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ACCF CLINICAL CONSENSUS DOCUMENT

Integrating Complementary Medicine Into Cardiovascular Medicine

A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine)

John H.K. Vogel, MD, MACC, Chair, Writing Committee Member, Steven F. Bolling, MD, FACC, Writing Committee Member, Rebecca B. Costello, PhD, Writing Committee Member, Erminia M. Guarneri, MD, FACC, Writing Committee Member, Mitchell W. Krucoff, MD, FACC, FCCP, Writing Committee Member, John C. Longhurst, MD, PhD, FACC, Writing Committee Member, Brian Olshansky, MD, FACC, Writing Committee Member, Kenneth R. Pelletier, MD(hc), PhD, Writing Committee Member, Cynthia M. Tracy, MD, FACC, Writing Committee Member, Robert A. Vogel, MD, FACC, Writing Committee Member, Robert A. Vogel, MD, FACC, Chair, Task Force Member, Jonathan Abrams, MD, FACC, Task Force Member, Jeffrey L. Anderson, MD, FACC, Task Force Member, Eric R. Bates, MD, FACC, Task Force Member, Bruce R. Brodie, MD, FACC, Task Force Member^_*, Cindy L. Grines, MD, FACC, Task Force Member, Peter G. Danias, MD, PhD, FACC, Task Force Member^_*, Gabriel Gregoratos, MD, FACC, Task Force Member^_*, Mark A. Hlatky, MD, FACC, Task Force Member, Judith S. Hochman, MD, FACC, Task Force Member^_*, Sanjiv Kaul, MBBS, FACC, Task Force Member, Robert C. Lichtenberg, MD, FACC, Task Force Member, Jonathan R. Lindner, MD, FACC, Task Force Member, Robert A. O’Rourke, MD, FACC, Task Force Member, Gerald M. Pohost, MD, FACC, Task Force Member, Richard S. Schofield, MD, FACC, Task Force Member, Samuel J. Shubrooks, MD, FACC, Task Force Member, Cynthia M. Tracy, MD, FACC, Task Force Member^_* and William L. Winters, Jr, MD, MACC, Task Force Member^_*

	Preamble

Top Preamble I. Introduction II. Nutrition and supplements III. Mind/body and placebo IV. Acupuncture V. Bioenergetics (energy... V. Spirituality/Intentionality Staff Appendix I Appendix II References

The Task Force on CECDs recognizes that considerable debate exists regarding the clinical utility of alternative medicine practices. By their nature, alternative medicine practices differ widely in their scientific support. Despite this varying evidence base, these practices are widely employed by patients, including those with CVD. Many practitioners are not familiar with many alternative medicine techniques. Thus, the reader should view this CECD as the best attempt of the ACCF to inform and guide clinical practice in an area where rigorous evidence is not yet available or the evidence to date is not widely accepted. Where feasible, CECDs include indications or contraindications. The ACC/AHA Practice Guidelines Committee may subsequently address some topics covered by CECDs.

The Task Force on Clinical Expert Consensus Documents makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force and updated as changes occur. Please see Appendix I for the relationship with industry information pertinent to this document.

Robert A. Vogel, MD, FACC Chair, ACCF Task Force on Clinical Expert Consensus Documents

	I. Introduction

Top Preamble I. Introduction II. Nutrition and supplements III. Mind/body and placebo IV. Acupuncture V. Bioenergetics (energy... V. Spirituality/Intentionality Staff Appendix I Appendix II References

 
Organization of Committee and Evidence Review.   The Writing Committee consisted of acknowledged experts in the field of complementary, alternative, and integrative medicine. Both the academic and private sectors were represented. The document was reviewed by five official reviewers nominated by the ACCF, representatives from the American Association of Critical Care Nurses, AHA, American Nurses Association, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons, as well as 20 content reviewers nominated by the Writing Committee. This document will be considered current until the Task Force on CECDs revises or withdraws it from publication.

Background.   Alternative medical therapies encompass a broad spectrum of practices and beliefs (1). From a historical standpoint, they may be defined as, "...practices that are not accepted as correct, proper, or appropriate or are not in conformity with the beliefs or standards of the dominant group of medical practitioners in a society" (2). The Institute of Medicine (IOM) has recently reviewed complementary and alternative medical practices in the U.S. from a general viewpoint (3). This document will focus on cardiac aspects of complementary medicine. From a functional standpoint, alternative (also known as "complementary" or "integrative") therapies may be defined as interventions neither taught widely in medical schools nor generally available in hospitals (4). Ernst et al. (5) contend that "complementary medical techniques [complement] mainstream medicine by contributing to a common whole, by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks of medicine." The terminology currently in use to describe these practices remains controversial. Many commonly used labels (e.g., "alternative," "unconventional," or "unproven") are judgmental and may inhibit the collaborative inquiry and discourse necessary to distinguish useful from useless techniques (6). Complementary and alternative medicine (CAM) is the language currently used by the National Institutes of Health (NIH) to describe this field of inquiry. The term "integrative medicine" has been used with increased frequency. Several recently published studies and editorials wrestle with the challenges of properly labeling and describing this field of inquiry (7–12). Herbs, vitamins, and non-herbal dietary products, as well as therapies conducted around issues such as spirituality, bioenergetics (i.e., acupuncture and energy fields), and mind/body, are all considered to be forms of complementary, alternative, or integrative medicine.

Purpose of This CECD.   The purpose of this CECD is to put the emerging area of CAM treatment and investigation into focus in order to enable the physician to provide better patient care in a meaningful and safe manner. The document will be concerned with the most recent advances and utilization of CAMs and therapies in a traditional cardiovascular practice.

In 2000, nearly 50% of all Americans sought the help of an alternative health care practitioner. This represents over 600 million visits (13). Nearly $30 billion was spent in the year 2001 on CAM (13,14). Many CAM interventions, including numerous herbal supplements, have been employed in an attempt to treat CVD. Of prime importance is putting CAM into perspective with its potential benefits and knowledge of important interactions with traditional cardiovascular medicines. In response to an enormous involvement in CAM, medical facilities have developed specialized CAM centers to investigate the potential benefits and integrate those benefits into routine care and lifestyle management.

The most complete and comprehensive findings to date on Americans’ use of CAM were released on May 27, 2004, by the National Center for Complementary and Alternative Medicine (NCCAM) and the National Center for Health Statistics (NCHS, part of the Centers for Disease Control and Prevention) (15). The new data came from a detailed survey on CAM included for the first time in 2002 in the National Health Interview Survey (NHIS). The NHIS, a survey done annually by the NCHS, interviews people in tens of thousands of American households about their health- and illness-related experiences.

The findings are yielding (and will continue to yield, through future analyses) a wealth of information on who uses CAM, what they use, and why. In addition, researchers can examine CAM use as it relates to many other factors such as age, race/ethnicity, place of residence, income, educational level, marital status, health problems, and the practice of certain behaviors that impact health (such as smoking cigarettes or drinking alcohol).

The survey showed that a large percentage of American adults are using some form of CAM—36% (15). When prayer specifically for health reasons is included in the definition of CAM, that figure rises to 62%. Dr. Stephen E. Straus, NCCAM Director, said, "The survey data will provide new and more detailed information about CAM use and the characteristics of people who use CAM. One benefit will be to help us target NCCAM’s research, training, and outreach efforts, especially as we plan NCCAM’s second five years, 2005 through 2009."

There is little doubt that CAM represents a revolution within our health care delivery system. Nevertheless, our traditional views of the medical establishment do not fully support CAM. There is a lack of significant instruction of CAM in medical schools, there is a paucity of CAM in most major hospitals, and there is little solid research published in peer-reviewed journals. Compensation by insurance companies for CAM is also an issue.

