Integrative Medicine in the Prevention of Cardiovascular Disease

Key Points

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Integrative medicine, which blends standard Western and nontraditional medical practices, is used by 38% of adults and 12% of children in the United States.
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Placebo responses, inherent in all conventional and integrative medical therapies, account for as much as 20% to 50% of clinical outcomes.
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Traditional Chinese medicine, incorporating acupuncture and herbals, reduces elevated systolic blood pressure and oxygen demand to improve supply-demand imbalances and myocardial ischemia. Tai Chi and Qigong, two forms of Chinese energy medicine, frequently involve a component of exercise that also may reduce blood pressure.
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Ayurvedic medicine, originating from India, includes lifestyle changes, particularly dietary and herbal prescriptions, as well as stress reduction through yoga and meditation.
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Chinese and Ayurvedic medicines, with a long history of traditional use, require further study to assess their actions on cardiovascular risk factors.
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Observational studies on single-nutrient dietary supplements suggest reduced cardiovascular risk that has not yet been validated by randomized trials.
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Blood pressure, body mass index, and cholesterol level are improved by a program of yoga incorporating vegetarian diet and stress management with meditation.
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Behavioral and cognitive training, guided imagery, meditation, biofeedback, and progressive muscle relaxation appear to be capable of reducing blood pressure.
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Naturopathic medicine incorporates a number of natural practices, such as dietary manipulation and exercise, to prevent disease and to promote healing; other naturopathic practices, like homeopathy, require validation before they can be recommended.
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Chelation therapy, which seeks to lower calcium and to alter atherosclerosis progression, has the potential for serious side effects and is not recommended on the basis of currently available evidence.

Complementary and alternative medicine (CAM) consists of a diverse group of practices and health care systems that generally are not considered to be part of usual Western or allopathic medical practices ( Box 17-1 ). Most academic medical centers in the United States have adopted the term integrative medicine, recognizing the usefulness of combining conventional and CAM practice. There is a large diversity of disciplines that make up CAM therapies (see Box 17-1 ), and because scientific and clinical studies supporting their mechanisms of action and clinical utility vary tremendously, most academically based centers tend to focus on only a few that are supported by evidence.

BOX 17-1

Types of Integrative Medical Therapies

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Whole medical systems (traditional Chinese, Ayurvedic medicine, naturopathy, homeopathy)
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Mind-body medicine (meditation, yoga)
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Biologically based practices (dietary supplements, herbs, foods, vitamins)
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Manipulative and body-based practices (chiropractic, osteopathic manipulation, massage)
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Energy medicine (Qigong, Tai Chi, and bioelectromagnetic therapies)

This chapter discusses areas of integrative medicine that are supported by evidence ( Box 17-2 ) and that can be used in preventive approaches to cardiovascular disease, particularly coronary artery disease. Some therapies have little rationale or support for efficacy in preventive cardiovascular medicine and are discussed only briefly ( Box 17-3 ). Most guidelines (48%) that have been developed are based on recommendations that are less scientifically rigorous and expert opinion, case studies, or standards of care. Despite the absence of high-quality prospective randomized clinical trials on cardiovascular prevention in integrative medicine, experimental studies have identified the mechanisms by which these therapies may reduce cardiovascular risk and, by extension, establish the potential for their clinical action.

BOX 17-2

Evidence-Based Integrative Medical Therapies for Cardiovascular Disease

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Acupuncture
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Tai Chi, Qigong
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Chinese herbals
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Ayurvedic medicine
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Yoga
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Meditation
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Ayurvedic herbals
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Naturopathic medicine
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Massage
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Western supplements

BOX 17-3

Unproven Integrative Therapies for Cardiovascular Disease

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Chelation therapy
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Homeopathy
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Bioidentical hormones

In addition to its action on traditional cardiovascular risk factors, the influence of CAM on stress is discussed throughout this chapter because it is linked to many aspects of coronary disease, including blood pressure dysregulation, diabetes, and elevated cholesterol. This chapter, therefore, provides a brief overview of available clinical and basic science evidence for the use of integrative approaches to reduce cardiovascular disease risk, focusing on our current Western understanding of CAM rather than on traditional CAM theory, which can be found in recent texts. Dietary and nutritional approaches are considered in Chapter 16 , although a discussion of supplements, including herbals and vitamins as they relate to cardiovascular risk reduction, is provided here.

Use of Integrative Medicine in the United States

The National Center for Complementary and Alternative Medicine (NCCAM) recently released an update on the use of CAM practices in the United States, taken from data collected in the National Health Interview Survey of 2007. Approximately 38% of adults and 12% of children use some form of CAM. CAM is used with higher frequency by women and children of families that use CAM. The most common uses are for pain, anxiety or stress, hypercholesterolemia, and insomnia ( Fig. 17-1 ). A major issue is the absence of communication between patients using integrative medical therapies and their physicians, in part because access is obtained outside the standard medical environment and because of the lack of approval of many of these unconventional therapies by the medical profession. Thus, interest in CAM is driven by the lay community more than by the medical community.

Despite the absence of acceptance in the past, there is increasing use and referral by some practitioners, mainly family physicians and other primary care providers, as they are encouraged by their patients, as studies begin to appear, and as many schools begin to introduce CAM education into their curriculum. It is apparent, however, that there are only a limited number of cardiologists who use or refer patients for CAM therapy and fewer yet who study it. The skepticism of many physicians stems from a common belief that much if not all of the clinical effect of CAM is equivalent to that of a placebo.

Role of Placebo in Complementary and Alternative Medicine

Placebo, translated from the Latin phrase “I shall please,” is part of every clinical intervention, whether standard Western therapy or CAM procedure, and clearly has been well recognized in many forms of cardiovascular medicine. Simple interaction between a provider and a patient frequently leads to clinical improvement unrelated to the intervention in many diseases. In fact, between 20% and 50% of response to any medical treatment, including standard Western therapies for cardiovascular disease, may be ascribed to a placebo effect, either because of a physiologic placebo-related response or because of regression to the mean with repetitive testing. Furthermore, placebo responses are more likely to occur in trials comparing continuous variables like pain and blood pressure.

Chronic stable angina improves by 30% to 50% and blood pressure can be reduced by as much as 20 to 40 mm Hg by reassurance or placebo interventions. In integrative medicine, the concern is that most if not all of the effect is a nonspecific response to placebo, that is, there is no active intervention. This belief is reinforced by the fact that many of the symptoms and diseases treated in cardiovascular medicine, such as angina and stress responses, have improved with placebo therapy. Compounding the difficulty in distinguishing between active and placebo responses is the finding that both operate through the endogenous opioid system, including shared regions of the brain like the periaqueductal gray that are activated by acupuncture and placebo. Furthermore, unwarranted or exaggerated expectation in patients using CAM interventions may heighten the placebo response.

Double-blind controls, placebo interventions, and nontreatment arms have been used to detect placebo responses. It is frequently difficult to truly blind the practitioner, however; for example, the acupuncturist has to know where to place the needle to achieve an optimal response. Furthermore, the use of no or inadequate controls has limited the interpretation of many clinical CAM trials. More than 50% of trials coming from Asian countries are limited by the absence of adequate controls, and once many trials use a suitable control, some studies have found little difference between the sham and the true (verum) intervention.

Despite the inherent problems with control intervention in studies of integrative medicine, they are extremely important, and many suitable control interventions have been devised. One example of a suitable control is in the study of electroacupuncture regulation of elevated blood pressure, in which a needle is placed in an acupoint known to exert biologic effects but is not stimulated. Alternatively, needles can be placed in acupoints known not to exert responses. In the first control, afferent nerves are not stimulated, and hence any response is related to interaction between the therapist and the subject. The latter control is associated with sensory stimulation, but neural input to the central nervous system does not involve the areas known to regulate blood pressure.

Uninformed study subjects cannot differentiate between control and active interventions. By use of this paradigm, 30 minutes of low-frequency, low-intensity acupuncture at active acupoints, but not sham acupuncture with either type of control intervention described earlier, lowers elevated blood pressure in experimental studies.

Traditional Chinese Medicine

Traditional Chinese medicine, originating more than 2000 years ago, incorporates several diverse treatment options, including acupuncture and acupressure, Chinese herbals, moxibustion (local heat with a Chinese herb), massage, Tai Chi, Qigong, and dietary therapy. Acupuncture, Tai Chi, and Qigong are forms of energy-based medicine, the energy referred to as Qi .

