Peripheral arterial disease (also known as peripheral arterial occlusive disease) is a broad term for a range of diseases that affect the vasculature (veins and arteries) of the peripheral circulatory system. The peripheral vasculature is mainly responsible for blood flow to the extremities, such as the legs and arms. PAD is caused primarily by atherosclerosis (a buildup of plaque in the arteries) and blood-clotting mechanisms that alter the normal structure and function of the aorta, the arterial branches and the arteries of the legs. The disease can lead to pain, decreased ability to walk, limb amputation and increased risk of death.1 The most common symptom is called intermittent claudication—characterized by leg discomfort during walking that is relieved by rest.2

Risk factors for PAD include cigarette smoking, diabetes, high cholesterol or triglycerides, hypertension (high blood pressure) and hyperhomocysteinemia (high plasma concentrations of homocysteine, an amino acid associated with inflammation).1^,3 Typical treatments for PAD may include B vitamins (folic acid, B-12 and B-6) to lower homocysteine levels, cholesterol-lowering drugs, antihypertensive medications and antiplatelet and antithrombotic (blood-thinning) medications, as well as smoking cessation and exercise.1 Supervised exercise is recommended as an initial treatment for intermittent claudication. Exercise should help increase distance, speed and duration of walking while decreasing symptoms like leg pain, according to guidelines set forth by the American College of Cardiology and the American Heart Association. Exercise treadmill tests are recommended during drug treatment for PAD to measure the degree of functional limitation, as well as response to therapy.

Several supplements have hit the radar screen as possible alternative therapies for PAD. These include a multi-ingredient Tibetan formula called Padma 28, ginkgo (Ginkgo biloba), L-arginine, garlic (Allium sativum), omega-3 fatty acids and L-carnitine, among others.

Padma 28
Padma 28, a Tibetan combination of 20 herbs, a mineral and camphor, has been used in Europe since the 1960s as an anti-inflammatory agent and to treat circulatory disorders, including PAD. Padma 28 is rich in antioxidants; it contains terpenes, flavonoids, polysaccharides and tannins, as well as saponins.

In a systematic review of randomized, placebo-controlled studies investigating the use of Padma 28 to treat intermittent claudication, Melzer et al examined Padma 28 trials of at least 12 weeks' duration in patients with Fontaine stage II PAD (having leg pain during walking but none at rest).4 They found a total of 19 trials, six of which met their inclusion criteria, and five were used in the pooled analysis of results. (One study was dropped because it showed significant differences between the treatment groups at baseline.) The meta-analysis, which included a total of 272 patients, showed that Padma 28 had a significant treatment effect relative to placebo. The studies used capsules containing 309 mg to 383 mg of Padma 28; these were taken two to three times per day. The analysis showed that a significant 18.2 percent of subjects taking Padma 28 increased walking distance by more than 100 m (more than 300 feet), compared with just 2.1 percent in the placebo group. The treatment was well-tolerated; only 2.4 percent of subjects taking Padma 28 reported indigestion.4

Ginkgo biloba
Standardized Ginkgo biloba extract is considered effective for the treatment of intermittent claudication.5 In a 2000 meta-analysis of eight double-blind, placebo-controlled, randomized trials investigating the effects of ginkgo in intermittent claudication, researchers concluded that treatment with 120 mg to 160 mg/day ginkgo significantly increased pain-free walking distance compared with placebo. Adverse effects were reported by people taking ginkgo in five trials; these included abdominal complaints, nausea and indigestion; three trials reported no adverse effects.5 However, the American College of Cardiology/American Heart Association guidelines state ginkgo's efficacy for improving pain-free walking distance is marginal and not well-established because the data is derived from single randomized trials or nonrandomized studies, a conclusion inconsistent with the results of the meta-analysis.1

L-arginine
Researchers have postulated that L-arginine, an amino acid important in nitric-oxide synthesis, may improve some of the symptoms associated with PAD. Nitric oxide plays many roles in the body, including preventing platelet aggregation (clumping of blood platelets) and relaxing smooth muscle, which in turn eases blood flow.6

One small, randomized, double-blind, crossover trial examined the effects of L-arginine on endothelial function (function of the cells of blood vessel walls) in older adults.⁷ Researchers measured the diameter of the brachial artery at rest, as well as its flow- mediated dilation, or FMD, which measures the ability of the artery to relax and expand to accommodate increased blood flow. (FMD is decreased in the presence of atherosclerotic risk factors.) In addition, the researchers looked at whether plasma concentrations of asymmetric dimethylarginine, or ADMA, an inhibitor of nitric-oxide synthase, are elevated in healthy older people. The hypothesis was that L-arginine would enhance nitric-oxide synthesis, leading to vasodilation and thereby improving blood flow.

