Cardiovascular Disease
16.1. INTRODUCTION
The cardiovascular diseases (CVDs) considered in this chapter have been the major cause of morbidity and mortality in developed countries over the last several decades, and developing countries are rapidly catching up with this epidemic. The underlying pathology is atheromatous vascular disease, resulting in coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease, and the subsequent development of heart failure and cardiac arrhythmias. The major risk factors for these disorders were recognized over many years, and they include high levels of low-density lipoprotein (LDL) cholesterol, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, insufficient consumption of fruits and vegetables, excess consumption of alcohol, and lack of regular physical activity. There has been continued research to help define more precisely the cardiovascular risk of an individual with respect to genetic factors, more complex lipid traits, and inflammatory markers, but it was reconfirmed in the INTERHEART study that the conventional risk factors accounted for over 90% of the population attributable risk for myocardial infarction (MI; Yusuf et al. 2004). There is extensive evidence to show that drug treatment of conventional risk factors is effective in reducing cardiovascular events. Many large clinical trials with the HMG CoA reductase inhibitors (statins) have showed that lowering of LDL cholesterol with these agents decreases coronary and cerebrovascular events (Baigent et al. 2005), and that the target for LDL cholesterol becomes lower with each new set of guidelines and the availability of more potent drugs (Anderson et al. 2007). Likewise, more effective treatment of hypertension with various classes of antihypertensive drugs has been associated with greater benefits (Turnbull et al. 2008), but some recent studies suggest we may be reaching the optimal level of treated blood pressure in some patient groups (ACCORD Study Group 2010). Apart from the treatment of cardiovascular risk factors with pharmacological agents and the use of antithrombotic drugs, there is growing awareness of the role of dietary factors and herbal medicines in the prevention of CVD and the possibility of their use in treatment. Much of this interest centers on the use of antioxidant vitamins and the antioxidant properties of herbal materials, although some herbal materials may also improve conventional cardiovascular risk factors or have antithrombotic effects. In this chapter, we focus mainly on the results from large clinical trials and meta-analyses rather than from mechanistic studies, and we start by considering the use of antioxidant vitamins and other essential micronutrients in Section 16.2 before moving to a discussion of individual herbs in Section 16.3.
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16.2. ESSENTIAL MICRONUTRIENTS AND CARDIOVASCULAR DISEASE
The use of supplements of essential micronutrients (EMNs) in orthodox medical practice remains controversial, although adequate amounts of these substances are known to be necessary for the maintenance of health. Although it has long been proved that vitamin D, ascorbic acid, and vitamin B12 are the key to treating rickets, scurvy, and pernicious anemia, respectively, it is less accepted that subclinical deficiency states exist for these and other essential substances that may escape recognition in chronic illness, including CVDs. The estimated average requirement (EAR) to prevent deficiency states for common EMNs have been formulated and modified over the years. Recommendations from the United Kingdom Department of Health guidelines according to age and sex are given in Table 16.1. However, the use of “supraphysiological” or pharmacological doses of these or other EMNs in CVD remains a controversial issue and has the potential to be harmful.
TABLE 16.1
Vitamin and Nutraceutical Supplements That Have Been Used for Prevention or treatment of CVD.
The value of pharmacological doses is questionable for most EMNs, with the possible exceptions of folic acid, niacin, and magnesium, although caution must be taken with their use. Only when a deficiency state exists does the administration of the appropriate supplement achieve the therapeutically desired result for the treatment or prevention of the disease in question. Supplements taken in deficiency states should not generally be taken indefinitely, unless the problem is related to some nonmodifiable underlying disease or environmental factor. Furthermore, some patient groups may have special needs for EMNs. For instance, smokers may require above-average intakes of vitamin C, as do diabetics and older persons. Moreover, even if the diet contains the theoretical EMN, the needs of an individual may not be met due to poor absorption, altered metabolism, or associated deficiencies and disease states. In most cases, supplementation should be given only until body stores are replenished, but sometimes, there may be a need to continue the dosage. Restoration of one EMN may result in improved absorption of another or, in some cases, may unmask a partial deficiency. When evaluating an EMN in clinical trials, the substance under study is often given alone for reasons of scientific purity; but deficiency of one EMN is frequently accompanied by others and, thus, an unnatural, even hazardous, situation (sometimes unrecognized) can result if a high dose of a single EMN is given. A classic example is the risk of adverse effects when folic acid is given alone. A minority of patients having cyancobalamin deficiency are put at risk of subacute combined degeneration of the spinal cord. It is safer to give folic acid and cyancobalamin together unless the B12 status is known to be normal.