Acupuncture, Acupressure, and Moxibustion

Acupuncture and its derivatives, acupressure and moxibustion, are based on a system of 12 principal channels or meridians that lie along the body surface. Along these meridians are small nodes or acupuncture points (acupoints) that direct the therapist where to place the needle to exert pressure or heat. Although neither the meridians nor the acupoints have a physical basis, they are useful because they direct the therapist to where stimulation should occur.

Mechanism of Action

Many if not all meridians lie over major neural pathways that contain both motor and, more important, sensory nerves. Thus, from a physiologic perspective, acupuncture needles penetrate the skin and in most circumstances are positioned through underlying nerves or sufficiently near the mixed nerve bundles that contain both sensory and motor fibers. Although stimulation of the muscle motor fibers is not important in the acupuncture effect because paralytic agents do not alter acupuncture’s action on the cardiovascular system, fine muscle contractions are helpful in alerting the practitioner that the needle is positioned in a proper location near the nerve bundle. Conversely, activation of sensory neural pathways provides input to regions of the central nervous system that regulate cardiovascular function.

Transection of the afferent pathway central to needle insertion eliminates all but the placebo response to acupuncture. More specifically, acupuncture-related activation of thin-fiber somatic sensory pathways provides strong input to the spinal cord, ventral hypothalamus, midbrain periaqueductal gray, and both pressor and depressor regions that regulate sympathetic (and probably parasympathetic) outflow in the medulla, located in the lower brainstem.

Manual acupuncture or low-frequency, low-intensity electroacupuncture is capable of causing the release of a number of modulatory (inhibitory) neuropeptides in the brain, including opioids (endorphins and enkephalins), γ-aminobutyric acid, nociceptin, serotonin, and endocannabinoids as well as excitatory amino acids like glutamate and acetylcholine, that ultimately inhibit sympathetic (and probably parasympathetic) outflow to the heart and vascular system. In the spinal cord, acupuncture appears to inhibit sensory inflow and sympathetic outflow through both opioid and nociceptin mechanisms of blockade.

Two important concepts in acupuncture are acupoint specificity and the nature of its action. Point specificity is the differential clinical response to stimulation of specific acupoints. For example, some acupoints, like those along the pericardial meridian overlying the median nerve in the wrist, exert a stronger influence on the cardiovascular system than other points do. The extent of influence is determined by the amount of input to regions of the brain that control cardiovascular function. The nature of acupuncture’s action is determined by the mode of sensory nerve stimulation, the duration of stimulation, and the extent of release of neurotransmitters in the central nervous system.

Low-frequency electrical (2 to 6 Hz) or manual acupuncture for 30 to 45 minutes seems to be most effective, reducing sympathetic outflow after 10 to 15 minutes of stimulation and lasting for many minutes to hours or even days after acupuncture, depending on the model of investigation and extent of repetitive stimulation. Thus, the cardiovascular influence of electroacupuncture can last for 1 to 2 hours in anesthetized experimental animal studies and for 10 to 12 hours in awake animals, whereas repetitive acupuncture in patients can exert an influence on blood pressure for several weeks.

Acupuncture’s Action on Cardiovascular Risk Factors

A number of cardiovascular risk factors, including hypertension, obesity, and hypercholesterolemia, potentially may be influenced by acupuncture. In addition, there is some evidence that acupuncture may be efficacious in stroke and coronary as well as peripheral arterial disease.

Because acupuncture can decrease sympathetic outflow and sympathoexcitatory reflex responses associated with elevated blood pressure, there is a rationale to use it for treatment of mild to moderate hypertension. However, the results of clinical trials are mixed. Experimental studies in quadriplegic rats suggest that transcutaneous electrical stimulation (TENS), which shares some features of stimulation and physiologic response with electroacupuncture, decreases the exaggerated blood pressure responses associated with colon distention. Although acupuncture appears to be safe, no clinical trials are available on its effect in spinal patients experiencing large fluctuations in blood pressure associated with autonomic dysreflexia. Blood pressure in spontaneously hypertensive rats is reduced by acupuncture at an acupoint located over the deep peroneal nerve for periods lasting up to 12 hours. A small study of 50 patients suggested that 30 minutes of acupuncture lowered both systolic and diastolic pressure. Conversely, the SHARP (Stop Hypertension with Acupuncture Research Program) trial, which treated patients with moderate hypertension during a 12-week period, demonstrated no influence on blood pressure over and above the response to an invasive sham control when blood pressure was measured intermittently with manual mercury sphygmomanometers. However, large and small trials incorporating ambulatory monitoring have demonstrated more consistent decreases in blood pressure in patients with mild to moderate hypertension, especially if acupoints that have been shown to have a strong cardiovascular influence (P5, P6, St36, St37, referring to points along the pericardial and stomach meridians overlying the median and deep peroneal nerves) are used. Acupuncture appears to influence systolic and mean blood pressure more than diastolic blood pressure. The onset of action is slow, frequently requiring several acupuncture treatments before a sustained decrease in blood pressure is observed. Blood pressure decreases by 5 to 20 mm Hg and tends to remain low for several weeks after cessation of treatment.

In addition to hypertension, experimental studies demonstrate that acupuncture can lower cholesterol. Daily acupuncture for a 2-week period reduces the increase in cholesterol in experimental animal models fed high-cholesterol diets. There are no good randomized controlled clinical trials, but a small nonrandomized, unblinded trial of electroacupuncture that did not incorporate a control acupoint group demonstrated similar or greater weight loss, low-density lipoprotein cholesterol (LDL-C) and triglyceride reductions compared with a control group fed a low-calorie diet.

Although stimulation of auricular acupoints to treat overweight patients provides input to regions of the brain that regulate food ingestion, its ability to assist with weight loss in obesity is less certain. Experimental studies in rats show that auricular (ear) acupuncture leads to a 5% loss in weight during a period of 2 to 3 weeks. However, clinical trials are mixed, with uncontrolled studies showing small decreases and controlled trials showing either very modest or no weight loss that could be ascribed to acupuncture. Many of the trials lacked suitable controls.

Because acupuncture leads to the release of endogenous opioids, it has been thought that it may be useful in treating addictive habits like smoking. In this regard, acupuncture reduces symptoms in subjects addicted to opiates like morphine. However, meta-analyses of relevant clinical trials reveal that many are of low quality, are frequently short term, lack suitable controls, and do not provide sufficient information to assess their quality. Thus, at present, insufficient data are available to determine the efficacy of acupuncture in smoking cessation.

Cardiovascular Responses to Transcutaneous Electrical Stimulation and Acupuncture

Through an opioid mechanism, acupuncture lowers myocardial oxygen demand and hence can reduce demand-supply imbalances and ventricular dysfunction in experimental myocardial ischemia. Similarly, both TENS and acupuncture reduce myocardial ischemia occurring during exercise in patients with angina and electrocardiographic evidence of ischemia. TENS shares some similarities with but is not exactly equivalent to acupuncture because much higher stimulation intensities and frequencies are used during the noninvasive TENS stimulation that is not directed at specific locations (acupoints) over neural pathways. Although there is some debate about whether acupuncture can increase coronary blood flow, the preponderance of evidence suggests that it mainly reduces ischemia by reducing the increase in blood pressure and double product (but not the elevated heart rate) associated with exercise, hence lowering myocardial oxygen demand.

Acupuncture also lowers the reflex excitatory responses to mental stress. The influence of acupuncture is not universal because it occurs in only 70% of individuals. This raises the question of which individuals are most likely to respond. Whereas there is no definitive answer to this question, those individuals demonstrating changes in pain threshold and skin finger temperature in response to acupuncture appear most likely to respond. Acupuncture’s action on skin temperature signals its action on the sympathetic nervous system, more specifically cutaneous vasomotor fibers.

Application of acupuncture over a course of several weeks decreases nitroglycerin consumption and the rate of anginal attacks in patients with stable angina. Finally, a prospective nonrandomized study of patients in whom acupuncture was administered as part of a lifestyle program incorporating stress reduction and healthy eating and living found reduced in-patient days, medication use, and accumulated mortality rate. The independent contribution of acupuncture to these beneficial effects was not determined.

TENS increases the survival of skin flaps in experimental models as well as in patients undergoing reconstructive surgery. Spinal cord stimulation, which may involve stimulation of many of the same central neural systems as in acupuncture, increases skin temperature and reduces pain, ulcer formation, and tissue salvage in patients with peripheral vascular insufficiency. No trials of acupuncture’s influence in patients with peripheral vascular disease have been published.