A recent report of the IOM entitled "Complementary and Alternative Medicine in the U.S." (3) described and characterized CAM therapies used by the American public. Additionally, the IOM sought to identify major scientific policy and practice issues related to CAM research and to the translation of validated therapies into conventional practice. In short, the report recommended that the same principles and standards of evidence of treatment effectiveness apply to all treatments, whether currently labeled as conventional medicine or CAM. Although randomized controlled trials (RCTs) remain the "gold standard" of evidence for treatment efficacy, the IOM noted that other study designs can be used to provide information about the effectiveness when RCTs cannot be done or may not be generalizable to CAM practice. Other acceptable clinical research designs included: preference RCTs (trials that include both randomized and non-randomized treatment arms); observational and cohort studies; case-control studies; studies of bundles (combinations) of therapies; studies that specifically incorporate, measure, or account for placebo or expectation effects; and attribute-treatment interaction analyses. Prioritization criteria were also proposed to assist researchers regarding which CAM therapies might warrant further investigation.

Integrating CAM into medicine must be guided by compassion, but enhanced by science, and made meaningful through solid doctor-patient relationships. Most importantly, CAM involves a commitment to the core mission of caring for patients on a physical, mental, and spiritual level. This document attempts to enable us to fulfill these objectives. A glossary of terms is contained in Appendix II. For additional information on CAM, please refer to www.acc.org for Appendix III: Internet Sources for Complementary Medicine Information and Appendix IV: Review of the Literature for Cardiovascular-Related Integrative Medicine.

	II. Nutrition and supplements

Top Preamble I. Introduction II. Nutrition and supplements III. Mind/body and placebo IV. Acupuncture V. Bioenergetics (energy... V. Spirituality/Intentionality Staff Appendix I Appendix II References

 
This section provides a discussion of general nutrition and dietary supplements, including vitamins, minerals, and herbs that are related to the prevention and reduction of risk of CVD. Please see Appendix V at www.acc.org for a sample dietary supplement intake form.

Nutrition.   Diet is a major determinant of cardiovascular health. General nutrition affects body weight, lipoproteins, blood pressure, blood glucose, endothelial function, inflammation, and coagulation. Dietary modification is an important component of primary and secondary prevention of coronary heart disease (CHD) and hypertension. The essentials of proper nutrition include appropriate caloric intake and consumption of the essential macronutrients (carbohydrate, proteins, and fats) and micronutrients (vitamins, minerals). Specific nutrients can either accelerate or retard the development of CVD.

Obesity
Obesity contributes to CHD, diabetes, and hypertension (16). Obesity (body mass index [BMI] greater than 30 kg/m²) increased 50% in this country from 1991 to 1998 (17). Almost one-third of Americans are now obese and another one-third are overweight (BMI 25 to 30 kg/m²). The major cause of this recent increase in obesity is a 150 to 200 kcal increase in our daily caloric intake, mainly from snacks (18). A decrease in physical activity associated with more television viewing has also contributed. A third factor has been an increase in sugar consumption, which now averages 150 lbs per person per year (19). The latter factor has also contributed to an increased prevalence of type 2 diabetes.

Weight loss is often an important part of the management of CHD, diabetes, and hypertension (20). Excess weight increases low-density lipoprotein (LDL) cholesterol, triglycerides, and markers of inflammation, such as C-reactive protein; and decreases high-density lipoprotein (HDL) cholesterol. Even modest weight reduction can improve these atherogenic markers (20). Weight loss only occurs when caloric intake is less than caloric expenditure. The daily caloric requirement for sedentary and physically active individuals, respectively, is about 12 and 15 kcal per lb of ideal weight. A 3,500 kcal deficit results in approximately 1 lb of weight loss. On the average, a deficit or excess of 500 calories a day brings about weight loss or gain at the rate of 1 lb a week. Increasing physical activity also results in weight loss. One mile walked or jogged is equivalent to about 100 calories burned. The most successful weight loss programs use calorie restriction, exercise, counseling, and group support.

Extremely low-carbohydrate or ketotic diets have become popular for weight loss (21). Some randomized trials have found that obese individuals lose more weight on low-carbohydrate diets than on low-fat diets, although the difference is not uniformly significant (22,23). The mechanisms by which extremely low-carbohydrate diets facilitate weight loss include osmotic diuresis, glycogen and associated water depletion, anorexia due to ketosis, and exclusion of foods. Although LDL cholesterol decreases during the weight loss phase of low-carbohydrate dieting, levels return to baseline in the long term. Two benefits of extremely low-carbohydrate diets are a decrease in triglycerides and an increase in insulin sensitivity. The long-term cardiovascular effects of low-carbohydrate/high-fat diets are unknown, but epidemiologic data suggest that they would increase atherosclerosis (24).

Extremely low-fat diets have been used to treat established coronary artery disease (CAD) (25). One small study has demonstrated modest CAD regression (26). Extremely low-fat diets are difficult to apply widely. Low-fat diets are consistent with the general epidemiologic finding that atherosclerosis prevalence correlates with saturated fat intake, and more specifically, with trans fat intake. However, low-fat diets can increase small LDL particles. These diets also do not recognize the cardiovascular benefits that can be derived from omega-3 fatty acids. They also may increase triglyceride levels and decrease insulin sensitivity.

Macronutrients
Fatty acids can be generally characterized into saturated, trans, monounsaturated, and polyunsaturated classes depending on the number and configuration of double bonds. Saturated and trans fatty acids increase serum LDL cholesterol and directly impair endothelial function (27,28). Trans fatty acids also decrease HDL cholesterol (29). Considerable data suggest an association between dietary saturated and trans fats and CHD (24). Dietary cholesterol is also associated with CHD, but elevations in serum cholesterol are individually variable with dietary intake. Monounsaturated fatty acids have neutral effects on serum LDL and HDL cholesterol (30). Polyunsaturated fatty acids reduce HDL cholesterol, but their use in randomized trials is associated with decreased cardiovascular events (27).

Omega-3 fatty acids have three to six double bonds, the first one occurring between the third and fourth carbon from the methyl end. The omega-3 fatty acids have triglyceride-reducing, membrane-stabilizing, antiplatelet, and anti-inflammatory properties (31). Omega-3 fatty acids include alpha-linolenic, eicosapentaenoic, and decosahexaenoic acids. The former is contained in plant oils, whereas the latter two are contained in fish oils. Prospective randomized trials have demonstrated that consuming plant and fish omega-3 fatty acids reduces cardiovascular events, sudden death, and overall mortality (32).

Carbohydrates include monosaccharides, such as sugars, oligosaccharides, and polysaccharides or starches. Complex carbohydrates consist of starches and indigestible fiber. Fiber adds bulk to food and slows carbohydrate digestion. Soluble fiber in the form of psyllium, guar gum, and oat bran reduces serum LDL cholesterol (33). The blood glucose raising property of a food per 50 g of carbohydrate and per portion is measured by its glycemic index and load, respectively (34). High glycemic load foods such as cookies, rice, and potatoes increase serum triglycerides, decrease insulin sensitivity, and probably facilitate obesity.

Dietary recommendations
There are two types of dietary guidelines. The first type recommends specific quantities of macronutrients, such as less than 200 mg of cholesterol per day and less than 7% of calories as saturated fat, as in the AHA Step 2 diet (1). A second type recommends consumption and exclusion of specific foods, often in combination. An example is the recommendation to eat stanol/sterol ester margarines, soy products, soluble fiber, and walnuts or almonds to lower LDL cholesterol (33,35,36). The latter specific food portfolio recommendation has been found to lower LDL cholesterol more (29%) than an AHA Step 2 approach (8%) (37). In general, diets containing unsaturated fats, whole grains, fruits, vegetables, fish, and moderate alcohol are optimal for preventing heart disease (38,39). In October 2000, the AHA revised its dietary guidelines for Americans (1). The new guidelines retain the principles of the Step 1 and Step 2 diet but place emphasis on foods and an overall eating pattern (see the following text) rather than on percentages of food components such as fat.