16.2.1. Vitamin A
Included under this heading are several related fat-soluble compounds derived from animal tissue, including retinal and retinoic acid, and a water-soluble vitamin A-related compound β-carotene, which is found in vegetables. These substances have antioxidant activity as quenchers of reactive oxygen species, with the potential to protect against inflammatory disease and atherosclerosis. However, clinical studies with β-carotene failed to show significant efficacy in the prevention of CVD.
16.2.2. Carotenoids
Numerous natural carotenoids are present in fresh fruits and vegetables, and some have been studied extensively in the prevention of coronary heart disease (CHD). Carrots are a primary source of β-carotene. Elevated levels of serum β-carotene were associated with a lower risk of cancer and were found to reduce overall mortality rates (Greenberg et al. 1996); early observational studies reported an association between a high dietary intake of β-carotene and a lowered incidence of CVD (Gey and Puska 1989; Kardinaal et al. 1993). However, the Medical Research Council/British Heart Foundation (MRC/BHF) Heart Protection Study showed no benefit from β-carotene taken 20 mg daily (in combination with 600 mg of vitamin E and 250 mg of vitamin C) on morbidity or mortality in high-risk individuals (Heart Protection Study Collaborative Group 2002). Likewise, the Women’s Antioxidant Cardiovascular Study (WACS) found no CVD risk reduction with β-carotene at 50 mg taken every other day, with ascorbic acid at 500 mg taken daily, or vitamin E at 600 IU taken every other day in women at high risk (Cook et al. 2007). The evaluation of the relation between vegetable intake and CHD risk in the Physicians’ Health Study concluded that the consumption of vegetables rich in carotenoids was associated with a reduced risk of CHD (Liu et al. 2001), but after 12 years’ follow-up there was no impact of supplementation of β-carotene 50 mg alternate days on CVD, cancer, or overall mortality among primarily nonsmokers (Hennekens et al. 1996).
16.2.3. Lycopene
Lycopene is an oxygenated carotenoid with twice the antioxidant activity of β-carotene. Tomatoes are the best source of lycopene, which is the focus of research as a precursor to vitamin A. Epidemiological studies and supplementation clinical trials suggest a decrease in CVD risk, but not all studies confirm this (Sesso et al. 2005), and controlled clinical studies conducted recently with lycopene and well-defined subject populations could find no definite evidence for CVD prevention (Riccioni et al. 2008). Current research is focusing more on the role of lycopene for prevention and treatment of prostate cancer.
16.2.4. B Vitamins
These EMNs are water soluble and consequently readily excreted. Depletion can occur as a result of the use of high-dose diuretics in the treatment of congestive heart failure (CHF). Thiamine supplementation is recommended for patients with refractory CHF who are unresponsive to diuretics, although its role in heart failure not related to proven thiamine deficiency remains controversial (Sica 2007). There may be a role for thiamine supplementation in preventing the cardiomyopathy sometimes seen with diabetes. A study conducted in the streptozotocin-induced diabetic rat model showed diabetic cardiomyopathy could be prevented by high-dose thiamine (Kohda et al. 2008). Nocturnal cramps and other involuntary leg muscle contractions in patients taking diuretics may be related to B vitamin depletion or magnesium deficiency. A small study conducted on 28 elderly patients showed considerable improvement in nocturnal leg cramps when they were treated with vitamin B complex (Chan et al. 1998).