Tai Chi and Qigong

Energy medicine stems from the belief that all living organisms radiate energy, although there is no sound scientific evidence that demonstrates the existence of bioenergy fields. Tai Chi and Qigong, belonging to energy medicine, are part of traditional Chinese medicine. Like yoga, they include slow movements of the body, diaphragmatic breathing exercises, and mental concentration that have an impact on the autonomic nervous system, catecholamines, and blood pressure. Chi or Qi is considered to be energy that helps maintain homeostasis. According to traditional Chinese medicine theory, this energy flows through channels called meridians. Although somewhat controversial, most modern scientists recognize that these meridians, rather than forming a physical entity, represent a road map overlying neural pathways that provide sensory input to the central nervous system when they are stimulated. A unique traditional Chinese medicine view is that the physical and emotional hearts are included as a single concept, taking into account our understanding that the brain (and spinal cord) strongly controls autonomic and hence cardiovascular function.

Qigong means Qi training or Qi practice. Of the different forms of Qigong, medical Qigong is most applicable to treatment of cardiovascular disease and risk factors that promote cardiovascular disease. A typical session of Qigong includes meditation (see later), deep breathing and relaxation, guided imagery, mindful focus, and exercise and is practiced in a quiet place in fresh air. Thus, practitioners seek to relax their muscles, to regulate their breathing, and to concentrate their mind. Exercise consists of small postural movements of the limbs, walking, and larger movements.

A number of studies have evaluated the influence of Qigong on blood pressure in patients with mild to moderate hypertension. For example, two small studies show that Qigong lowers serum catecholamines and blood pressure in patients with essential hypertension. However, in general, the quality of these studies is low, and they need to be repeated with larger numbers of patients, better blinding, randomization, and concealment of allocation.

Tai Chi is a type of Qigong that involves meditation, breathing, and slow movements of the limbs. It has roots in dance as well as in martial arts. Although there are many styles of Tai Chi, it can be modified for physical disability. Typically, the degree of exercise stress is considered mild to moderate, increasing heart rate reserve in one study by 58% and oxygen consumption to 55% of peak capacity. Tai Chi increases aerobic capacity to the greatest extent in deconditioned subjects. A small study has shown that compared with sedentary age-matched controls, during a 5-year period, elderly male and female subjects who regularly use Tai Chi experience smaller decrements in peak oxygen consumption and weight gain and smaller increments in body mass index and body fat as measured by skinfold thickness, although differences between the control and intervention groups were small.

During a 12-week period, Tai Chi mildly lowers systolic and diastolic arterial blood pressure (−7/2 mm Hg) much like moderate exercise in patients with mild hypertension. Decreases in anxiety and in total cholesterol and LDL-C and elevations in HDL-C, in addition to the blood pressure reduction, have been noted in hypertensive patients participating in a 12-week program of Tai Chi. However, a review of approximately 70 articles on Qigong for hypertension suggests that most reports are in low-level scientific journals, conference proceedings, book excerpts, and informal reports that were not peer reviewed. Only five studies reported a randomized design.

A few studies have investigated the role of Tai Chi and Qigong in patients with coronary artery disease. Patients randomized to Tai Chi and Qigong 3 weeks after an acute myocardial infarction demonstrate a reduction in systolic blood pressure similar to that of a music exercise group and show a greater reduction in diastolic blood pressure.

Reiki and therapeutic touch are two other forms of energy medicine. Reiki uses what is believed to be “healing energy” to improve health by inducing deep relaxation. However, there are no studies demonstrating that a practitioner can “transfer energy” through strategic points (chakras) to cause a demonstrable cardiovascular response. In contrast, therapeutic touch, in which the hands are used to direct healing energy, in several studies has demonstrated reduction of anxiety in coronary care unit patients. There is no evidence showing that there is any direction of energy in therapeutic touch. The responses most likely are simply a “placebo” interaction involving reassurance and stress reduction that occurs between the therapist and the patient.

Chinese Herbs

Traditional Chinese medicine employs herbs as frequently as acupuncture and frequently in conjunction with acupuncture. Herbs in traditional Chinese medicines are used to correct energy flow and balance as noted earlier for acupuncture and other traditional Chinese medicine therapies. Most commonly, herbs are taken as a fixed formula or in a fixed combination of several herbs. Each individual herb is thought to address a particular imbalance. In the less formal practice of Chinese folk medicine, herbs are used more simply, somewhat in the manner of Western herbal medicine.

Herbs most commonly used include astragalus (Astragalus mongholicus); danshen, commonly referred to as Chinese salvia (Salvia miltiorrhiza); dong quai (Angelica sinensis); ginger (Zingiber officinale); kudzu (Pueraria lobata); licorice (Glycyrrhiza glabra); lycium (Lycium chinense); Asian ginseng (Panax ginseng); and schizandra (Schisandra sphenanthera) (see Appendix). Herbal preparations may be administered in many forms, including as a tea, tablet, capsule, or decoction; as such, their standardization and use in clinical trials have been challenging. In China today, traditional Chinese medicine is used alongside conventional pharmaceutical treatment in a holistic approach to treatment.

In a recent review of 167 randomized controlled trials on the use of traditional Chinese medicine involving more than 18,000 participants, the authors noted that the overall methodologic quality of the trials was rated poor because of lack of description or incorporation of adequate sample sizes, randomization, allocation and blinding procedures, and disclosure of sample size estimates. Description of the quality control of herbal products also has been lacking from randomized controlled clinical trials reported in the literature addressing such issues as quality of the herbs selected, growing conditions, methods of preparation, testing for heavy metals and microbial contaminants, and use of good manufacturing processes.

Despite some severe limitations with traditional Chinese medicine herbal interventions used in clinical trials, a number of compounds have been reported to be efficacious for treatment of cardiovascular conditions ( Table 17-1 ), such as angina pectoris (danshen, compound salvia, suxiao jiuxin wan, tongxinluo) and hyperlipidemia (preparations of red yeast rice).

TABLE 17–1

Composition of Popular Traditional Chinese Medicines for Cardiovascular Indications

Common Name	Latin Name	Active Constituents	Uses	Purported Actions
Single-ingredient Preparations
Danshen	Salvia miltiorrhizae	Tanshinones, phenolic compounds	Angina pectoris	Coronary vasodilation
Red rice yeast	Monascus purpureus	Monocolin K	Lipid lowering	HMG-CoA reductase inhibitor
Compound-ingredient Preparations
Compound salvia preparations			Angina pectoris
Danshen	Salviae miltiorrhizae	Tanshinones, phenolic compounds		Coronary vasodilation
Sanqui	Panax notoginseng	Ginsenosides
Borneol	Cinnamomum camphora
Suxiao jiuxin wan			Angina pectoris
Radix chuanxiong	Ligusticum chuanxiong Hort			Coronary vasodilation
Borneol (synthetic formulation)	Borneolum syntheticum			Increase plasma levels of radix chuanxiong
Tongxinluo			Angina pectoris
Ren shen	Radix ginseng, 10%-20%	Ginsenosides		Increase cardiac contractility
Scorpion	Scorpio, 10%-20%			Decrease blood pressure
Leech	Hirudo, 20%-30%			Anticoagulant
Ground beetle	Eupolyphaga seu steleophage, 10%-20%			Increase cardiac output
Centipede	Scolopendra, 6%-15%			Increase cardiac contractility, decrease blood pressure
Cicada slough	Periostracum cicadae, 10%-20%			Decrease heart rate
Root of common peony	Radix paeoniae rubra, 5%-15%			Anticoagulant, coronary vasodilation
Borneol (synthetic formulation)	Borneolum syntheticum, 2%-10%			Analgesic and sedative

Modified from Wu T, Harrison RA, Chen X, et al: Tongxinluo (Tong xin luo or Tong-xin-luo) capsule for unstable angina pectoris. Cochrane Database Syst Rev (4):CD004474, 2006.

Danshen

According to traditional Chinese medicine, chronic stable angina belongs within the scope of pectoral pain and stuffiness (obstruction of Qi and blood in the chest). The traditional Chinese medicine herbal danshen, obtained from the dried root of Salvia miltiorrhiza , promotes blood circulation and relieves blood stasis. It is one of the most versatile traditional Chinese medicine herbals that has been used for hundreds of years in the treatment of numerous ailments. Much of the early research on the pharmacologic actions of danshen has been documented through intravenous use in animal models and human subjects. Because of its properties related to improving microcirculation, enhancing coronary vasodilation, and protecting against myocardial ischemia through its negative chronotropic effects as well as suppressing the formation of thromboxane and inhibiting platelet adhesion and aggregation, danshen is widely used either alone or in combination with other herbals.

Danshen has also been studied with respect to its actions on lipid lowering (inhibition of LDL oxidation) and hypertension (inhibition of angiotensin-converting enzyme). It is indicated for use for patients with coronary artery disease and other cardiovascular diseases in China and to a lesser extent in Japan, the United States, and other European countries. In China, danshen is used to treat angina pectoris, hyperlipidemia, and acute ischemic stroke.