The National Cholesterol Education Program (NCEP) has issued new practice guidelines on the prevention and management of high cholesterol in adults (40). The Third Adult Treatment Panel (ATPP III) of the NCEP further modified its dietary recommendations to include a more intense and effective eating plan than previously advocated. The new Therapeutic Lifestyle Changes (TLC) treatment plan complements that of the AHA guidelines and recommends less than 7% of calories from saturated fat and less than 200 mg of dietary cholesterol daily. Total allowed fat ranges from 25% to 35% of total daily calories provided that saturated fats and trans fatty acids are kept low. The ATP III encourages the use of foods that contain plant stanols and sterols or are rich in soluble fiber, to achieve greater LDL cholesterol-lowering power.

Mediterranean diet
The prevalence of CVD is considerably less in Mediterranean and Pacific Rim countries than in the U.S. at equivalent cholesterol levels (41). Common to such societies is a diet high in fruits, vegetables, beans, whole-grain carbohydrates, nuts, fish, and monounsaturated and polyunsaturated oils. Dairy products are consumed in low-to-moderate amounts and little red meat is eaten. Alcohol is consumed in moderation. The Lyon Diet Heart Study (42,43) tested the effectiveness of a Mediterranean-type diet, modified by substitution of an alpha-linolenic acid-enriched canola oil margarine for olive oil, on cardiovascular risk after a first myocardial infarction. After an average follow-up of 46 months, subjects following the modified Mediterranean-style diet had 72% fewer cardiovascular events and 60% lower all-cause mortality. Findings from the Lyon Diet Study have been reproduced recently using an Indo-Mediterranean diet in subjects with CHD (44). The intervention diet recommending increased consumption of fruits, vegetables, nuts, whole grains, and mustard and soybean oils reduced cardiovascular events by 45% and sudden cardiac death by 66%. Additionally, recommendations to increase fruit, vegetables, and low-fat dairy product consumption has been found to lower blood pressure in the Dietary Approaches to Stop Hypertension (DASH) study (45).

Summary of general nutritional recommendations

• Achieve and maintain ideal body weight by limiting foods high in calories and low in nutrient density, including those high in sugar, such as soft drinks and candy.

• Eat a variety of fruits, vegetables, legumes, nuts, soy products, low-fat dairy products, and whole grain breads, cereals, and pastas.

• Eat baked or broiled fish at least twice per week.

• Choose oils and margarines low in saturated and trans fat and high in omega-3 fat, such as canola, soybean, walnut, and flaxseed oils, including those fortified with stanols and sterols.

• Avoid foods high in saturated and trans fats, such as red meat, whole milk products, and pastries.

• If you drink alcohol, limit consumption to no more than 2 drinks per day for a man or 1 drink per day for a woman.

• Eat less than 6 g of salt or less than 2,400 mg of sodium per day.

• Be physically active. Get 30 min of exercise daily.

Bioactive Components in Foods.   Food components recommended for lowering the risk of CVD include plant sterols, soluble fiber, omega-3 fatty acids, nuts, and soy. Additional foods, such as garlic and teas, and moderate alcohol use will be discussed.

Omega-3 fatty acids
Individual fatty acids have remarkably diverse effects on coronary risk factors and vascular biology (41–45). Omega-3 and -6 fatty acids are essential nutrients. Dietary fatty acids affect eicosanoid products (e.g., thromboxanes, leukotrienes, prostaglandins) responsible for vasoregulation, inflammation, and coagulation. Omega-3 fatty acids may also affect CHD outcomes by decreasing triglyceride levels, ventricular arrhythmias, decreasing fibrinogen levels and platelet counts, modestly reducing blood pressures, and decreasing cell proliferation. Improvements in arterial compliance and endothelial function have also been documented with fish oil, a major supply of dietary omega-3 fatty acids. There are changes in autonomic tone (as observed by improvement in heart rate variability measures) and in mood (depression) (46).

Epidemiologic studies (47–51) have generally shown an inverse correlation between consumption of fish or other sources of dietary omega-3 fatty acids and cardiovascular events. Conversely, other epidemiologic studies (52–55) have failed to document the benefits of fish consumption. Good plant sources of the 18 carbon omega-3 fatty acid, alpha-linolenic acid, include flaxseed, canola, pumpkin seed, walnut, and soybean oil.

Omega-3 fatty acids have been tested in several secondary prevention trials. Four prospective, controlled intervention trials with either oily fish (56) or omega-3 fatty acid capsules (42,57,58) have demonstrated reduced cardiovascular events. However, in the DART trial, fish consumption reduced overall mortality early after myocardial infarction (MI) (56), but was associated with higher risk over the subsequent three years of the study (53). The GISSI-Prevenzione study is the largest of the controlled trials investigating omega-3 fatty acid supplements (1 g per day) and CHD risk. In this trial, total mortality was reduced by 20% and sudden death by 45% in an intention-to-treat analysis. Mortality was reduced through a decreased incidence in sudden death.

Studies published to date are mixed regarding a role for dietary omega-3 fatty acids in the prevention of restenosis after percutaneous coronary angioplasty (59–62). They have not been found to reduce coronary atherosclerosis progression to a significant extent (58,63). One study demonstrated that occlusion of aortocoronary venous bypass grafts was reduced after one year by daily ingestion of 4 g of fish-oil concentrate (64).

Stanol/sterol esters
Plant sterols or phytosterols have been known to have a cholesterol-lowering effect since the 1950s. The esterification of plant stanols renders them soluble in dietary fat, an effective vehicle for delivering plant stanols and sterols to the site of cholesterol absorption in the small intestine. Commercially available margarines that provide 3.4 to 5.1 g a day of plant stanol esters can significantly reduce serum total and LDL cholesterol levels without affecting HDL cholesterol or triglycerides (65–67). A decrease in LDL cholesterol levels of 9% to 20% can be achieved with consumption of approximately 2 g per day of plant sterol esters (36). In a randomized, eight-week placebo-controlled trial in 167 subjects, using plant stanol esters incorporated into an oil-based margarine, there was a significant reduction in serum total (12%) and LDL (17%) cholesterol levels in individuals taking a stable dose of a statin drug (68). No trials have studied the effects of stanol/sterol esters on cardiovascular risk. Stanol and sterol esters should be avoided by the rare individual with familiar sitosterolemia.

Garlic (Allium sativum)
Garlic is an herb that has been used for thousands of years as a food and spice. Garlic potentially affects plasma lipids, fibrinolytic activity, platelet aggregation, blood pressure, and blood glucose (69). Various formulations/preparations of garlic and different study designs have led to contradictory results. The Agency for Healthcare Research and Quality (AHRQ) (70) noted on review of 36 randomized trials modest, short-term effects of garlic supplementation on lipid and antithrombotic factors. Various garlic preparations led to small but significant reductions in total cholesterol at one month and at three months (range of average pooled reductions 11.6 to 24.3 mg/dl). Eight six-month controlled trials showed no significant reductions. Effects on clinical outcomes are not established, and effects on glucose and blood pressure are none to minimal. A similar meta-analysis conducted by Stevinson et al. (71) that included 13 randomized, placebo-controlled trials concluded that the use of garlic for hypercholesterolemia was of questionable value. Superko and Krauss (72) demonstrated in a randomized, placebo controlled trial in hypercholesterolemic subjects that garlic has no effect on major plasma lipoproteins and that it does not impact HDL subclasses, Lp(a), apolipoprotein B, postprandial triglycerides, or LDL subclass distribution.