16.2.5. Homocysteine and B Vitamins
A lot of research interest on homocysteine has been aroused since McCully hypothesized that homocysteine could accelerate vascular disease in homocysteinuria, a rare autosomal-recessive deficiency of cystathione β-synthetase (McCully 1969). A connection between high plasma homocysteine levels and occlusive vascular disease, CHD, and CHF has since been confirmed (Selhub et al. 1995). Women may be especially vulnerable to this condition. Homocysteine levels have been found to be higher in CVD patients compared to controls, although the effects were attenuated after adjusting for other risk factors and not all studies have found an association (Ridker et al. 1999; Zee et al. 2007; Pradhan et al. 2008). High homocysteine levels were reported in association with hypertension, resulting in a 25 times higher incidence of stroke in a study of postmenopausal women (Ridker et al. 1999). Supplements of B vitamins decreased homocysteine plasma levels significantly, and this decrease was dose dependent. Doses greater than the EAR doses have been given to patients with hyperhomocysteinemia and documented CHD (Hankey and Eikelboom 1999).
Plasma homocysteine levels are partly genetically determined by a common polymorphism in the enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR), which is involved in the metabolism of folate. About 10% of people are homozygous for a C677T polymorphism in the MTHFR gene that increases homocysteine levels by about 20%. A large meta-analysis found the odds ratio for stroke to be 1.26 (95%; confidence intervals [CI]: 1.14-1.40) for TT versus CC homozygotes, which is in proportion to the difference in homocysteine that can be attributed to the polymorphism (Casas et al. 2005). A study in healthy Japanese men reported that subjects with the TT genotype MTHFR C677T showed the greatest decrease in plasma homocysteine levels with folic acid supplementation, suggesting that a pharmacogenetic preventative approach for atherosclerosis is possible (Miyaki et al. 2005).
High-dose supplementation with a combination of folic acid, vitamin B12, and vitamin B6 slowed the progression of early-stage subclinical atherosclerosis measured by carotid artery intima media thickness (CIMT) compared with placebo (p = .02) in well-nourished, healthy, B vitamin-“replete” individuals at low risk for CVD and with a fasting plasma homocysteine ≥ 9.1 μmol/L, but there was no significant treatment effect in subjects with baseline fasting plasma homocysteine < 9.1 μmol/L (Hackam, Peterson, and Spence 2000; Hodis et al. 2009). Similar findings have been reported from other studies. Concomitant treatment with antioxidant vitamins did not improve the response to folic acid in some studies (Title et al. 2000). Folic acid and cyancobalamin together were more efficacious than vitamin B6 in lowering plasma homocysteine (Lee et al. 2004). A decreased rate compared with placebo of exercise electrocardiogram (ECG) tests showing myocardial ischemia (odds ratio: 0.40 [0.17-0.93]; p = .035) was found with folic acid and vitamin B6 supplementation for 2 years in high-risk subjects (Vermeulen et al. 2000). The effect of folic acid in improving endothelial function in CHD patients may be independent of decreases in plasma homocysteine (Doshi et al. 2002) and was suggested to be dose dependant (Moat et al. 2006). However, formal clinical trials have not confirmed encouraging early results in the prevention of CVD. There is so far no clear evidence of benefit from B vitamin supplementation on CVD risk reduction (Lonn 2008), including the Vitamins Intervention for Stroke Prevention trial, Heart Outcomes Prevention Evaluation (HOPE) trial, the Cambridge Heart Antioxidant study, the Norwegian Vitamin trial, and the more recent Western Norway B Vitamin Intervention Trial (Toole et al. 2004; Bonaa et al. 2006; Lonn et al. 2006; Ebbing et al. 2008). In HOPE 2, lowering of homocysteine with folic acid and vitamins B6 and B12 did decrease the overall risk for stroke, but not stroke severity or disability (Saposnik et al. 2009). There are a number of trials that are still in progress; until positive results become available, B vitamin supplements at the EAR for adults (folic acid: 400 μg; B6: 2 mg; B12: 6 μg) are considered safe in CVD prevention but not routinely recommended (Lonn 2008).