The primary active ingredients containing tanshinones and phenolic compounds in danshen are found in dried root and rhizome preparations. Although danshen has no major side effects, it has the potential to interact with anticoagulants and antiplatelet drugs or supplements with those properties. Hence, it may increase the international normalized ratio (INR) and the risk of bleeding and should be avoided in patients taking warfarin. Danshen also may interfere with serum digoxin measurements. Side effects include pruritus, upset stomach, and reduced appetite.

Evidence to support use of danshen preparations is too weak for any judgment to be made about its effects. Collectively, evidence from randomized controlled trials is insufficient and of low quality. The first documented systematic review on the quality of randomized trials of danshen was recently published according to the CONSORT standards (Consolidated Standards for Reporting of Trials for Traditional Chinese Medicine), which used the Jadad quality scale, for studies published in China from 1998 to 2007. A total of 150 studies were identified, with only 6.7% of the randomized controlled trials being identified as high quality (Jadad score ≥4). The authors concluded that the overall quality of these trials has not improved over time, and the evidence base for danshen is still poorly developed. More evidence from high-quality trials is needed to support the clinical use of danshen preparations.

Recommendation

Evidence to support the use of danshen preparations is weak. Collectively, information from randomized controlled trials is insufficient and of low quality. Danshen has the potential to potentiate the effects of warfarin, and as such, it is prudent not to combine use of danshen with any anticoagulant or antiplatelet drugs.

Salvia

Compounded salvia has been promoted to improve blood circulation and is one of the alternative therapies widely used in China when long-acting nitrates are not an option. The primary herbal ingredients in this formulation include danshen (Salviae miltiorrhizae), sanqi (Panax notoginseng), and borneol (Cinnamomum camphora) . The principal active component in the compound is danshen (see Table 17-1 ). A recent meta-analysis supported by the Chinese Cochrane Center of 27 randomized trials (n = 3722) to evaluate the effectiveness of compounded salvia preparations (danshen pill) compared with isosorbide dinitrate concluded that the salvia preparations demonstrated a significant improvement in angina symptoms along with electrocardiographic improvements and few adverse events. The adverse event rate was significantly less than that of nitrates (2.4% versus 29.7%), leading to greater withdrawal of patients from the nitrate intervention compared with the salvia intervention group. However, there was significant heterogeneity in study endpoints, such as anginal symptoms and electrocardiographic changes. Methodologic improvements with more well defined outcomes are needed. A subsequent systematic review of 17 randomized controlled trials in patients with unstable angina noted significant improvement with compounded salvia in combination with standard therapy. Salvia preparations compared with standard therapy alone demonstrate greater improvement in electrocardiographic parameters and reduced anginal symptoms. Again, the methodologic quality of the studies was low, thus limiting the clinical application of this herbal preparation.

Recommendation

Compounded salvia may be a viable alternative to standard therapy for the control of anginal symptoms if other standard therapies fail. However, the data are not robust, and caution should be used in patients receiving warfarin or other anticoagulants.

Suxiao Jiuxin Wan

Another popular Chinese herbal that has been used for the treatment of angina pectoris is suxiao jiuxin wan. This preparation may cause remission of angina pectoris, improve anginal symptoms, and reduce the use of nitroglycerin. The ingredients in suxiao jiuxin wan include radix chuanxiong (Ligusticum chuanxiong) and borneol (Borneolum syntheticum) (see Table 17-1 ). A recent Cochrane Review identified 15 randomized controlled trials ranging from 4 weeks to 2 years in 1776 patients comparing the effects of suxiao jiuxin wan with nitroglycerin, danshen, and isosorbide dinitrate by evaluating electrocardiographic and angina endpoints. Unfortunately, the treatment regimen varied tremendously. In 10 studies, suxiao jiuxin wan provided better electrocardiographic results, better improvement in anginal symptoms, and less nitroglycerin use compared with patients randomized to nitroglycerin alone. Two studies reported electrocardiographic improvements with suxiao jiuxin wan compared with danshen. Clinical symptoms of angina were also improved with suxiao jiuxin wan. The one study that compared suxiao jiuxin wan with isosorbide dinitrate noted no improvement in the electrocardiographic or anginal symptoms. As noted before, studies tended to be of poor quality and lacked clinically relevant event outcomes that varied between trials. Headaches and bradycardia were reported in some studies, but none required medical management.

Recommendation

Suxiao jiuxin wan is not recommended for cardiovascular use until further well-controlled trials with clinically relevant endpoints can substantiate benefits and reduction of anginal symptoms comparable to that of current standard therapies.

Tongxinluo

A new drug studied clinically only since 1995 for its efficacy in reducing episodes of angina pectoris is tongxinluo. Studies have demonstrated that tongxinluo possesses pleiotropic effects that are cardioprotective, including the improvement of endothelial function, lipid lowering, antioxidation, vasodilation, antithrombosis, anti-inflammation, antiapoptosis, and enhancement of angiogenesis. These effects are similar to those of statin therapies.

In a study using a rabbit model of induced atherosclerosis, tongxinluo in a dose-dependent manner increased the thickness of fibrous caps and plaque contents of smooth muscle cells and collagen; reduced serum lipoprotein levels, inflammatory biomarkers, and mRNA expression of matrix metalloproteinases; and decreased the incidence of plaque rupture. Tongxinluo capsules contain both herbal and insect (scorpion, leech, and centipede) ingredients (see Table 17-1 ).

A systematic review performed by the Cochrane Collaboration identified 18 short-term studies (15 randomized) involving 1413 subjects that evaluated the benefit of tongxinluo with or without other treatments (danshen, isosorbide mononitrate, or low-molecular-weight heparin) in patients with unstable angina. The caliber of the studies was rated low, and thus no definitive conclusions were drawn about its efficacy with respect to myocardial infarction, angioplasty, or coronary artery bypass grafting. However, the authors noted some benefit in reduction of angina and electrocardiographic improvement. Although there were no recorded severe adverse events, slight gastrointestinal discomfort and ecchymoses were noted in a few cases. The safety of tongxinluo remains to be evaluated in appropriately designed trials. Additional efficacy studies are necessary for a thorough evaluation of this herbal preparation.

Recommendation

Data are preliminary and weak; the safety of tongxinluo remains to be determined. Use of this combination product is not recommended.

Red Yeast Rice

Perhaps the most well known traditional Chinese medicine herbal therapy in Western clinical practice is red yeast rice (Monascus purpureus), used to treat hypercholesterolemia. Single herbs touted for lipid lowering include tumeric (Curcuma longa) , hawthorn fruit (Crataegus monogyna), coptis or goldthread (Coptis deltoidea), soybean (Glycine max), five-leaf gynostemma (Gynostemma pentaphyllum), green tea (Camellia sinensis), Chinese rhubarb (Rheum palmatum), fleece flower tuber (Polygonum multiflorum), cassia seed (Cinnamomum aromaticum), and Panax ginseng (see Appendix). A number of compound recipes for lipid lowering have been used in recent years and have shown therapeutic effects by improving either clinical signs and symptoms or pathologic changes.

Red yeast rice is derived from a yeast that grows on rice. It has been an Asian food staple and traditional remedy for thousands of years. One of the active ingredients in the yeast, monacolin K or lovastatin, is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme in the pathway of cholesterol synthesis. The concentration of lovastatin varies in red rice yeast but averages nearly 0.4% by weight.

A meta-analysis of 93 randomized controlled trials (n = 9625) using three different commercial preparations of red yeast rice (cholestin, xuezhikang, and zhibituo) demonstrated a mean reduction in total cholesterol of 0.91 mmol/L, LDL-C of 0.73 mmol/L, and triglyceride of 0.41 mmol/L and a mean rise in HDL-C of 0.15 mmol/L compared with placebo. These levels are comparable to those achieved by many of the standard pharmacologic lipid-lowering agents, except for the most powerful statins.

Xuezhikang, a commercial red yeast rice product containing 0.8% lovastatin, or approximately equivalent to 10 mg of lovastatin, has shown impressive results in clinical studies. The China Coronary Secondary Prevention Study carried out in 65 hospitals in China randomized 4870 patients with a prior history of myocardial infarction to either xuezhikang 600 mg twice daily or placebo for a mean duration of 4.5 years. The primary endpoints of nonfatal myocardial infarction and fatal coronary events, cardiovascular mortality, and total mortality were significantly reduced in the treatment group. The need for coronary revascularization was similarly reduced. Total cholesterol was reduced by 13% and LDL-C by 20%, with a noted 4.2% rise in HDL-C. No treatment-related serious adverse events or deaths were reported during the study period.