Soy
Soy-based foods have cholesterol-lowering, estrogenic, and antioxidant properties. The mechanism underlying the cholesterol-lowering effect of soy is likely multifactorial. Soy-based foods reduce lipid oxidation, promote increased vascular reactivity, and improve arterial compliance (73). Favorable effects of soy phytoestrogens on lipid profiles, vascular reactivity, thrombosis, and cellular proliferation have been reported (74). Dietary intake of foods containing phytoestrogens is associated with a favorable cardiovascular risk profile as was demonstrated in 939 postmenopausal women participating in the Framingham Off-Spring Study (75). The consumption of soy protein can improve lipid profiles in hypercholesterolemic individuals above a background NCEP Step I diet. Soy decreases LDL cholesterol more in hypercholesterolemic individuals. Soy supplementation may also increase the levels of HDL cholesterol regardless of whether an individual is hypercholesterolemic or not. A meta-analysis of 38 trials of soy protein demonstrated reductions in total cholesterol of 9.3%, LDL cholesterol of 12.9%, and triglyceride levels of 10.5%, accompanied by an increase of 2.5% in HDL cholesterol (76). However, more recent studies in postmenopausal women fail to show improvements in plasma lipids (77). A recent placebo-controlled study in 108 men and 105 postmenopausal women randomized to either soy protein isolate or casein placebo for three months demonstrated an increase in levels of Lp(a) on soy supplementation with no improvement in indices of arterial function (78). Extracts of soy isoflavones given to human subjects do not result in cardiovascular benefits except for improvements in systemic arterial compliance (79).

The clinical benefit of isoflavones is unclear. In light of the recent findings about estrogen from the Women’s Health Initiative, the U.S. Preventive Services Task Force has stated that the evidence is inconclusive to determine whether phytoestrogens, such as soy isoflavones, are effective for reducing the risk of CVD (80).

Soluble fiber
Soluble or viscous fibers, such as oat bran, psyllium, guar, and pectin, are thought to reduce heart disease by lowering total and LDL cholesterol levels without affecting serum triglycerides. Conversely, insoluble wheat fiber and cellulose have no cholesterol-lowering effects unless used in the diet to replace foods supplying saturated fats or cholesterol (81). Increasing dietary fiber has been recommended as a safe and practical approach to cholesterol reduction. Large epidemiologic studies (82–84) have demonstrated a reduced risk for MIs and death from CHD in both men and women who consume higher amounts of dietary fiber. These studies provide strong support linking dietary fiber intake to protection from CHD. These data are supported by numerous ecological, cohort, case-comparison, population-based, and, most recently, clinical trials demonstrating an inverse relationship between dietary fiber consumption and atherosclerotic CVD (85).

The hypocholesterolemic effects of psyllium (86), guar gum (87), and oat bran (88) are documented by meta-analyses (89). A meta-analysis of 67 controlled trials studying the cholesterol lowering effect of four types of soluble fiber (oat, psyllium, pectin, and guar gum) reported small but significant reductions in total cholesterol (1.7 mg/dl per g soluble fiber) and LDL (cholesterol (1.9 mg/dl per g soluble fiber) (81). Hypercholesterolemic subjects with initially higher cholesterol levels experienced the most significant reductions. Triglycerides and HDL cholesterol were not significantly influenced by soluble fiber. The magnitude of lipid lowering was found to be similar for oat, psyllium, or pectin-based fibers.

Because of the favorable effect of soluble fiber on LDL cholesterol levels, the ATP III panel recommends that the diet be enriched by foods that provide a total of at least 5 to 10 g of soluble fiber daily (90). Dietary fiber also reduces blood pressure, obesity, insulin resistance, and clotting factors—all independent risk factors for CHD (85).

Nuts
The few studies that have looked at the consumption of whole nuts in relation to CHD have reported a consistent and substantial protective effect. Three of the largest nutritional epidemiologic prospective studies evaluating multiple population groups, ages, races, and gender have found a consistent inverse relationship between nut consumption and coronary risk (91–93).

The improvement in serum lipids associated with the consumption of nuts does not explain the magnitude of the CHD risk reduction of approximately 40% to 50% found in the epidemiologic studies. Nuts, especially walnuts and almonds, are high in arginine, magnesium, folate, plant sterols, and soluble fiber. Some nuts contain high levels of omega-3 essential fatty acids (e.g., walnuts), and they are an excellent source of vitamin E. In a prospective study of 86,016 women between the ages of 34 to 59 years, without previously diagnosed CHD, eating 5 oz of nuts per week was associated with a relative risk (RR) of 0.66 (95% confidence interval [CI] 0.47 to 0.93, p for trend = 0.005) of coronary events adjusted for risk factors and independent of fiber, fruit, and vegetable supplements (92). Recent prospective data from the Physicians’ Health Study demonstrated consumption of nuts two or more times a week significantly reduced the risk of sudden cardiac death (RR) of 0.53 (95% CI 0.30 to 092, p for trend = 0.01) and a RR of 0.70 (95% CI 0.50 to 0.98, p for trend = 0.06) for total CHD deaths compared with men who rarely or never consumed nuts (93). The association between nut consumption and sudden cardiac death became stronger after adjustment for lifestyle, cardiac risk factors, and diet. Like some nuts, canola oil and flaxseed oil are the richest known source of alpha-linolenic acid, an omega-3 fatty acid.

Tea
Tea drinking appears to be protective against CHD in a number of epidemiologic studies (94–97). In the older cohort of the Rotterdam Study, an inverse association was demonstrated between tea drinking and advanced aortic atherosclerosis (98). Data from a more recent follow-up of the Rotterdam Study highlighted a strong inverse relation between tea intake (greater than 375 ml/day) and MI with the relation being stronger in women than in men. The inverse association with tea drinking was stronger for fatal events than for nonfatal events. For flavonoid (quercetin + kaempferol + myricetin) intake, a strong association with MI was observed only in women (99). Results are inconclusive for clinical and case control studies. However, a recent prospective cohort study of 1,900 patients hospitalized with an acute MI followed for 3.8 years found a significantly reduced hazard ratio for subsequent total and cardiovascular mortality of 0.56 (95% CI 0.37 to 0.84) for heavy tea drinkers (more than 14 cups/week) compared to non-tea drinkers (100). A recent clinical study has shown that consumption of black tea improves brachial artery flow-mediated dilation in patients with CAD (101). Despite the favorable epidemiology and mechanistic investigations, no studies have prospectively documented a reduction in cardiovascular risk with tea drinking.

Alcohol
Epidemiologic studies have shown that the incidence of MI, angina pectoris, and coronary-related deaths are inversely related to moderate alcohol intake, as defined by 1 to 3 drinks daily. Although many mechanisms for this effect have been suggested, the best documented effect is an increase in HDL cholesterol by alcohol (102). Recent studies have shown that moderate drinkers are less likely to suffer ischemic stroke (103,104), peripheral vascular disease (105), and death following an acute MI (106). Cooper et al. (107) found that light-to-moderate drinkers with left ventricular systolic dysfunction had fewer adverse outcomes. In the Framingham Heart Study, Walsh et al. (108) found that the incidence of congestive heart failure was lower in subjects who consumed moderate amounts of alcohol. Abramson et al. (109) were able to demonstrate that subjects who consumed moderate levels of alcohol had a significantly lower risk of developing heart failure.

Moderate consumption of alcohol-containing beverages does not appear to result in significant morbidity; however, heavy alcohol consumption can result in cardiomyopathy, hypertension, hemorrhagic stroke, cardiac arrhythmia, and sudden death. Alcohol ingestion poses such a number of health hazards with irresponsible consumption that the AHA recommends that physicians and patients discuss the adverse and potentially beneficial aspects of moderate drinking (39).

Overview of dietary supplements
The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined dietary supplements as a product (other than tobacco) intended to supplement the diet for such ingredients as vitamins, minerals, herbs, or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Whatever their form, the DSHEA places dietary supplements in a special category under the general umbrella of "foods," not drugs, and requires that every supplement be labeled a dietary supplement. The establishment of dietary supplements as foods limited the Food and Drug Administration (FDA)’s premarketing regulatory authority and placed the FDA in a reactive, postmarketing role. Thus, for the FDA to remove a supplement from the market it most prove that the supplement presents a significant or unreasonable risk of injury or illness when used as recommended on the label. Recently, the IOM has urged that the U.S. Congress and federal agencies, in conjunction with industry, research scientists, consumers, and other stakeholders, amend DSHEA and the current regulatory practices for dietary supplements in an effort to improve product consistency and reliability (IOM, 2005). Just prior to the release of the IOM report on Complementary and Alternative Medicine in the U.S., the FDA announced three major regulatory initiatives designed to further implement DSHEA (http://www.cfsan.fda.gov/~lrd/fr04119a.html, docket no. 2004N-0458). These initiatives serve to inform the dietary supplement industry on a regulatory strategy involving the monitoring and evaluation of product and ingredient safety, assurance of product quality via good manufacturing practice (CGMP regulations), and monitoring and evaluation of product labeling. At the same time these new initiatives will give consumers a higher level of assurance about the safety of dietary supplement products and the reliability of their labeling.