16.2.6. Niacin
High-dose niacin (nicotinic acid, vitamin B3) is used in the treatment of hyperlipidemia and hypercholesterolemia to improve the plasma lipid profile and prevent atherosclerosis. Recent studies suggest that niacin additionally improves the vascular endothelial cell redox state, by inhibiting vascular inflammatory genes, oxidative stress, and key cytokines that are involved in atherosclerosis (Ganji et al. 2009). Other studies suggest that high-density lipoprotein (HDL)-cholesterol directly improves endothelial function. Nicotinic acid dose-dependently raises serum HDL cholesterol, lowers triglycerides, and, with higher doses, lowers LDL cholesterol, resulting in a decreased cardiovascular risk score (Poldermans et al. 2008). Extended-release (ER) niacin improved endothelial function in patients with CHD who had low baseline HDL cholesterol but not those with normal HDL cholesterol (Warnholtz et al. 2009). In addition to improving serum lipid concentrations and lipid particle characteristics, treatment with niacin has also been found to improve inflammatory markers in some studies (Kuvin et al. 2006).
Although niacin may increase insulin resistance and blood glucose levels, its beneficial effects on plasma lipids, lipoproteins, and other factors appear to outweigh these potential disadvantages. In a subgroup analysis from the HDL-Atherosclerosis Treatment Study (HATS), similar decreases in the rate of progression of coronary stenosis and in primary clinical events were seen in patients with metabolic syndrome and insulin resistance compared to the overall patient group. In another study, patients with dysglycemia showed less benefit than those with normal glucose levels from treatment with a combination of niacin and a statin for 3 years compared to placebo (Vittone et al. 2007). It is therefore important to monitor glucose levels in patients with diabetes or the metabolic syndrome treated with high doses of niacin. In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6-HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study, patients with CHD or a CHD risk equivalent on long-term statin therapy were randomized to additional treatment with ER niacin (target dose: 2000 mg/day) or ezetimibe (10 mg/day). The primary end point was the change from baseline in CIMT. The change in CIMT was significantly decreased with niacin but not with ezetimibe (Taylor et al. 2009). The incidence of major cardiovascular events was also lower in the niacin group than in the ezetimibe group (1% vs. 5%; p = .04), suggesting niacin may be useful in addition to statins in some patient groups.
16.2.7. Vitamin C
The role of vitamin C supplementation in CVD remains unproved. The antioxidant properties of vitamin C are thought to act synergistically with those of vitamin E, decreasing the formation of peroxyl radicals and blocking lipid peroxidation. Vitamin C also has an action on endothelial vasodilator function in heart failure by increasing available nitric oxide (NO; Frishman 1999), but high doses of vitamin C have also been associated with decreased levels of NO production by endothelial cells (Mikirova, Ichim, and Riordan 2008). One clinical trial reported that vitamin C slowed progression of atherosclerosis in men and women over 55 years of age (Kritchevsky et al. 1995). The elderly and other groups in the population, including males, smokers, diabetics and hypertensives, who are at increased risk of CHD, have been found to have lower-than-average vitamin C blood levels. Women taking oral estrogen contraceptives may also have below-average vitamin C levels. In the Nurse’s Health Study, vitamin C supplements were associated with a lower risk of CHD in women (Osganian et al. 2003), and a British study found vitamin C blood levels at entry to be inversely related to death during extended follow-up from all causes, including ischemic heart disease in both sexes (Khaw et al. 2001). The authors concluded that the equivalent of one extra portion of vitamin C-rich food per day as fruit and vegetables could lower the risk of death by 20%. However, in that study, intake of other essential nutrients may have influenced the results. Furthermore, the MRC/BHF Heart Protection Study showed no benefit from vitamin C supplementation (250 mg daily) on morbidity and mortality in high-risk patients with CVD (Heart Protection Study Collaborative Group 2002). The WACS also showed no overall effect of ascorbic acid on cardiovascular events among women considered at high risk for CVD (Cook et al. 2007). A similar conclusion came from the Physicians’ Health Study II, which showed no benefit from taking 500 mg of vitamin C daily to prevent CVD events (Sesso et al. 2008). The value of vitamin C in established CVD remains unknown.