It is possible that other monacolins or lovastatin hydroxyl acid, plant sterols, isoflavones, and isoflavone glycosides present in xuezhikang also could have cardioprotective effects in addition to that attributed to monacolin K. Reported side effects to red rice yeast are limited but include gastrointestinal upset, headaches, and dizziness. Similar cautions typical of HMG-CoA reductase inhibitors regarding potential side effects, including myopathy, hepatitis, and rhabdomyolysis, should be considered with red rice yeast products and will depend on the levels of monacolin K present. As different concentrations of monacolins exist in an array of red yeast rice products, clinicians should examine the specifications of individual products before prescribing. Purity of products also may be variable; some may possess a toxic byproduct of yeast fermentation called citrinin. Future use of xuezhikang as well as of other traditional Chinese recipes for lowering of cholesterol will depend on the separation, identification, characterization, and development of carefully formulated preparations. Additional well-controlled trials are needed before clinicians can use these products confidently. Although red yeast rice remains available in the United States, it is now fermented by a different process and the active ingredient has been removed, making its ability to lower cholesterol questionable.

Recommendation

Red yeast rice products lower cholesterol and may be recommended to patients who prefer alternative treatments or who cannot tolerate standard drug therapies. Choice of products should be carefully scrutinized, and standard laboratory monitoring as used for HMG-CoA reductase inhibitors should be employed.

Conclusion

Collectively, the data on the effectiveness of Chinese herbs in the treatment of angina pectoris is not compelling, except possibly for danshen, which must be used with care when it is combined with conventional medications. Herbs used to treat hyperlipidemia (red yeast rice) are supported by limited data for efficacy. Additional well-controlled clinical trials with standardized preparations in appropriately studied population groups are needed to further define the efficacy and safety of these products.

Ayurvedic Medicine

Ayurvedic medicine is one of the oldest systems of natural medicine (originating 4000 to 5000 years ago), older even than traditional Chinese medicine because Chinese and other medical systems originated from it. It originated in India, and the Sanskrit word ayurveda means knowledge or science of life. The principal concept in ayurveda is living in harmony with the universe (environment) across one’s life span. The original Vedic text, forming the foundation for this system, provides treatment of disease that includes diet, herbals, lifestyle, and disease prevention. Disease occurs when there is an imbalance between the body and the mind. Treatment, based on mind-body constitutions called doshas, uses dietary, lifestyle, and herbal prescriptions to evoke natural healing. There is a strong correspondence to traditional Chinese medicine and other integrative therapies like naturopathy. Heart disease, called hydroga, is related to several different causes, including, among others, emotional turmoil, dietary indiscretion, and sedentary lifestyle.

Ayurvedic therapies include yoga and transcendental meditation (a variant of yoga) in addition to dietary alterations and herbals. Yoga means “to join” and includes breath control, physical exercise, and meditation. A 3-month residential yoga program, which includes a vegetarian diet and regular yoga practice, can improve a number of cardiovascular risk factors, including blood pressure, weight (body mass index), and LDL-C. These responses are similar to those noted in small early studies of lifestyle modification that incorporated dietary modification, exercise, and stress management. Patients with angiographic coronary disease, not receiving lipid-lowering therapy, who practice yoga experience less angina and improved exercise capacity in association with atherosclerosis regression or reduced progression of disease. Small controlled and uncontrolled studies suggest that yoga reduces blood pressure in patients with hypertension. Regular yoga enhances mood and emotional well-being, indicating improved quality of life. Much of the yoga relaxation response is related to reduced neuroendocrine stress as measured by urinary catecholamines, dopamine, and aldosterone or by heart rate and skin conductance. The long-term cardiovascular influence of yoga has not been adequately studied.

Herbs in Ayurvedic Medicine

The medical system of Ayurveda is popular worldwide, not just in India. Recent analysis of the U.S. National Health Interview Survey 2007 Complementary and Alternative Medicine Supplement estimates that 214,000 adults used an Ayurvedic product in the past 12 months, a 28% increase from the 2002 survey on CAM use. Herbs, minerals, and metals are used in Ayurvedic herbal products. Ayurvedic medicines are divided into two major types: herbal only and rasa shastra. In the practice of rasa shastra, herbs are combined with metals, minerals, and gems and appear to have been used safely for centuries when they are properly prepared. A number of the more popular Westernized Ayurvedic preparations with randomized controlled trials have been evaluated for efficacy, quality, and product effectiveness. Among these preparations are garlic (Allium sativum) for hyperlipidemia and hypertension and guggul (Commiphora mukul) and arjuna (Terminalia arjuna) for hyperlipidemia.

Garlic (Allium sativum)

Garlic has long been touted as a natural product useful for modulation of immune system activity, treatment of hyperlipidemia and hypertension, and primary and secondary prevention of myocardial infarction. Allicin, the bioactive component responsible for the cardiovascular activity of garlic, is rapidly formed from the allyl sulfur compounds (such as alliin) in the garlic. Raw crushed garlic has the highest concentration of allicin. Multiple mechanisms of action have been proposed, including decreases in cholesterol and fatty acid synthesis and cholesterol absorption as well as potent antioxidant properties.

Epidemiologic studies have shown an inverse correlation between garlic consumption and a reduced risk of cardiovascular disease progression. Clinical studies of garlic’s efficacy in lipid lowering, however, have yielded mixed results, with significant design flaws compromising the trials of garlic’s effectiveness. Short-term studies have shown some benefit in lipid lowering, whereas long-term studies of 6 months or more fail to show sustained benefit when garlic is used as a single agent. A recent well-designed randomized controlled trial using highly characterized diet and supplement interventions comparing the effects of raw garlic, powdered garlic supplement, aged garlic supplement, and placebo in 192 moderately hypercholesterolemic adults demonstrated no significant difference in LDL-C between treatment groups. A systematic review of 21 garlic studies to evaluate the reporting quality, safety, and efficacy of randomized controlled trials for lipid lowering demonstrated that 53% of the garlic trials reported positive efficacy with a mean safety score of 63 of 100.

Studies of garlic’s effectiveness in hypertension also have suffered from poor methodology, and results have revealed small, mostly insignificant decreases in blood pressure. A meta-analysis published in 1994 reported promising results in subjects with mild hypertension but found insufficient evidence to recommend garlic for clinical therapy. A subsequent systematic review of 27 small, randomized controlled trials of at least 4 weeks’ duration comparing garlic with placebo, no garlic, or another active agent reported mixed effects of various garlic preparations on blood pressure. Two meta-analyses published in 2008 concluded that compared with placebo, garlic significantly lowered systolic blood pressure in hypertensive individuals but not in normotensive individuals. However, the sample sizes of these two meta-analyses of hypertensive patients were not large. Garlic preparations and doses of 600 to 900 mg/day, providing 3.6 to 5.4 mg of allicin, were common in both meta-analyses. The level of blood pressure lowering was comparable to reductions seen with some antihypertensive drugs, suggesting that garlic may be a nonpharmacologic alternative for individuals with borderline or mild hypertension. However, additional studies with adequate sample size and standardized garlic preparations are needed to confirm these findings. Evidence for supplementation with garlic for either primary or secondary prevention of heart disease is not sufficient for its use to be recommended for hypertension.

Garlic preparations have been used in clinical studies for up to 4 years without reports of toxicity. The concomitant use of garlic with herbs or drugs that have warfarin constituents or affect platelet aggregation could increase INR and risk of bleeding. Garlic combined with fish oils and eicosapentaenoic acid (EPA) may increase antithrombotic effects. As such, individuals taking warfarin should be monitored more closely if they are consuming garlic supplements. Additive effects on cholesterol lowering have been seen when garlic is taken with prescription drugs.

Recommendation

Garlic at best may offer modest cardiovascular risk reduction for lowering of blood pressure. It is not recommended for cholesterol lowering. Consumption of dietary sources of garlic is safe and can be incorporated into a heart-healthy dietary plan. Pharmacologic treatment guidelines should be followed for individuals identified with cardiovascular risk factors. Garlic as adjuvant therapy may be an option for some patients, although the American Heart Association notes that garlic has “no major role” in lipid lowering (total cholesterol and LDL-C).

Guggul (Commiphora mukul)

Guggul is the gummy resin derived from the bark of the mukul myrrh tree in India but can also be found in countries extending from northern Africa to central Asia. In fact, the mukul myrrh tree has been placed on the Red Data List for further evaluation as it is on the threatened list in two regions in India where it is found because of excessive harvesting. It has played a role in Ayurvedic medicine for several thousand years and, in addition to its cardiovascular role, is used in the treatment of arthritis and digestive, skin, and menstrual problems.