Vitamin and Mineral Supplements.   Antioxidant vitamins
Antioxidant therapies are potentially useful in preventing both atherosclerosis and its complications by retarding LDL oxidation and by inhibiting the proliferation of smooth muscle cells, platelet adhesion and aggregations, the expression and function of adhesion molecules, and the synthesis of leukotrienes (110). Antioxidants may improve endothelial function, reduce ischemia, and stabilize atherosclerotic plaques to prevent plaque rupture (110).

Vitamin E
Primary Prevention Trials. A potential benefit of vitamin E in CHD is suggested by two large prospective epidemiologic trials, which found lower event rates in subjects who took at least 100 units of vitamin E per day (111,112). However, 50 mg of vitamin E in the Alpha-Tocopherol, Beta-Carotene (ATBC) cancer prevention trial of male smokers did not decrease nonfatal MIs, and increased hemorrhagic stroke (113,114). Vitamin E use was not associated with decreased stroke in the Health Professionals Follow-Up Study (115), the Nurses Health Study (112), and the Iowa Women’s Health Study (116). Most recently, the Collaborative Group of the Primary Prevention Project (PPP) found no decrease in cardiovascular events in 4,495 subjects with one or more risk factors after 3.6 years of synthetic vitamin E (300 units) therapy compared to none (117). These data have been confirmed by a recent pooled analysis of nine cohort studies (Pooling Project of Cohort Studies on Diet and Coronary Disease) in 293,172 subjects free of CHD. A lower CHD risk at higher intake of dietary vitamin E was present when adjusted for age and energy intake. However, supplemental vitamin E intake was found not to be significantly related to a reduced risk of CHD (118).

Secondary Prevention Trials. Only one of several controlled trials of vitamin E has shown a reduction in some aspect of cardiovascular risk. In the Cambridge Heart Antioxidant Study (CHAOS) (119) vitamin E reduced the risk of nonfatal MI, but not of fatal MI. The Heart Outcomes Prevention Evaluation (HOPE) study found no effect of vitamin E for several of primary and secondary CVD end points, including disease progression monitored by carotid ultrasound (120). The GISSI-Prevenzione trial (42) failed to show benefit from vitamin E supplementation on CHD or stroke in almost 8,000 patients. The Vitamin E Atherosclerosis Prevention Study (VEAPS) provided additional evidence that vitamin E supplementation (400 units) did not reduce the progression of atherosclerosis as evaluated by change in intimal medial thickness (121). A meta-analysis of seven randomized trials of vitamin E (50 units to 800 units) in 81,788 patients confirmed that vitamin E did not reduce mortality, decrease cardiovascular death, or cerebrovascular accident (122). A more recent and larger (135,967 participants in 19 clinical trials) meta-analysis that considered the dose dependent effects of vitamin E supplementation noted that at high dosage (400 units/day or more) a pooled risk difference of 34 per 10,000 persons (95% CI 5 to 63 per 10,000 persons, p = 0.022). However, it is unclear whether the investigators isolated the effects of vitamin E from those of other supplements. Most of the evidence for an elevated mortality risk came from two trials that administered vitamin E together with beta-carotene. It is uncertain whether an increased risk for death from high-dose vitamin E based on this most recent analysis of RCTs exists (123).

Vitamin C
Primary Prevention. When examined individually, most observational and prospective cohort studies do not demonstrate a relationship between vitamin C intake and CVD (124,125) and there have been no RCTs specifically examining the effects of vitamin C supplementation on cardiovascular end points (115,126). In the Iowa Women’s Health Study, women in the top quintile of vitamin C intake versus the lowest quintile had a nonsignificant increased risk for CHD mortality and a borderline significant trend toward increased stroke (127). Long-term use of vitamin C in a large prospective investigation was not associated with a reduced risk of stroke, as well (115). However, a more recent analysis from the Nurses’ Health Study indicates that women in the highest quintile of intake for vitamin C (greater than 360 mg per day from diet and supplements) compared with the lowest quintile (less than or equal to 93 mg per day), had a 27% lower risk for CHD, and women taking supplemental vitamin C had a 28% lower risk of nonfatal MI and fatal CHD compared with women who took no vitamin C (128). In the recent pooled analysis from the Pooling Project of Cohort Studies on Diet and Coronary Disease (118), those subjects with higher supplemental vitamin C intake (greater than 700 mg/day) had a 25% reduced risk of CHD. Nevertheless, the current consensus does not find a value for supplemental vitamin C in preventing heart disease (129).

Beta-carotene
Trials of beta-carotene have demonstrated no cardiovascular benefit, and one demonstrated an adverse clinical outcome. An increased incidence of lung cancer and CVD mortality were observed in the ATBC cancer prevention study (130). Beta-carotene supplementation was also associated with a slight increase in the frequency of angina pectoris (131). A meta-analysis of eight trials evaluating beta-carotene in 138,113 patients revealed a small but significant increase in all-cause mortality and cardiovascular death (128). Thus, beta-carotene supplementation is discouraged (1).

Combination Vitamin Trials. The Heart Protection Study (HPS) randomized 20,536 subjects at high risk for CHD to 40 mg simvastatin daily or placebo and vitamin E (600 mg), vitamin C (250 mg), and beta-carotene (20 mg) or placebo. After 5.5 years of study, no benefit from combination vitamin therapy was evident (132). A small RCT, the HDL Cholesterol Atherosclerosis Treatment Study (HATS), found that vitamin C (1 g), vitamin E (800 units), beta-carotene (50 mg), and selenium (100 mcg) reduced the benefit of simvastatin plus niacin therapy on CAD progression and cardiovascular events (133) suggesting a potential drug/supplement interaction affecting the efficacy of statin therapies. Lack of benefit for combination vitamin E (400 units) and vitamin C (500 mg) was also documented in 423 postmenopausal women with CAD participating in the Women’s Angiographic Vitamin and Estrogen (WAVE) trial (134).

In contrast to the aforementioned negative trials, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study of 440 hypercholesterolemic patients randomized to vitamins E and C, reported that combination therapy decreased the rate of atherosclerosis progression (especially in men) over a six-year period as measured by carotid artery intima-media thickness. This study selected subjects with high oxidative stress and maximized absorption of the antioxidants by giving them with meals (135).

In summary, aside from the recent pooled analysis of vitamin C cohort studies, the consensus of antioxidant vitamin study results do not support a cardiovascular benefit related to the use of vitamins E and C and beta-carotene (129).

Folic acid, vitamin B₆, and vitamin B₁₂
Elevated homocysteine levels are associated with increased risk of coronary artery and vascular disease. The mechanisms by which elevated homocysteine impairs vascular function are not completely understood, but may involve the stimulation of vascular smooth muscle cell growth and collagen synthesis, oxidative-endothelial injury and dysfunction, lipid peroxidation and platelet activation, and hypercoagulability (136). Intakes of folate, vitamins B₆, and B₁₂ are inversely related to homocysteine levels as all three vitamins are directly involved in the metabolism of homocysteine. Beginning in 1996 and mandatory in 1998, the FDA issued a regulation requiring all enriched grain products be fortified with folic acid (140 mcg/100 g serving portion), primarily for the reduction of congenital neural tube defects. The fortification of enriched grain product with folic acid has been associated with an improvement in the folate status of middle-aged and older adults (137). In the Framingham Offspring Study cohort, mean homocysteine levels decreased from 10.1 to 9.4 µmol/l with the introduction of fortified products (138).