16.2.8. Vitamin D
Vitamin D receptors are found in vascular smooth muscle (Somjen et al. 2005), the endothelium (Merke et al. 1989), and cardiomyocytes (Holick 2006). There is evidence to suggest an association between low levels of 25-hydoxyvitamin-D and the accelerated development of CVD (Moats and Rimm 2007; Dobnig et al. 2008; Giovannucci et al. 2008; Wallis, Penckofer, and Sizemore 2008). Studies show an inverse relationship between vitamin D levels and plasma renin activity, hypertension, and coronary artery calcification (Resnick, Muller, and Laragh 1986; Zittermann, Schleithoff, and Koerfer 2007). Recent results from the Framingham offspring study suggest a direct association between vitamin D deficiency and the subsequent incidence of CVD (Wang et al. 2008). Low levels of vitamin D have also been linked with the occurrence of fatal strokes (Pilz, Dobnig et al. 2008), heart failure (Moats and Rimm 2007), sudden cardiac death (Pilz, Marz et al. 2008), and calcific aortic stenosis.
The prevalence of CHD was noted to increase with increasing distance from the equator, suggesting that a deficiency of sunlight, and therefore vitamin D, could cause CHD (Fleck 1989). Recent studies also suggest that disproportionately low vitamin D levels may largely explain the higher cardiovascular death rates among black Americans (Fiscella and Franks 2010). Despite these findings, it is not clear what dosage of vitamin D is necessary for the prevention of CVD (Zittermann and Koerfer 2008). Prospective studies need to be performed to test whether vitamin D supplementation can actually prevent CVD.
16.2.9. Vitamin E
A great deal of work has been done in studying tocopherols, the principal lipid-soluble antioxidants found in tissue and plasma. Oxidation of unsaturated fatty acids in LDL particles is widely recognized as a key factor in atherogenesis. Vitamin E blocks the lipid peroxidation chain reaction in the LDL particle (Pryor 2000). Supplements can decrease lipid peroxidation by as much as 40%. Stabilizing plaque, reducing inflammation, platelet aggregation, expression of adhesion molecules on the arterial wall, and enhancing vasodilation are the potential mechanisms of cardioprotection with vitamin E (Pryor 2000). The antioxidant and anticoagulant properties of vitamin E are believed to protect against MI and thrombotic stroke. The value of vitamin E in the prevention of atherosclerosis is the subject of an extensive review article (Pryor 2000).
Prospective controlled clinical trials give a confusing picture. Statistical reanalysis of all data from previous major clinical trials of supplementation suggests that treating patients with preexisting CVD with vitamin E is ineffective (Stephens et al. 1996; Rapola et al. 1997; GISSI-Prevenzione Investigators 1999; Yusuf et al. 2000; Jialal, Traber, and Devaraj 2001; Vivekananthan et al. 2003). The results of the MRC/BHF Heart Protection Study (Heart Protection Study Collaborative Group 2002) on 20,536 high-risk individuals showed no benefit from vitamin E supplementation (600 mg daily) on morbidity and mortality. However, 100 and 200 mg of vitamin E caused a marked improvement in arterial compliance (Rasool et al. 2008), and a recent report from the Women’s Health Study showed that women receiving supplements of vitamin E had a lower risk of venous thromboembolic disease (Glynn et al. 2007). The WACS tested the effects of ascorbic acid (500 mg/day), vitamin E (600 IU every other day), and β-carotene (50 mg every other day) on the combined outcome of MI, stroke, coronary revascularization, and CVD death among 8171 female health professionals and found no significant overall benefits (Cook et al. 2007). In addition, the Physicians’ Health Study II revealed no cardiovascular benefits from supplements of vitamin E at doses of 400 IU on alternative days when administered to 14,641 male physicians over 50 years of age (Sesso et al. 2008). The National Centre for Complementary and Alternative Medicine (NCCAM) is currently studying the effect of α-tocopherol supplements (1200 IU/day) on the progression of carotid atherosclerosis in patients with CHD (stable angina pectoris or previous MI) in a placebo-controlled, randomized, double-blind trial over 2 years. Despite the large number of studies conducted with vitamin E, proof of its value in healthy individuals and in those with CVD has not been obtained as yet.
An explanation for the disappointing clinical results with vitamin E may come from a recent study showing that the α isomer (found in supplements) suppresses the gamma isomer (found in dietary foods). A standardized preparation of the gamma isomer, when and if available, merits clinical study (Gutierrez et al. 2009).