The cardiovascular therapeutic benefits for guggul appear to be due to its multiple pharmacologic activities, notably the hypolipidemic, antioxidant, and anti-inflammatory effects. Gugulipid is the ethyl acetate extract of the gum containing 4.09 Z – and E -guggulsterones per 100 g. The lipid-lowering effect of gugulipid and guggulsterone, the bioactive constituent of guggul, has been consistently demonstrated in a number of animal species.

Guggulsterone has been identified as an antagonist to the farnesoid X nuclear receptor (FXR), a key transcriptional regulator of cholesterol and bile acid homeostasis. More recently, guggulsterone has also been shown to be an antagonist at the mineralocorticoid, glucocorticoid, and androgen receptors and an agonist of the pregnane X receptor (PXR), progesterone, and estrogen receptors (ERα).

Clinical studies of guggul have demonstrated significant reductions in total cholesterol and LDL-C of 15% to 23% and triglyceride reduction of 20%, but results have been variable because populations under study have had different ethnic backgrounds, dietary habits, body weight, and severity of existing hyperlipidemia. The largest clinical study to date with 205 hypercholesterolemic or hypertriglyceridemic patients was conducted in 1989. After an 8-week diet and placebo lead-in, patients were randomized to gugulipid or placebo daily for 12 weeks. Total serum cholesterol was lowered by 24% and triglycerides were decreased by 23% in 70% to 80% of patients taking gugulipid. In a subsequent 12-week crossover study of 125 patients taking gugulipid compared with a comparable dose of clofibrate, gugulipid decreased serum cholesterol by 11% and triglycerides by 17% compared with clofibrate reductions of 10% and 22%, respectively. Unlike clofibrate, gugulipid increased HDL levels by 60%. A longer term study (24 weeks) administering 100 mg of gugulipid daily, as guggulsterone, in conjunction with dietary modification also has shown significant reductions in lipid levels in hypercholesterolemic patients but no improvement in HDL-C. In a randomized placebo-controlled trial of gugulipid in the United States, 103 healthy adults with hypercholesterolemia were given 1000 mg (low dose) or 2000 mg (high dose) gugulipid containing 2.5% guggulsterones for 8 weeks. Patients treated with gugulipid experienced no improvement in their lipid levels. In fact, their LDL levels increased by 4%, whereas patients who received placebo experienced a 5% decrease in LDL levels. The effects of gugulipids on HDL were mixed. Also noted was a median serum high-sensitivity C-reactive protein level that was decreased by 29% in the high-dose gugulipid group, whereas it increased by 25% in the placebo group, thus suggesting that gugulipid may also possess anti-inflammatory effects. A hypersensitivity rash was reported in a small number of subjects. A systematic review of seven guggul studies (133 subjects) to evaluate the reporting quality, safety, and efficacy of published randomized controlled trials for lipid lowering concluded that 86% of the guggul trials reported positive efficacy with a mean safety score of 71 of 100. It appears that individuals on a Western-style diet may achieve less of a lipid-lowering effect from gugulipid compared with those consuming a more traditional Indian diet.

Currently, no clinical studies have been conducted to evaluate the safety of long-term use of guggul or guggulsterone, but gugulipids have been shown to cause gastrointestinal upset, headache, mild nausea, belching, hiccups, and rash, depending on the dose and formulation (gugulipid versus crude guggul). Currently, 2.5% guggulsterone content is the minimum standard for quality gugulipid preparations. Concomitant oral administration can reduce propranolol and diltiazem bioavailability and hence may reduce the therapeutic effects of these drugs. Guggul also may have antiplatelet effects.

Recommendation

Data on the efficacy of guggul for treatment of cardiovascular risk factors are mixed and limited. At this time, guggul is not recommended as a substitute for standard pharmacologic therapies for lipid lowering.

Terminalia arjuna

This is a deciduous tree found throughout India. Its bark has been used in Ayurvedic medicine for more than three centuries, primarily as a cardiac tonic. Arjuna is purported to be useful in alleviating anginal pain, hypercholesterolemia, heart failure, and coronary artery disease. It has been shown in animal studies and clinical trials to have cardiotonic, antihypertensive, antihyperlipidemic, antioxidant, and anticoagulant properties.

Among the bioactive constituents in arjuna are tannins, triterpenoid saponins, flavonoids, gallic acid, ellagic acid, oligomeric proanthocyanidins, phytosterols, and several minerals (calcium, magnesium, zinc, and copper). The antioxidant cardioprotective effects are attributed to flavonoids and oligomeric proanthocyanidins; the positive inotropic effects may be caused by saponin glycosides.

A systematic review of six studies of Terminalia arjuna incorporating 390 patients to evaluate the reporting quality, safety, and efficacy of published randomized controlled trials for lipid lowering demonstrated that 100% of the trials reported benefit and had a mean safety score of 20 of 100. Terminalia arjuna has been shown to be efficacious in a small randomized clinical trial to evaluate the effectiveness of an extract in patients with stable angina compared with placebo and isosorbide mononitrate. The arjuna preparation used in these studies was a commercial herbal-mineral compound containing more than eight different herbs, making it uncertain whether the cardioprotective benefit was due solely to arjuna.

Recommendation

Data for Terminalia arjuna are limited to a single product formulation evaluated in a small number of subjects. Additional well-controlled comparative trials are needed, and safety profiles must be established before its use can be recommended.

Conclusion

Several studies have shown poor quality control of some Ayurvedic medications, particularly some rasa shastra Ayurvedic medicines containing high levels of lead, mercury, and arsenic. More than 80 cases of lead poisoning associated with Ayurvedic medicine use have been reported worldwide since 1978. A recent random sample of commercially prepared Ayurvedic medicines purchased from the Internet had high metal concentrations determined by x-ray fluorescence spectroscopy. One fifth of both the U.S.- and Indian-manufactured medicines contained detectable lead, mercury, or arsenic exceeding at least 1 regulatory standard for acceptable daily metal intake. The presence of metals in non– rasa shastra medicines is also of concern because 17% of these have been determined to have higher levels of metals, the consequence of environmental contamination of the herbs or incidental contamination during manufacturing. Rasa shastra experts claim that these medicines have been used for centuries and, if properly prepared and administered, are safe and therapeutic.

Collectively, the data on the effectiveness of Ayurvedic herbs in the treatment of hyperlipidemia or hypertension are not compelling. Additional well-controlled clinical trials with standardized preparations in appropriately studied population groups are needed to further define the efficacy and safety of these products.

Meditation and Stress Reduction

During meditation, there is concentration on a word or a phrase, called a mantra. Meditation reduces blood pressure, heart rate, oxygen consumption, and plasma cortisol as subjects relax. Likewise, meditation in elderly subjects with congestive heart failure is associated with reduced catecholamine production and improvement in the quality of life. Depression, which predisposes to poor outcome after myocardial infarction, due in part to low adherence to a low-fat diet, regular exercise, and stress management, can be reduced by mindfulness-based stress reduction. However, cognitive therapy for these patients may not improve survival after a myocardial infarction. Conversely, rehabilitation programs that include emotional support can reduce anxiety and improve mortality by up to 25%. One phase of deep relaxation that has been called the fourth state of consciousness, to distinguish it from waking, dreaming, and sleeping, is characterized by reduced plasma cortisol and lactate levels, decreased metabolism, reduced breathing, increased brain alpha wave activity, and increased cerebral blood flow. Many publications come from international journals or American CAM journals with relatively low impact factors because studies in this area are small, frequently inadequately controlled, and often not blinded.

Substantial research has examined the effects of lifestyle modification involving stress relaxation on blood pressure. These studies have used a number of different methods, such as autogenic training, cognitive and behavioral therapy, guided imagery, meditation, biofeedback, progressive muscle relaxation, and yoga. There is substantial overlap between the various techniques of relaxation. Autogenic training, for example, includes focusing on a physiologic sensation like the heartbeat and self-suggestion, which also can be used during meditation. Cognitive therapy involves control of irrational thought processes; behavioral reinforcement rewards certain behaviors that promote relaxation. Guided imagery focuses on calming images. A review of more than 25 randomized trials suggests that relaxation lowers systolic and diastolic blood pressure a small amount, ranging from 2 to 8 mm Hg. However, many trials have been poorly constructed, and the use of so many different techniques to lower stress makes comparison difficult. Furthermore, 15 of the trials that compared relaxation with sham demonstrated an insignificant decrease in blood pressure. More rigorous evaluation of this commonly included aspect of lifestyle modification is warranted.