Initial retrospective case-control studies (139–141) and prospective studies (142–147) suggested an inverse relationship between homocysteine and CVD. A recent meta-analysis, combining 30 prospective and retrospective studies, concluded that elevated homocysteine is less strongly related to ischemic heart disease and stroke risk in healthy populations than has been suggested (148). A meta-analysis of 14 prospective cohort studies, using the inclusion criterion of time to first cardiac or cerebrovascular event, found that elevated homocysteine levels moderately increased the risk of a first cardiovascular event, regardless of age and duration of follow-up (149).

In secondary prevention studies, two nonrandomized trials in patients with vascular disease found an inverse relationship between the intake of folic acid and vitamin B6 and vascular events (150). One study conducted in open-label fashion in 593 patients with coronary artery disease on statin therapy showed no benefit of folic acid in reducing cardiovascular events despite an 18% lowering in homocysteine levels (151–153).

Most recently, a trial of folic acid (1 mg), vitamin B₁₂ (400 units), and pyridoxine (B₆) (10 mg) found a significantly reduced homocysteine levels, rate of restenosis, and need for revascularization in a group of 553 CAD patients at one year of follow-up (151,152). A similar RCT of 626 patients treated with B-vitamin therapy following coronary stenting procedures, however, found increased rates of restenosis, particularly in patients receiving bare-metal stents and major adverse cardiac events in the vitamin treated group after one year of follow-up. The rate of restenosis in the homocysteine-lowering group was 35% compared with 27% in the group receiving placebo (154). Although striking differences exist between the study populations, it raises the potential of possible harm from use of high-dose B-vitamins. Strong evidence for a benefit for B vitamins in CVD is pending; there remain a number of ongoing trials, including WACS, SEARCH, PACIFIC, NORVIT, and CHAOS-2 (155).

Minerals
Magnesium
Magnesium metabolism is involved in insulin sensitivity and blood pressure regulation, and magnesium deficiency is common in both diabetes and hypertension. The links among magnesium, diabetes, and hypertension suggest the possibility that magnesium can affect CVD (156,157). Magnesium depletion is associated with electrocardiographic changes, arrhythmias, and increased sensitivity to cardiac glycosides (158). Epidemiologic studies have suggested that ingesting hard water that contains magnesium, consuming a diet higher in magnesium, or using magnesium supplements decreases CVD (159). The Honolulu Heart Program found a 1.7- to 2.1-fold excess risk of CHD among those subjects in the lowest versus highest quintile of magnesium intake after 15 years of follow-up (160). Similarly, epidemiologic evidence suggests that magnesium may play a role in regulating blood pressure (161–165). A recent meta-analysis of 20 randomized studies including both normotensive and hypertensive subjects detected a dose-dependent blood pressure reduction with magnesium supplementation (166). The DASH intervention study demonstrated that a diet of fruits and vegetables, which increased magnesium intake from an average of 176 to 423 mg per day, significantly lowered blood pressure in adults who were not classified as hypertensive (167). However, studies in hypertensive patients have led to conflicting results. Ascherio et al. (168) found an inverse correlation between the intake of magnesium and the risk of stroke.

Magnesium intake has been found to be inversely associated with carotid artery thickness in women but not in men (163). Oral magnesium therapy (365 mg twice daily for 6 months) in 187 patients with CAD demonstrated a 14% improvement in exercise duration combined with a decrease in exercise-induced chest pain compared to no change in the placebo group (169). In patients with congestive heart failure (CHF), a population at high risk for magnesium deficiency, oral magnesium replacement decreases the frequency of ventricular arrhythmias (170).

Dietary intakes of magnesium are suboptimal in the U.S. as evidenced by recent NHANES survey intake data (171). Diets rich in magnesium and magnesium supplementation may be helpful in preventing CVD, especially hypertension.

Other bioactive supplements
Coenzyme Q10
Coenzyme Q10 (CoQ10) is involved in oxidative phosphorylation and the generation of adenosine triphosphate (ATP). The CoQ10 acts as a free radical scavenger and membrane stabilizer. There have been over 40 controlled trials of the clinical effect of CoQ10 on CVD, a majority of which show benefit in subjective (quality of life, decrease in hospitalizations) and objective (increased left ventricular ejection fraction, stroke index) parameters. A recent review (172) and meta-analysis (173) have shown benefit of CoQ10 as adjunctive treatment in patients with CHF. The largest trial to date was a one-year, placebo-controlled study of CoQ10 in 651 New York Heart Association (NYHA) functional class III or IV CHF patients (174). These investigators found a significant decrease (38% to 61%) in the number of hospitalizations, incidences of pulmonary edema, and episodes of cardiac asthma. No differences in death rates were documented. However, two of the most recent placebo-controlled trials found that the addition of 100 to 200 mg/day of oral CoQ10 to conventional medical therapy did not result in significant improvement in left ventricular ejection fraction, peak oxygen consumption, exercise performance, or quality of life in patients with advanced heart failure (175,176).

A mortality benefit for CoQ10 has not been established in contrast to angiotensin-converting enzyme inhibitors, beta-blockers, and aldosterone antagonists. Case reports associate CoQ10 therapy with decreased internation normalized ratio (INR) in patients taking warfarin (177); however, CoQ10 had no effect on the INR in patients on warfarin in a randomized, double-blind, placebo-controlled, crossover trial (178). Caution is advised if patients are taking CoQ10 and warfarin. The HMG-CoA reductase inhibitors may inhibit the natural synthesis of CoQ10, and reduced levels of CoQ10 have been documented in small controlled clinical trials in patients on statin therapies (179). Reduced levels of CoQ10 may place the patient at increased risk for myopathy (180–183); however, studies of CoQ10 for decreasing myalgias and myositis are not definitive. One unique formulation of CoQ10 has received FDA Orphan Drug status for treating mitochondrial disorders. The value of CoQ10 in CVD and with statin use has not been clearly established.

L-carnitine
In 1986, the FDA-approved L-carnitine for use in primary carnitine deficiency, which manifests as a disruption in the transport of free fatty acids across the mitochondrial membrane for energy production. In myopathic carnitine deficiency, muscle weakness is paramount (184). Convincing evidence is lacking for the use of carnitine in patients without carnitine deficiency undergoing cardiac surgery, in patients with angina pectoris, acute myocardial infarction, shock, and peripheral vascular disease (185). Urinary carnitine excretion is known to be increased in patients with heart failure (186). Several clinical RCTs have evaluated the addition of L-carnitine to standard medial therapy for heart failure with mixed results (187–189). Significant improvements in maximum exercise times and ejection fractions were reported by Mancini et al. (190) in 60 patients with NYHA functional class II or III CHF who were randomized either to propionyl-L-carnitine (50 mg t.i.d.) or placebo for 180 days. Two other small trials reported similar results, and one trial showed improvement at a higher dose. In a double-blind randomized trial in 155 patients with claudication, a significant improvement in exercise treadmill performance (54% increased walking time) and functional status was achieved with oral propionyl-L-carnitine 2 g/day for 6 months (191). Differences in effect may be due to the dose and formulation of carnitine. In contrast, the investigators of the Study on Propionyl-L-Carnitine in Chronic Heart Failure did not show improved exercise tolerance on L-carnitine supplementation (187).

At present, it is unclear whether L-carnitine provides any benefit beyond well-established therapies. A more definitive answer will come from the Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM-2) trial, which will assess the efficacy of L-carnitine in approximately 4,000 patients with acute MI over six months (192). Supplements containing D- or DL-carnitine, often present in over the counter preparations and dietary supplements, should not be substituted for L-carnitine. Carnitine frequently causes nausea, pyrosis, dyspepsia, and diarrhea. Concomitant use of carnitine with warfarin may potentiate warfarin’s anticoagulant effects.

L-arginine
L-arginine is the precursor of nitric oxide (NO) and has been shown to improve coronary and brachial artery endothelial function and reduce monocyte/endothelial cell adhesion (193–195). In patients with recurrent chest pain, improvements in coronary blood flow in response to acetylcholine have also been documented. In hypercholesterolemic subjects, dietary supplementation with L-arginine over two weeks has been shown to normalize the adhesiveness of mononuclear cells (196) and reduce platelet aggregability (197). However, in a study in 30 patients with CAD, supplemental L-arginine did not affect measures of NO bioactivity and NO-regulated markers of inflammation (198).

