green tea patients drink, the less likely they are to suffer from coronary artery disease (Sano J et al 2004). This study supported an earlier study that found that greater green tea consumption was related to a reduced presence of coronary artery disease in Japanese men—although not in women (Sasazuki S et al 2000).
Vitamin C (ascorbic acid). Vitamin C inhibits damage caused by oxidative stress. In cigarette smokers, daily supplementation with 500 mg vitamin C significantly decreased the appearance of oxidative stress markers (Dietrich M et al 2002). Another study showed that supplementation with 500 mg vitamin C and 400 IU vitamin E daily significantly reduced the development of accelerated coronary arteriosclerosis following cardiac transplantation (Fang JC et al 2002). Vitamin C’s benefits seem especially profound in people who suffer from both diabetes and coronary artery disease. One study demonstrated that, in this group, vitamin C significantly improved vasodilation (Antoniades C et al 2004).
Vitamin K. Vitamin K is steadily gaining attention for its ability to reduce calcification and help prevent cardiovascular disease (Jie KSG et al 1996). Evidence for the ability of vitamin K to prevent calcification can also be found in an animal study in which researchers administered the anticoagulant warfarin to rats. Warfarin is known to deplete vitamin K. At the end of the study, all the animals had extensive calcification, suggesting they had lost the protective effect of vitamin K (Howe AM 2000).
Vitamin E. Vitamin E is often studied in conjunction with vitamin C for its potent antioxidant powers. It has been shown to decrease lipid peroxidation and inhibit smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxidized LDL uptake, and cytokine production—all of which occur during atherosclerosis (Munteanu A et al 2004; Harris A et al 2002). In cultured arterial endothelial cells, vitamin E increased the production of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation (Wu D et al 2004). Most vitamin E supplements come in the form of alpha tocopherol. Life Extension recommends about 400 IU alpha tocopherol a day, along with at least 200 mg gamma tocopherol and 100 mg of coenzyme Q10. There is a concern that taking only the “alpha” form of vitamin E could deplete the body of gamma tocopherol, a critically important antioxidant. Coenzyme Q10 helps regenerate oxidized vitamin E in the body.
Hormone Therapy for Healthy Arteries
Atherosclerosis is closely associated with hormonal changes in women. However, after menopause, as the levels of all sex hormones decline, the rates of atherosclerosis go up. Both men and women experience significant decline of hormones that play a role in maintaining healthy arterial function. Atherosclerosis is known to increase at the same time that hormone levels are decreasing as a result of age. Overall, levels of dehydroepiandrosterone (DHEA), testosterone, and other hormones decline in aging humans—the same group that is especially at risk for atherosclerosis.
DHEA. DHEA is a precursor to sex hormones such as testosterone and estrogen. Levels of steroid hormones, including DHEA, decline with the age-associated onset of a variety of medical conditions, including chronic inflammation, hypertension, and atherosclerosis. Levels of DHEA in humans are inversely correlated with inflammatory markers (Sondergaard HP et al 2004). Animal studies show a protective role for DHEA in preventing atherosclerosis. Providing DHEA to human vascular endothelial cells in culture increases nitric oxide synthesis, which boosts blood flow (Simoncini T et al 2003). A study showed that men with high levels of DHEA tended to have greater protection against aortic atherosclerosis progression (Hak AE et al 2002).
Phytoestrogens. Following menopause, circulating levels of estrogen are depleted. Phytoestrogens are plant hormones with estrogenic activity. In postmenopausal women, phytoestrogens appear to have estrogen-like benefits such as protection against osteoporosis (Atkinson C et al 2004; Crisafulli A et al 2004a) and possibly hot flashes (Crisafulli A et al 2004b). Phytoestrogens have also been shown to improve vascular function, which tends to decline with age. In one study genistein, a phytoestrogen, provided in a daily 54-mg supplement for one year, significantly improved endothelium-dependent vasodilation in postmenopausal women. Moreover, its benefits were as substantial as those observed in women receiving an estrogen-progestin regimen (Squadrito F et al 2003).
For more information on bioidentical hormone replacement, please see Female Hormone Restoration and Male Hormone Replacement.
Life Extension Foundation Recommendations
Atherosclerosis is a far-reaching disease with devastating consequences. Life Extension’s program for reducing the risk associated with atherosclerosis is based on aggressive measures to promote a healthy endothelium and reduce risk factors associated with coronary artery disease. Because all adults are at risk of atherosclerosis, all adults should make the necessary lifestyle changes to protect their arteries. This means getting adequate exercise under the supervision of a physician and eating a diet rich in fruits and vegetables and low in saturated fat. Also, weight loss by obese and overweight adults is an important element in reducing risk of atherosclerosis.
People who have risk factors for atherosclerosis should take measures to modify them. Risk factors such as diabetes, high blood pressure, abnormal cholesterol, obesity, elevated homocysteine, elevated risk of blood clots, and a pro-inflammatory state are covered elsewhere in this book. The ideal nutritional approach to atherosclerosis takes into consideration all existing risk factors and attempts to modify each one.