Naturopathic Medicine

Naturopathic medicine is both a health system and a philosophy ( Box 17-4 ). It originated from a number of traditional medical systems from India (Ayurvedic), China (traditional Chinese medicine), Greece (Hippocratic), and Germany (homeopathy, hydrotherapy), among others. It is largely based on the belief that the body can heal itself and thus subscribes to the healing power of nature. The goal is to live as naturally as possible and to use healing practices that support normal physiologic function rather than drugs that would be considered an artificial enhancement. Naturopathic physicians believe that most (not all) disease is the result of violation of natural laws of living. Thus, healing results from a variety of practices that support normal function.

BOX 17-4

Healing Practices in Naturopathic Medicine

•

Consuming natural unrefined and organically grown foods
•

Sufficient exercise
•

Living a lifestyle that is in moderation
•

Thinking constructive thoughts and emotions
•

Avoiding environmental toxins
•

Maintaining proper elimination

Naturopathy consists of health maintenance, disease prevention, education, and self-responsibility. The practice of naturopathy relies on diagnosis and the use of natural therapies that evoke the body’s endogenous healing mechanisms. Naturopaths function as primary care physicians; because they realize that not all disease can be prevented or treated by the natural approach, practitioners will employ office surgery, prescription drugs, and referrals as appropriate. Clinical nutrition, botanical medicine, acupuncture, hydrotherapy, physical medicine, and counseling form the most compelling therapies. Homeopathy, although practiced by most naturopaths, has little documented value for cardiovascular disease.

Clinical nutrition uses the diet as therapy and in prevention of disease. It is the foundation of naturopathic practice. Botanicals, including herbals, can be used in place of some drugs, but they are more commonly used to support natural healing of the body. In fact, nutritional training in naturopathy generally is much greater than that received by allopathic students. Other chapters in this textbook provide information that would be recommended by naturopathic practitioners, including dietary fiber, omega fatty acids, walnuts and almonds to reduce LDL-C, soy-based foods, and the Mediterranean diet.

Chelation Therapy

Chelation therapy with disodium ethylenediaminetetraacetic acid (EDTA), which is used by some naturopathic practitioners, has clear clinical value in treating lead intoxication. It also has been used “off label” for more than 30 years to treat atherosclerosis. Chelation therapy with EDTA, supplemented with some vitamins, heparin, and magnesium, has been promoted by the American College for Advancement in Medicine. EDTA binds divalent and trivalent cations, including calcium. Proposed mechanisms of action, including lowering of calcium from plaques, inhibition of platelet aggregation, mobilization of parathyroid hormone to remove calcium, vascular antioxidant effects including chelation of iron, and transient lowering of cholesterol, are unproven. Because calcification of plaques tends to occur late in plaque development, mobilization of serum calcium is not likely to be effective in altering atherosclerotic progression.

EDTA infusion carries a risk of congestive heart failure because EDTA is administered in large volumes as the disodium salt. Renal toxicity, hypoglycemia, and hypocalcemia and tetany also can occur if the infusion rate is too rapid. There also is evidence that EDTA may be a pro-oxidant. Studies show that 100,000 to 800,000 individuals in the United States have received this therapy.

Clinical trials of chelation therapy are few, small in size, and poorly designed. The majority of the studies of coronary or peripheral arterial disease are case reports and case studies, most uncontrolled and retrospective. One large study and a smaller follow-up study of patients with peripheral vascular disease found no difference between control and treatment groups in symptomatic relief or in angiographic disease and transcutaneous oxygen tension. Three prospective randomized trials of chelation therapy have been published. A Danish trial of 153 patients in 1992 reported no long-term therapeutic effect at 3 or 6 months; a small trial of 32 patients from New Zealand showed some improvement in patients with peripheral vascular disease at 3 months. Both trials had significant methodologic deficiencies that preclude accurate conclusions. A final 6-month prospective study called the PATCH trial (Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health) of 39 patients with well-documented coronary disease observed no significant difference in clinical outcome or quality of life score. Unfortunately, this study was underpowered, and the placebo arm contained vitamin C, which may have provided an antioxidant effect. A larger randomized trial to assess chelation therapy (TACT) is ongoing. It is unclear why NCCAM funded this $30 million trial without definitive mechanistic evidence for the action of EDTA infusion or support from previous clinical trials.

Recommendation

Given the lack of firm evidence supporting a beneficial effect of chelation therapy and the potential for serious side effects, the American College of Cardiology and the American Heart Association have not endorsed its use in chronic stable angina.

Nutritional Supplements

It is estimated that 52% of adults participating in the 1999-2000 National Health and Nutrition Examination Survey (NHANES) had consumed some form of a dietary supplement within a month before participating in the survey; 35% took a multivitamin-multimineral supplement. Dietary supplement use in individuals with coronary artery disease or risk factors for coronary artery disease is common; 60% of adults with coronary artery disease, stroke, hypertension, or elevated cholesterol used at least one dietary supplement within the month preceding the survey. Individuals with a history of coronary artery disease or stroke commonly report the use of vitamin E, folic acid, and niacin; those with a history of hypertension or elevated cholesterol report higher use of herbals, commonly ginseng, as tabulated from the 1999-2002 NHANES data.

A number of popular dietary supplements with a significant evidence base lack public health recommendations for primary or secondary prevention of cardiovascular disease. These include B vitamins, the antioxidant vitamins C and E, vitamin D, and magnesium. On occasion, as appropriate, these supplements may be warranted for individual use.

Other nutrient supplements purported for cardiovascular disease or prevention that have been less well studied in clinical trials, or for which there is a lack of data from the United States, remain alternative therapies and should be integrated with great care. Supplements in this category include α-lipoic acid, l -arginine, l -carnitine, nonprescription niacin products, and selenium (see Appendix). Dietary supplements continue to be popular as documented by the spending of more than $23.7 billion by Americans on products in 2007. The most popular products for heart health are shown in Table 17-2 .

TABLE 17–2

Sales of Dietary Supplements for Heart Health

	Supplements	$ Million	% of Sales
1	Fish/animal oils	326	25
2	CoQ10	272	21
3	Multivitamins	225	17
4	Vitamin E	125	9
5	Plant oils	109	8
6	B vitamins	104	8
7	Potassium	58	4
8	Magnesium	41	3
9	Homeopathics	39	3
10	Vitamin A/beta carotene	31	2

Source: Nutrition Business Journal’s 2008 Business Report.

B Vitamins

Moderate elevations of plasma homocysteine levels have been associated with an enhanced risk for atherosclerotic disease. The metabolism of homocysteine requires several B vitamins as cofactors, specifically vitamin B ₆, vitamin B ₁₂, and folate. Homocysteine levels can be decreased by the administration of supplemental folate, with or without vitamin B ₆or B ₁₂. Although epidemiologic studies suggest potential cardiovascular benefit with B vitamin supplementation, most intervention trials (such as HOPE-2, VISP, and NORVIT) using combined B vitamin therapy of folic acid and vitamins B ₆and B ₁₂have shown no benefit.

More recently, results from the Women’s Antioxidant and Folic Acid Cardiovascular Study, a secondary prevention trial of 5442 women, revealed that combination B vitamin therapy, including 2.5 mg folic acid, 50 mg vitamin B ₆, and 1 mg vitamin B ₁₂, after 7 years of treatment and follow-up demonstrated no reduction in total cardiovascular events compared with placebo. A meta-analysis of four randomized, controlled trials of B vitamin therapy found no evidence that B vitamin supplements slowed the progression of atherosclerosis. However, it has been postulated that folic acid supplementation, through lowering of homocysteine levels, may positively influence vascular function in the early stages of cardiovascular disease by modulating endothelial dysfunction. A recent meta-analysis of 14 intervention trials in which high doses of folic acid were administered for 4 months or more and flow was measured demonstrated that folic acid improved flow-mediated dilation by only 1.08% compared with placebo.

A protocol for a collaborative meta-analysis of homocysteine-lowering trials for prevention of vascular disease has been proposed by the B-Vitamin Treatment Trialists’ Collaboration. By pooling of the data from 12 B vitamin supplementation trials for the prevention of coronary heart disease and stroke, it is hoped that more definitive recommendations on the use of folic acid and vitamin B ₁₂for prevention of cardiovascular disease will emerge. Presently, seven studies with 33,755 subjects are being monitored for major coronary events. Until such time, the American Heart Association notes that the available evidence is inadequate for the recommendation of folic acid and other B vitamin supplements as a means of primary or secondary prevention of cardiovascular disease.