There are a few documented reports of adverse effects from oral use of L-arginine. Several patients with hepatic impairment and a recent history of spironolactone use were reported to develop severe hyperkalemia upon initiation or arginine hydrochloride for management of metabolic alkalosis (199). Oral L-arginine appears to have potential benefit in CHD, but hard evidence for its value is currently not available.

Herbal Preparations.   In the U.S. today, herbs may be marketed as dietary supplements providing their intended use is not to diagnose, treat, cure, or prevent disease. A number of approved drug substances have their origin in plants, such as digoxin, atropine, reserpine, and amiodarone. However, only a few herbal products available in the U.S. have been tested for cardiovascular purposes: hawthorn (heart failure and coronary insufficiency), garlic (atherosclerosis), ginkgo (arterial occlusive disease), and horse chestnut (chronic venous insufficiency) (200). Few U.S. products benefit from rigorous characterization and standardization necessary for clinical study.

Hawthorn (Crataegus)
Hawthorn has positive inotropic effects and is a peripheral vasodilator. It increases myocardial perfusion and stroke volume and reduces afterload. Antiarrhythmic effects have been reported in an ischemia-reperfusion model. Orally, hawthorn leaf extract has been used for CHF, cor pulmonale, ischemic heart disease, arrhythmias, blood pressure reduction, atherosclerosis, and cerebral insufficiency (200). Preparations made from flowers with leaves are sold as a prescription medication in parts of Europe and Asia. For example, in Germany, hawthorn can be prescribed for "mild cardiac insufficiency."

Several double-blind clinical studies of patients diagnosed with heart failure have shown objective improvement in cardiac performance using bicycle ergometry (201,202) or spiroergometry. In one study, hawthorn was found to be as effective as captopril in improving exercise tolerance. Based on ergometric performance parameters, the minimum effective daily dose of hawthorn extract is 300 mg. In most trials, the maximum benefit was seen after 6 to 8 weeks of therapy. Weikl et al. (203) demonstrated an improvement in exercise performance in 136 stage II CHF subjects receiving 160 mg hawthorn special extract WS 1442 (leaves and flowers). The efficacy and safety of hawthorn extract WS 1442 (900 and 1,800 mg) were evaluated in a 16-week randomized, controlled trial in 209 patients with NYHA functional class III heart failure. The investigators found a dose-dependent effect of WS 1442 on enhancing exercise capacity and reducing heart failure-related signs and symptoms. The preparation was shown to be well-tolerated and safe (204). A recent pharmacokinetic study was conducted in 8 healthy subjects consuming 0.25 mg digoxin alone or with hawthorn extract WS 1442, which demonstrated no significant alterations in the pharmacokinetic parameters for digoxin (205). Clinical trials are underway in the U.S. to evaluate further the safety and efficacy of hawthorn in patients with heart failure.

Hawthorn may offer some advantages over digoxin in mild heart failure. Compared to digitalis, hawthorn has a wider therapeutic range, lower risk in case of toxicity, has less of an arrhythmogenic potential, is safer to use in renal impairment, and can be safely used with diuretics and laxatives (200). However, hawthorn can markedly enhance the activity of digitalis (206), and care should be taken when combining it with beta-blockers and class III antiarrhythmics.

Ginkgo biloba (ginkgo leaf extract)
Ginkgo has been used for relief of intermittent claudication in patients with peripheral arterial occlusive disease. Ginkgo leaf, obtained from the Ginkgo biloba tree, and its extracts, or GBE, contain several bioactive constituents including flavonoids, terpenoids, and organic acids. As with other phytomedicines, several constituents of ginkgo extracts may contribute to its therapeutic effect. The mechanism of benefit is unknown. Two meta-analyses of the efficacy of ginkgo leaf extract for the treatment of intermittent claudication concluded that only modest benefits resulted from its use (207,208). In the meta-analysis performed by Pittler and Ernst (207), eight randomized, placebo-controlled, double-blind studies involving a total of 415 participants were evaluated. All of the studies used pain-free walking distance as the primary outcome measure. Several different formulations of ginkgo were used with doses ranging from 120 to 160 mg a day. The majority of trials lasted 24 weeks. Statistical pooling of the results from the eight trials showed that ginkgo significantly increased pain-free walking distance by 34 m. The clinical relevance of this increase is unclear.

Ginkgo is considered relatively safe, with a few documented adverse effects being mild gastrointestinal upset and headache. Ginkgo has been reported to increase the risk of bleeding. The concomitant use with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and anticoagulants, such as warfarin and heparin, is not advised. Ginkgo can increase blood pressure in patients taking thiazide diuretics (209). Ginkgo does not appear to interact or adversely affect concomitant therapy with cardiac glycosides, and it appears to provide a small benefit in the treatment of peripheral arterial disease.

Horse chestnut (Aesculus hippocastanum)
Horse chestnut seed extract (HCSE) contains escin, a triterpene glycoside, and the toxic glycoside aesculin, a hydroxycoumarin derivative that is used to treat venous insufficiency (210). A systematic review of 14 randomized, placebo-controlled trials (a total of 1,071 subjects) was recently completed evaluating the efficacy of HCSE for the treatment of chronic venous insufficiency. The HCSE was found to be superior to placebo and as effective as compression therapy in decreasing lower leg volume and leg circumference at the calf and ankle. Symptoms such as leg pain, pruritus, and feeling of fatigue and tenseness were also reduced (211). Side effects are uncommon, but gastrointestinal irritation and toxic nephropathy may occur (212).

Contraindications to use include hypersensitivity to escin or horse chestnut and renal or hepatic impairment (213). At present there is no human drug interaction data available, but the increased risk of bleeding due to the naturally occurring coumarin constituents is possible. Also, HCSE has been suspected of causing hypoglycemic effects (209). The German Commission E has approved the use of HCSE in chronic venous insufficiency. It may be effective in that role.

Guggulipid (guggul gum)
Guggulipid has a long history of use in Ayurvedic medicine, which is an ancient Indian system that uses an integrated approach (diet, lifestyle, herbs, exercise, and meditation) to the prevention and treatment of illness by maintaining harmony among the mind, body, and forces of nature. Both guggul and its purified extracts have been used as hypolipidemic agents in patients with ischemic heart disease, hypercholesterolemia, and obesity (214). Clinical studies performed in India have demonstrated that 25 mg of guggulsterone extracts t.i.d. may be an effective treatment for hypercholesterolemia and hypertriglyceridemia. Reductions in total cholesterol levels of approximately 24% and reductions in triglycerides of 16% to 23% have been reported (215,216). The majority of these trials were not randomized.

In one randomized, controlled study of 125 hyperlipidemic patients, a standardized extract of guggulsterone was compared with clofibrate with mean reductions in serum cholesterol and triglycerides of 11% and 16%, respectively (217). In the first randomized, controlled trial of guggulipid outside of India, 103 healthy adults with hypercholesterolemia given 1,000 or 2,000 mg guggulipid containing 2.5% guggulsterones experienced no improvement in their lipid levels. A hypersensitivity rash was reported in a small number of subjects (218). Effects of guggulipids on HDL were mixed. A standard dose is 75 to 100 mg of guggulsterones daily divided into three doses. Guggulipids can cause gastrointestinal upset, headache, mild nausea, belching, hiccups (209), and rash (218). Concomitant oral administration can reduce propranolol and diltiazem bioavailability and might reduce the therapeutic effects of these drugs (219). Although in vitro studies suggest a plausible mechanism of action for guggulipid as a cholesterol-lowering agent (220), definitive safety and efficacy data are lacking.