16.2.10. Flavonoids
The traditional French diet is high in saturated fats, but residents of France have a lower incidence of CAD than Americans. This is the so-called French paradox. The typical French diet includes regular intake of fresh fruit and vegetables. These contain phytonutrients that may lower peroxidative tendencies and retard atherogenesis and thrombosis. Consumption of red wine could be another factor. Ethyl alcohol in small quantities may help to prevent cardiovascular or cerebrovascular disease (Frishman et al. 2003). In healthy men, both cava (sparkling wine) and gin, although to a lesser extent, have been shown to decrease inflammatory markers of atherosclerosis (Vazquez-Agell et al. 2007). However, the rich polyphenolic content of red wine (and green tea) has made both of them popular choices for possible cancer and CVD prevention (Ullah and Khan 2008). A study of the antioxidant activity of red wine in volunteers showed that two glasses of red wine taken before food increase serum antioxidant activity for at least 4 hours (Maxwell, Cruickshank, and Thorpe 1994). Red wine increases antioxidant activity through a flavonoid-polyphenol effect. A small study performed in the Netherlands (Hertog et al. 1993) studied the use of the dietary bioflavonoids, phenolic acids, and quercetin. There was a decrease in the incidence of heart attack and sudden death over 5 years in relation to increasing tertiles of flavonoid (quercetin, kaempferol, myricetin, apigenin, and luteolin) intake assessed by dietary history. Quercetin-rich black tea and apples and onions were considered the most suitable foods studied, since they contain polyphenols in amounts similar to those found in red grapes. Short- and long-term consumption of black tea was found to reverse endothelial vasomotor dysfunction but not to decrease ex vivo platelet aggregation in patients with CHD (Duffy, Keaney et al. 2001; Duffy Vita et al. 2001).
Resveratrol, which is found in grape skin and seeds, activates platelet NO synthase and inhibits production of reactive oxygen species and platelet activation. This may explain the beneficial effects of moderate wine intake on ischemic CVD (Gresele et al. 2008). The potential beneficial effects of resveratrol were reviewed recently (Bertelli and Das 2009). It has been suggested that resveratrol acts as an antiaging compound, induces the expression of several longevity genes, and prevents aging-related decline in cardiovascular function (Das, Mukherjee, and Ray 2010), but this has not been confirmed by intervention trials.
Oligomeric proanthocyanidins are free-radical scavengers that inhibit lipid peroxidation and have anti-inflammatory and antiallergenic properties. Like carotenoids, they are found predominantly in brightly colored fruits and vegetables. These foods represent a safe source of polyphenols and quercetin, which is believed to be particularly active in preventing LDL oxidation. In a placebo-controlled crossover study of supplementation with quercetin at 150 mg daily for 6 weeks in overweight or obese subjects with metabolic syndrome traits, there was a decrease in systolic blood pressure by 2.6 mmHg (p < .01) and a decrease in plasma concentrations of atherogenic oxidized LDL; there was also a small but significant decrease in serum HDL cholesterol concentrations (p < .001), although the ratio LDL:HDL cholesterol was unchanged (Egert et al. 2009).
The optimal amount and form of flavonoids in the diet is not known, and some of these flavonoids have rather low bioavailability. Despite the uncertainties, many individual flavonoids are available as food supplements in doses as high as 500 and 1000 mg, and amount to 10-20 times the daily intake of a typical vegetarian diet. The Physician’s Health Study did not show any association between intake of flavonoids and all CAD events (Rimm et al. 1996). The Kuopio Ischemic Heart Disease Risk Factor Study concluded that a high intake of flavonols and the mean CIMT were negatively associated (Mursu et al. 2007). Other studies are in progress (Frishman, Beravol, and Carosella 2009). Until the results of prospective controlled studies are available, patients and those at risk of CVD may be encouraged to include tea, apples, and onions in their diet, but current research does not support the use of supplemental flavonoids.