Recommendation

Current evidence is inadequate for the recommendation of folic acid and other B vitamin supplements for primary or secondary prevention of cardiovascular disease. However, they can be used to lower plasma homocysteine levels in high-risk subjects.

Antioxidant Vitamins

Despite a large body of epidemiologic evidence suggesting a favorable association between a diet high in antioxidants and reduced risk of coronary heart disease, no clinical trial has confirmed such benefit. Higher overall intake of vitamin C was associated with lower rates of coronary disease in some cohort studies with information on supplemental vitamin C intake but not in others. Improved endothelial function has been observed with vitamin C supplementation in patients at risk for cardiovascular disease. An inverse relationship between vitamin E intake and the risk of coronary disease demonstrated that 30 IU/day of vitamin E potentially can lower coronary disease risk by 4%. Supplementation with vitamin E alone also has shown an inverse correlation with coronary heart disease.

Randomized trials have evaluated antioxidant supplements in varying doses for lowering of coronary heart disease risk. In the Heart Protection Study, 20,536 patients with coronary artery disease or diabetes were randomized to antioxidant vitamins (600 mg of vitamin E, 250 mg of vitamin C, and 20 mg of beta carotene) versus placebo. Although the vitamin regimen was found to be safe, there was no evidence for a therapeutic effect after 5 years of treatment. Similarly, the Physicians’ Health Study follow-up also found that neither vitamin C nor vitamin E reduced the incidence of major cardiovascular events, myocardial infarction, stroke, or cardiovascular mortality after 8 years of study. Furthermore, use of vitamin E was associated with an increased risk of hemorrhagic stroke.

In contrast, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study in hypercholesterolemic patients randomized to twice-daily supplements of 136 IU of vitamin E, 250 mg of slow-release vitamin C, both, or placebo demonstrated that only combined supplementation of vitamin E and vitamin C slowed the progression of common carotid intima-media thickness (25% decrease). However, in the Women’s Angiographic Vitamin and Estrogen study, postmenopausal women with some degree of coronary stenosis who took vitamin E and vitamin C twice a day or placebo for more than 4 years experienced no cardiovascular benefit, and in fact, all-cause mortality was significantly higher in women taking the supplements. Whereas this latter observation may have been a chance finding, it follows a trend toward an increase in mortality that was observed in the Heart Protection Study.

Randomized clinical trials also have cast doubt on the efficacy of vitamin E as monotherapy to prevent coronary disease. Although the Cambridge Heart Antioxidant Study (CHAOS) demonstrated a reduction in events of the combined endpoint of death or nonfatal myocardial infarction by 47%, HOPE and HOPE-2 provide strong evidence that moderately high doses of vitamin E supplements do not reduce the risk of serious cardiovascular events among men and women with established heart disease or diabetes. In fact, participants taking vitamin E in the HOPE-2 trial were 13% more likely to experience and 21% more likely to be hospitalized for heart failure, an unexpected and statistically significant finding. Possible explanations for this harmful effect of vitamin E could relate to the potential for α-tocopherol to become a pro-oxidant in an oxidative environment, thereby depressing myocardial function, or to the higher doses than those normally consumed in the diet employed in the study.

Data from randomized controlled trials in women have provided much needed information for clinicians to make appropriate therapeutic choices in the management of cardiovascular risk in women. The Women’s Heath Study of 39,876 apparently healthy women aged 45 years and older found that vitamin E (600 IU on alternate days) reduced cardiovascular death, a secondary endpoint, by 24% but had no effect on total cardiovascular events, myocardial infarction, or stroke. In further analysis of the same data, women randomized to vitamin E demonstrated an overall 21% reduced risk of venous thromboembolism. The observed risk reduction was 44% among those with prothrombotic mutations or a personal history of venous thromboembolism. Overall, vitamin E was associated with lower risk of bleeding than that observed for low-dose aspirin.

The American Heart Association concluded in their 2007 update of the women’s prevention guidelines that antioxidant vitamin supplements should not be used for the primary or secondary prevention of cardiovascular disease. However, as observed in the Women’s Heath Study, there may be certain populations, such as the elderly (>65 years) or those with a history of venous embolism, that could benefit from targeted therapy.

A number of meta-analyses have evaluated a range of cardiovascular disease outcomes for varying forms and doses of vitamin E in a number of populations of patients. Most analyses concluded that vitamin E provided no benefit and no increased risk. Lacking from most antioxidant intervention trials are plasma measures of vitamins or determination of a subject’s baseline oxidative stress status. Future studies should determine whether those with marginal vitamin status based on measurements will benefit from supplementation.

Recommendation

The American Heart Association does not recommend the use of antioxidant vitamin supplements for the primary or secondary prevention of cardiovascular disease. Patients should be encouraged to supplement their diet with foods rich in antioxidants and to consume a multivitamin-mineral supplement if they are concerned that their diets are inadequate.

Vitamin D

Recent literature suggests that vitamin D inadequacy is pandemic, and a growing body of evidence is emerging to show that low levels of vitamin D may adversely affect the cardiovascular system. In this regard, data are accumulating in populations with elevated cardiovascular disease risk factors, such as hypertension and metabolic syndrome, as well as in subjects with established disease, such as diabetes, coronary heart disease, peripheral arterial disease, stroke, congestive heart failure, and cardiovascular mortality associated with low vitamin D. In 1739 participants in the Framingham Offspring Heart Study, researchers found that those with vitamin D blood levels <15 ng/mL had twice the risk of a cardiovascular event in the next 5 years compared with those with higher levels of vitamin D. Interestingly, the risk remained significant after adjustment for traditional cardiovascular disease risk factors. Calcium and vitamin D supplementation was found neither to increase nor to decrease coronary or cerebrovascular risk in generally healthy postmenopausal women participating in the Women’s Health Initiative.

Low circulating levels of 25-hydroxyvitamin D also are associated with increased evidence of inflammation, oxidative burden, and cell adhesion, suggesting that vitamin D plays a role in processes that contribute to cardiovascular risk and mortality. Unfortunately, no dose-response studies with supplemental vitamin D are available yet to test the association of vitamin D with cardiovascular disease. Unlike the data and association of vitamin D with osteoporosis, the cardiovascular data are mixed and less robust and thus lack the evidence base to suggest causation. It is premature to recommend screening for at-risk individuals and supplementation with vitamin D above the recommended levels.

There is considerable discussion of the appropriate serum concentrations of 25-hydroxyvitamin D associated with deficiency versus optimal overall health ( Table 17-3 ). The current level of variability in 25-hydroxyvitamin D measurements calls into question the stability of 25-hydroxyvitamin D assays and their ability to reflect accurately the vitamin D status in individuals.

TABLE 17–3

Serum 25-Hydroxyvitamin D Concentrations and Health

ng/mL *	nmol/L *	Health Status
<11	<27.5	Associated with vitamin D deficiency and rickets in infants and young children
<10-15	<25-37.5	Generally considered inadequate for bone and overall health in healthy individuals
≥30	≥75	Proposed by some as desirable for overall health and disease prevention, although a recent government-sponsored expert panel concluded that insufficient data are available to support these higher levels.
Consistently >200	Consistently >500	Considered potentially toxic, leading to hypercalcemia and hyperphosphatemia, although human data are limited. In an animal model, concentrations ≤400 ng/mL (≤1000 nmol/L) demonstrated no toxicity.

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Tags: Preventive Cardiology: Companion to Braunwald's Heart Disease

Jul 10, 2019 | Posted by drzezo in CARDIOLOGY | Comments Off

Thoracic Key

Fastest Thoracic Insight Engine

Integrative Medicine in the Prevention of Cardiovascular Disease

Key Points

Use of Integrative Medicine in the United States

Role of Placebo in Complementary and Alternative Medicine

Traditional Chinese Medicine

Acupuncture, Acupressure, and Moxibustion

Mechanism of Action

Acupuncture’s Action on Cardiovascular Risk Factors

Cardiovascular Responses to Transcutaneous Electrical Stimulation and Acupuncture

Tai Chi and Qigong

Chinese Herbs

Danshen

Recommendation

Salvia

Recommendation

Suxiao Jiuxin Wan

Recommendation

Tongxinluo

Recommendation

Red Yeast Rice

Recommendation

Conclusion

Ayurvedic Medicine

Herbs in Ayurvedic Medicine

Garlic (Allium sativum)

Recommendation

Guggul (Commiphora mukul)

Recommendation

Terminalia arjuna

Recommendation

Conclusion

Meditation and Stress Reduction

Naturopathic Medicine

Chelation Therapy

Recommendation

Nutritional Supplements

B Vitamins

Recommendation

Antioxidant Vitamins

Recommendation

Vitamin D

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