In the study, 12 healthy elderly volunteers with impaired FMD of the brachial artery and no clinical evidence of cardiovascular disease took 8 g of L-arginine or placebo twice a day for 14 days, separated by a washout period of 14 days. The diameter of the brachial artery in the study group was 3.88 ? 0.18 mm at baseline. Neither L-arginine nor placebo had any effect on brachial artery diameter or plasma concentrations of ADMA.7 However, L-arginine did significantly enhance vasodilation, while placebo had no effect. Though this study was small and short-term, it lends support to the possibility that L-arginine may improve endothelial functioning, possibly helping to reduce cardiovascular disease risk by improving endothelial-dependent vasodilation. The theory here is that improved blood flow would improve the symptoms of PAD; future studies should examine how L-arginine-mediated vasodilation impacts PAD.

Supplementation with L-arginine also yielded positive results in another, similar study in older adults.8 Thirteen hypertensive patients with angina (chest pain) were given 2 g of L-arginine three times daily for four weeks. The researchers measured blood pressure and endothelial function before and after supplementation. L-arginine resulted in a significant decrease in mean systolic blood pressure at rest. In addition, treatment led to a significant increase in forearm blood flow after induced oxygen deprivation.8 This study was limited, however, by not having a placebo control group.

Another double-blind, randomized, placebo-controlled trial tested the effect of L-arginine on vascular stiffness (lack of elasticity in the arteries). Some vascular stiffening is common with age and results in decreased nitric-oxide production and an increase in systolic blood pressure.9 A total of 153 patients with recent acute myocardial infarction (heart attack) were randomly assigned to receive 3 g of L-arginine or placebo three times a day for six months.10 The endpoints measured were vascular stiffness and ejection fraction (the portion of blood pumped out of a filled ventricle after each heartbeat). There were no significant changes in plasma-arginine levels after supplementation, and there were no changes from baseline in vascular stiffness or left ventricular ejection fraction in either group. Also, after six months, 12 patients in the supplemented group (16.7 percent) and seven patients in the placebo group (10.1 percent) died, had a heart attack or were hospitalized for heart failure. Six participants in the L-arginine group, but none in the placebo group, died during the study—a significant difference. The researchers terminated the study early and concluded that L-arginine should not be recommended following MI because it does not improve vascular stiffness or function and may increase post-MI mortality.10This study has resulted in a great deal of controversy over results, trial design and the role of L-arginine in cardiovascular disease. Some suggest that L-arginine may not have yielded positive changes because the patients were not deficient in L-arginine and were already taking medications to improve vascular functioning. Researchers have also postulated that L-arginine may be harmful after heart attack for several potential reasons: It may increase the production of both free radicals and homocysteine.10 The jury may still be out on this supplement, but it is probably best avoided by those who already have heart disease.

Garlic
Garlic (Allium sativum) has been touted as a beneficial supplement for both preventing and treating atherosclerosis. Though the mechanism by which it may work is still unclear, it has been suggested that because it is a rich source of L-arginine, garlic may function as a vasodilator. However, one would have to eat several cloves or take a concentrated supplement for any effect, as one clove of garlic contains just 0.019 g of arginine.11 To assess the effects of garlic on PAD, reviewers examined randomized trials of garlic therapy in patients with PAD, including studies from several databases. Only one 12-week trial involving 78 participants met their inclusion criteria.¹² The treatment group took 800 mg of garlic powder daily. Pain-free walking distance increased nonsignificantly (from 161.0 ? 65.1 meters to 207.1 ? 85.0 meters) in the supplemented group and 172.0 ? 60.9 meters to 203.1 ? 72.8 meters in the placebo group. However, the increase in pain-free walking distance from baseline in the supplemented group (46 m) was significantly higher than the control group (31 m). There were no changes in blood pressure, heart rate or ankle and brachial pressures after treatment. However, diastolic blood pressure, blood clotting, plasma viscosity and cholesterol decreased significantly.13

Omega-3 fatty acids
Studies show low rates of death from cardiovascular disease in populations with high fish consumption.14^,15 Fatty fish is full of omega-3 essential fatty acids, which may have an effect on several cardiovascular risk factors. For instance, omega-3 consumption has been shown to reduce triglyceride levels and blood pressure. In fact, the relationship between omega-3s and triglyceride levels is dose-dependent, with higher doses of omega-3s leading to greater decreases in triglyceride levels.16 Therefore, it makes sense to think omega-3 EFAs might also benefit individuals with PAD.