Blood testing is a very important part of any risk-reduction program for coronary heart disease. Healthy adults should have their blood tested at least once a year. People who have heart disease or multiple risk factors should have their blood tested twice a year to monitor their progress. A comprehensive blood test will measure levels of blood lipids, C-reactive protein, homocysteine, fibrinogen, and other blood markers. Regular blood pressure monitoring is also important. Life Extension recommends an optimal blood pressure reading of 119/75. Life Extension also recommends that people aim for low levels of C-reactive protein, LDL, homocysteine, and other markers of disease. The following table summarizes the optimal ranges for various blood levels:
1)Blood Test:Fibrinogen
Standard Range:Up to 460 mg/dL
Life Extension’s Optimal Range:Less than 300 mg/dL
2)Blood Test:C-reactive proteinStandard Range:Up to 4.9 mg/L
Life Extension’s Optimal Range:Less than 0.55 mg/L (men)
Life Extension’s Optimal Range:Less than 1.5 mg/L (women)
3)Blood Test:Homocysteine
Standard Range:Up to 15 mmol/L
Life Extension’s Optimal Range:7–8 mmol/L
4)Blood Test:Cholesterol
Standard Range:Up to 199 mg/dL
Life Extension’s Optimal Range:180 to 200 mg/dL
5)Blood Test:LDL
Standard Range:Up to 100 mg/dL
Life Extension’s Optimal Range:Less than 100 mg/dL
6)Blood Test:HDL
Standard Range:No lower than 40 md/dL
Life Extension’s Optimal Range:More than 50 mg/dL
7)Blood Test:Triglycerides
Standard Range:Up to 199 mg/dL
Life Extension’s Optimal Range:Less than 100 mg/dL
Finally, the following nutrients have been shown to improve endothelial function and reduce the damage caused by oxidized LDL, slowing the progression of atherosclerosis:
Folic acid—800 to 5000 micrograms (mcg) daily
Vitamin B12—300 to 2000 mcg daily
EPA and DHA—1400 milligrams (mg) EPA and 1000 mg DHA daily
PLC—1000 to 2000 mg daily
L-arginine—3000 to 12,000 mg daily (in 3 divided doses)
Lipoic acid—150 to 300 mg daily
Garlic—1200 mg daily (Kyolic aged garlic extract)
Ginkgo biloba—120 mg daily
Green tea extract—725 mg daily (93 percent polyphenols)
Quercetin—500 to 1000 mg daily (water-soluble quercetin)
Vitamin C—1000 to 3000 mg daily
Vitamin E—400 international units (IU) daily (with 200 mg gamma tocopherol)
Vitamin K—10 mg daily
Vitamin B6—100 to 750 mg daily
In addition, bioidentical hormone therapy may be recommended, depending on blood testing results. For more information on comprehensive blood testing visitweb site.
Product Availability
All the nutrients and supplements discussed in this chapter are available through
LifeExtension.com
Atherosclerosis Safety Caveats
An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:
Acetyl-L-Carnitine
Acetyl-L-carnitine can cause gastrointestinal symptoms such as nausea and diarrhea.
EPA/DHA
Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.
Discontinue using EPA/DHA 2 weeks before any surgical procedure.
Folic acid
Consult your doctor before taking folic acid if you have a vitamin B12 deficiency.
Daily doses of more than 1 milligram of folic acid can precipitate or exacerbate the neurological damage caused by a vitamin B12 deficiency.
Garlic
Garlic has blood-thinning, anticlotting properties.
Discontinue using garlic before any surgical procedure.
Garlic can cause headache, muscle pain, fatigue, vertigo, watery eyes, asthma, and gastrointestinal symptoms such as nausea and diarrhea.
Ingesting large amounts of garlic can cause bad breath and body odor.
Ginkgo biloba
Individuals with a known risk factor for intracranial hemorrhage, systematic arterial hypertension, diabetes, or seizures should avoid ginkgo.
Do not use prior to or after surgery.
Avoid concomitant use of ginkgo with NSAIDS, blood thinners, diuretics, or SSRI’s.
Gastrointestinal symptoms (nausea and diarrhea) may occur.
Allergic skin reactions may occur.
Elevations in blood pressure may occur.
Green Tea
Consult your doctor before taking green tea extract if you take aspirin or warfarin (Coumadin). Taking green tea extract and aspirin or warfarin can increase the risk of bleeding.
Discontinue using green tea extract 2 weeks before any surgical procedure. Green tea extract may decrease platelet aggregation.
Green tea extract contains caffeine, which may produce a variety of symptoms including restlessness, nausea, headache, muscle tension, sleep disturbances, and rapid heartbeat.
L-Arginine
Do not take L-arginine if you have the rare genetic disorder argininemia.
Consult your doctor before taking L-arginine if you have cancer. L-arginine can stimulate growth hormone.
Consult your doctor before taking L-arginine if you have kidney failure or liver failure.
Consult your doctor before taking L-arginine if you have herpes simplex. L-arginine may increase the possibility of recurrence.
Lipoic Acid
Consult your doctor before taking lipoic acid if you have diabetes and glucose intolerance. Monitor your blood glucose level frequently. Lipoic acid may lower blood glucose levels.
Quercetin
Quercetin can cause headache, mild tingling of the extremities, and gastrointestinal symptoms such as nausea.
Vitamin B6
Do not take 5 milligrams or more of vitamin B6 daily if you are being treated with levodopa, unless you are taking carbidopa at the same time.
Vitamin B12 (cyanocobalamin)
Do not take cyanocobalamin if you have Leber's optic atrophy.
Vitamin C
Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.
Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.
Vitamin E
Consult your doctor before taking vitamin E if you take warfarin (Coumadin).
Consult your doctor before taking high doses of vitamin E if you have a vitamin K deficiency or a history of liver failure.
Consult your doctor before taking vitamin E if you have a history of any bleeding disorder such as peptic ulcers, hemorrhagic stroke, or hemophilia.
Discontinue using vitamin E 1 month before any surgical procedure.
Vitamin K
Do not take vitamin K if you are taking warfarin sodium unless, the vitamin K is specifically prescribed by your physician.
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