Red yeast rice (Monascus purpureas)
Red yeast is the rice fermentation product of a mixture of several species of Monascus fungi, principally Monascus purpureas. It contains monacolin K (lovastatin, mevinolin) and other HMG-CoA reductase inhibiting compounds. Red yeast has been used to reduce cholesterol levels (221,222). In a 12-week placebo-controlled study conducted in the U.S. in 83 healthy subjects with hyperlipidemia (222), 2.4 g of red yeast rice significantly reduced total cholesterol by 16%, LDL cholesterol levels by 22%, and total triglycerides by 7% compared with placebo. No serious side effects were reported, but additional longer-term studies are needed.

Red yeast should be treated as an HMG-CoA reductase inhibitor, with all the possible side effects, drug interactions, and precautions associated with this class of drugs. Red yeast rice is no longer marketed with standardized lovastatin levels in U.S. owing to legal issues, and it is now sold without lovastatin levels declared. Because of the availability of statins, its use is not recommended.

Policosanol
Policosanol is a sugar cane extract that contains a mixture of aliphatic alcohols. Lipid-lowering effects of policosanol have been shown in a variety of animal species; however, little is known about its mechanism of action or its exact composition. Over 1,000 subjects have been studied for periods of six weeks to one year in 15 randomized, placebo-controlled trials using policosanol (5 to 20 mg per day) for lipid lowering. At doses of 10 to 20 mg per day, significant reductions were observed for total cholesterol (17% to 21%) and LDL cholesterol (21% to 29%) with increases in HDL cholesterol (8% to 15%) (223). There are no data on efficacy determined by clinical end points. Although policosanol appears to be well-tolerated, caution should be exercised when combining policosanol with antiplatelet or anticoagulant agents, including garlic, ginkgo, and high doses of vitamin E (224), as policosanol has been shown to inhibit platelet aggregation in both healthy and diseased patients (225). The majority of the existing studies have been conducted in Cuba, and independent verification is needed before its use can be recommended.

Ephedra (Ma huang)
Ephedra, together with its principal alkaloid ephedrine, was one of the first of the Chinese herbal medicines to be used in Western medicine. Ephedra is used to treat bronchospasm, asthma, bronchitis, allergic disorders, and nasal congestion, or as a central nervous system stimulant (209). Ephedrine acts by stimulating alpha, beta-1, and -2 adrenergic receptors, and indirectly by releasing norepinephrine from body stores. The cardiovascular effects of ephedrine last 10 times longer than those of epinephrine and consist primarily of increased heart rate and peripheral vascular resistance. Ephedrine and related alkaloids have been associated with adverse cardiovascular events, including acute MI, severe hypertension, myocarditis, and lethal cardiac arrhythmias. Dietary supplements that contain ephedra alkaloids were widely promoted and used in the U.S. for weight loss and increased energy. Their use was associated with a number of adverse events, including MI, stroke, arrhythmias, and death (226), and in December 2003 the FDA announced a ban on the sale of ephedra products in the U.S. Of developing concern is the herbal Citrus aurantium, or bitter orange, which contains similar stimulant amines as ephedra and is now being marketed in weight loss products. The Joint National Committee (JNC)-7 guidelines list it as a possible cause of resistant hypertension (227). One case report of acute MI has been associated with its use as contained in a multi-ingredient weight loss product. Table 1 provides a list of herbs containing stimulants.

Herb-Drug Interactions: What We Need to Know.   The increased use of herbal and phytomedicines by both health professionals and consumers has raised questions about herb-supplement and herb-drug interactions because herbs are making a resurgence in the U.S. market. Kaufman et al. (228) described the patterns of prescription and nonprescription drugs in the U.S. population, noting that:

• 14% of the population took supplements and herbals over the prior week

• 16% of prescription drug users also took herbs or supplements

• 40% of the population used one or more mineral or vitamin supplements

In 1997, an estimated 15 million adults took prescription medications along with herbal remedies and/or high dose vitamins (229). These individuals are potentially at risk for adverse herb-supplement or herb-drug interactions. The following tables delineate possible drug interactions with herbal or botanical products. Table 2 lists herbs that may potentiate the effect of cardiac glycosides and antiarrhythmics. Table 3 lists the potential adverse effects of herbal remedies and their major constituents. Table 4 lists potential interactions between some herbal medicinal products and cardiovascular drugs. Table 5 lists the interference of herbal products in therapeutic drug monitoring.

1 Omega-3 supplements 1 to 2 g per day if insufficient omega-3 intake from fish

2 Stanol/sterol ester margarines (2 g per day)

3 Soluble fiber (5 to 20 g per day)

4 Soy foods and soy protein (equivalent to 25 g soy protein daily

Possibly useful for indications noted

1 Moderate alcohol intake (1/2 to 2 drinks per day—a drink is 5 oz of wine, 12 oz of beer or 1.5 oz of 80 proof whiskey) for cardiovascular risk reduction

2 Tea (1 to 2 cups daily) for cardiovascular risk reduction

3 Recommended dietary intake of magnesium (RDA adult men 420 mg; women 320 mg daily). Consider supplementation for those at risk (poor dietary intake or conditions that increase renal magnesium losses).

4 Folic acid supplementation (plus vitamins B₆ and B₁₂) if homocysteine is elevated.

Cannot recommend at this time (for some individuals in some situations, probably not harmful)

1 Folic acid supplementation if homocysteine is not elevated for vascular disease

2 Garlic for lipid lowering

3 Soy isoflavones for lipid lowering

4 L-arginine supplementation for nutritional support

5 CoQ10 for nutritional support

6 Hawthorn for mild heart failure

7 Ginkgo biloba for peripheral vascular disease

8 HCSE for peripheral vascular disease

Supplements/interventions not recommended (possibly harmful)

1 Levels exceeding the upper tolerable limits (IOM, 2001) for vitamins C (2,000 mg/day) and E (1,000 mg/day); and beta-carotene supplementation not recommended; limit to food sources.

2 Ephedra, oleander, and other herbs/botanicals with well-defined contraindications to cardiovascular drug and/or CVD conditions.

Related Alternative Therapy.   Chelation
Chelation therapy is a form of alternative medicine utilized in the treatment of atherosclerotic CVD. Over 800,000 patient visits were made for chelation therapy in the U.S. in 1997. Chelation therapy consists of a series of intravenous infusions containing disodium ethylene diamine tetraacetic acid (EDTA) in combination with other substances, such as vitamins. Use of EDTA has been found to be effective in chelating and removing toxic heavy metals from the blood (238). It is purported that the removal of polyvalent cations, notably calcium ions, can lead to the regression of atherosclerotic plaques by a yet undefined mechanism. Use of EDTA chelation therapy is FDA-approved in treating lead poisoning and toxicity from other heavy metals. The FDA has not approved the use of chelation therapy to treat CAD.

The bulk of the evidence supporting the use of EDTA chelation therapy is in the form of case reports and case series. A systematic review on chelation therapy for peripheral arterial occlusive disease has shown that chelation therapy is not superior to placebo and is associated with considerable risks (239). At present, the benefit of chelation therapy remains controversial as highlighted by a recent Cochrane Review (240) of five randomized controlled studies in small numbers of subjects evaluating outcomes of disease severity and subjective measures of improvement.

The ACC position statement reapproved in 1990 states "that there is insufficient scientific evidence to justify the application of chelation therapy for atherosclerosis on a clinical basis. At the present time, therefore, chelation therapy for atherosclerosis should be applied only under an investigation protocol."

In an effort to advance the evidence base for the use of chelation therapy, the NCCAM and the National Heart, Lung, and Blood Institute (NHLBI) have launched the first large-scale clinical trial to determine the safety and efficacy of EDTA chelation therapy in individuals with coronary artery disease. The five-year Trial to Assess Chelation Therapy (TACT) will involve over 2,300 patients at more than 100 research sites across the country. The study will determine whether EDTA chelation and/or high-dose vitamin supplements improve event-free survival, whether these are safe for use, improve the quality of life, and are cost-effective. The primary end point in the trial will be a composite of death, MI, stroke, hospitalization for angina, and coronary revascularization.