In a review that examined randomized, double-blind, placebo- controlled trials of omega-3 fatty acids in intermittent claudication, researchers found four studies of good quality involving a total of 203 subjects.¹⁷ Three of the studies used fish oil capsules providing the following dosages of EFAs: 1.8 g eicosapentaenoic acid and 1.2 g docosahexaenoic acid/day,18 2.8 g EPA and 1.8 g DHA/day,19 and 1.8 g EPA per day.20 The remaining study in this review used capsules containing a mix of omega-3 and omega-6 fatty acids (1.12 g gamma-linolenic acid from evening primrose oil, which was increased to 1.68 g after two weeks, plus 190 mg EPA, increased to 270 mg after two weeks), making it more difficult to attribute the results solely to the omega-3s.21 Placebo preparations included either omega-6 fatty acids or monounsaturated fats or both. All studies were considered clinically heterogeneous in terms of dose, duration of therapy and placebo used. The combined results indicate that omega-3 fatty acid supplementation in individuals with intermittent claudication led to decreases in diastolic blood pressure, blood viscosity and triglycerides with increases in total and low-density lipoprotein cholesterol levels. (This increase in both total and LDL cholesterol is consistent with some but not all other studies;22 some show no changes in total and LDL cholesterol with omega-3 supplementation.23^,24) Omega-3 supplementation had no effect on ankle brachial pressure index, pain-free or maximal walking distance, plasma viscosity or vascular mortality and morbidity, although according to the reviewers, the lack of results may be due to methodological shortcomings.

In conclusion, supplementation with EPA and DHA omega-3s appears to offer some benefit for people with intermittent claudication. However, further research is needed to shed more light on the effects of fish oil supplements on cholesterol levels.

Propionyl-L-carnitine
Propionyl-L-carnitine may be beneficial for people with PAD because of its potential to improve the exercise performance of muscles affected by oxygen deprivation. Two multicenter trials with a total of 730 patients showed improvement in treadmill walking distance with this supplement.25 Additional reviews also indicate that propionyl-L-carnitine may help ease intermittent claudication.26^,27 In one small, placebo-controlled study, seven subjects with intermittent claudication were studied over 12 weeks in four-week phases; during supplementation, participants took 2 g/day of propionyl-L-carnitine and were blinded as to when they received the supplement or the placebo. Calf strength and endurance were assessed, as was walking performance. Muscle strength increased significantly following supplementation. Maximal walking time increased, though not significantly, but calf endurance did not change, possibly due to the short duration of this study.

However, these results are promising, and longer studies may show additional benefits for patients with intermittent claudication.28 In a double-blind, randomized, placebo-controlled study examining the effect of propionyl-L-carnitine on peak walking time in patients with claudication, 155 people received either 2 g/day of propionyl-L- carnitine or placebo for six months. After three and six months, they were tested on a treadmill. Peak walking time increased a significant 54 percent in the supplemented group, compared with placebo (25 percent). In another study, propionyl-L-carnitine significantly improved walking speed and reduced pain.29 Propionyl-L-carnitine appears to have great potential for reducing one of the main symptoms associated with peripheral arterial disease and presents no known safety concerns.

Conclusions
In a systematic review of complementary treatment options for PAD, researchers found seven systematic reviews and meta-analyses and three additional, randomized, controlled trials that met their inclusion criteria.30 They looked at a variety of supplements, including garlic, ginkgo, omega-3 fatty acids, Padma 28, and vitamin E. Both Padma 28 and ginkgo were deemed effective for people with intermittent claudication, though the researchers indicated more data is needed to definitively confirm results with Padma 28. The review also concluded that no evidence beyond a reasonable doubt suggests any of the other supplements examined were effective for people with PAD.30 The ACC/AHA guidelines made a similar conclusion when examining the research on vitamin E, indicating that it is not recommended for patients with intermittent claudication due to lack of evidence.1

The increasing rates of obesity and cardiovascular disease in recent years are likely to lead to a greater prevalence of peripheral arterial disease as well. While treatment for this disease typically involves a combination of traditional medicines and physical therapy, natural options also offer hope. Of these, Padma 28 and ginkgo currently show the most promise. Future studies on L-arginine (although not for patients with a history of heart attack), propionyl-L-carnitine and garlic may reveal a role for them in treating PAD as well. Inositol nicotinate, glycosaminoglycans and vitamin C also show potential for treating some symptoms associated with PAD. Additional research should also examine whether any of these supplements can help prevent the onset of symptoms associated with PAD.

Marie Spano, M.S., is a registered dietitian, food industry consultant and vice president of the International Society of Sports Nutrition.

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