16.2.11. Flavanol-Rich Cocoa
There is evidence from short-term in vitro and in vivo studies of a cardioprotective effect of cocoa and chocolate (Hollenberg and Fisher 2007; Mehrinfar and Frishman 2008). They are suggested to have antioxidant properties, anti-inflammatory properties, antiplatelet aggregation, and antihypertensive effects (Cohen and Townsend 2007; Flammer et al. 2007), and to improve vascular function. Evidence for the cardiovascular benefits of cocoa flavanols comes largely from shortterm and uncontrolled studies, and additional well-designed long-term clinical trials of cocoa are required (Mehrinfar and Frishman 2008). A recent study from Germany with follow-up of 19,357 participants over 8 years, as part of the European Prospective Investigation into Cancer and Nutrition, found a significant decrease in the risk of the combined outcome of first MI or stroke in people in the top quartile compared to those in the bottom quartile of chocolate consumption (Buijsse et al. 2010). This appeared to be in part due to lower blood pressure in those with higher chocolate consumption.
16.2.12. Vitamin K
Insufficient vitamin K in the diet has been associated with an increased risk of soft-tissue calcification and atherosclerosis (Erkkila and Booth 2008). In animal models, the multiple forms of vitamin K have been found to reverse the arterial calcification caused by vitamin K antagonists, and it has also been reported that matrix Gla protein (MGP) may act as a vitamin K-dependent calcification inhibitor. A study of phylloquinone (vitamin K1) 500-μg daily supplementation compared with a multivitamin in older men and women showed in a subgroup analysis of participants with good adherence to therapy (≥85% adherent) that there was less progression of coronary artery calcification in the phylloquinone group than in the control group (p = .03; Shea et al. 2009). These data should be considered only as hypothesis-generating data, and further studies are warranted. Vitamin K supplementation might prove useful in preventing bone and vascular disease in patients with chronic kidney disease or end-stage renal disease (Krueger et al. 2009).
16.2.13. Magnesium
A high intake of magnesium, potassium, and calcium from an increased consumption of fruit and vegetables may lower blood pressure and decrease CAD and stroke (Houston and Harper 2008). The epidemic-like increase in diabetes and associated CVD in Pacific Islanders was found to coincide with a change in diet from traditional fish and fruit to a Western-style diet with high fat, high carbohydrate, and low magnesium intake, among other things (Ringrose and Zimmet 1979). Magnesium deficiency has been found to induce vasoconstriction and enhance vascular endothelial injury, thereby promoting the development and progression of atherosclerosis. A relationship between low magnesium concentration in serum at 48 hours after onset of ischemic stroke and the intensity of the resulting neurological deficit has been reported (Cojocaru et al. 2007). For angina resulting from coronary artery spasm, treatment with magnesium has been found efficacious (McLean 1994; Shechter et al. 2000). Magnesium status is better measured by mononuclear white blood cell magnesium levels than blood levels. Low levels have been found to predispose patients with acute MI to excess mortality and morbidity.
Studies show an association between intravenously administered magnesium supplementation during the first hour of admission for MI and decreases in morbidity and mortality. The multiple physiological and cardioprotective activities of magnesium include antiarrhythmic effects, calcium channel-blocking effects, improvement in NO release from coronary endothelium, and inhibition of blood coagulation (Shechter et al. 1999). Intravenously administered magnesium has been reported to be effective in preventing atrial fibrillation and ventricular arrhythmias following cardiac and thoracic surgery; in decreasing ventricular response in acute-onset atrial fibrillation (including in patients with Wolff-Parkinson-White syndrome); and in the treatment of digoxin-induced supraventricular and ventricular arrhythmias, multifocal atrial tachycardia, and polymorphic ventricular tachycardia or ventricular fibrillation resulting from drug overdoses. Although intravenously administered magnesium is not of value in monomorphic ventricular tachycardia and electroshock-resistant ventricular fibrillation, it may be useful as an adjunct to digoxin in controlling ventricular response in new-onset atrial fibrillation. (Ho, Sheridan, and Paterson 2007; Ho 2008).
Studies show other benefits of magnesium in various cardiovascular conditions, including antiplatelet effects (Shechter et al. 1999), ability to relieve symptoms of mitral valve prolapse (Lichodziejewska et al. 1997), and ability to improve left ventricular function in patients with stable CHD (Pokan et al. 2006). Magnesium sulfate is commonly used for prevention of eclamptic seizures. The specific mechanisms of action remain unclear but may include cardiovascular effects of peripheral and cerebral vasodilation, as well as blood-brain barrier protection and anticonvulsant effects (Euser and Cipolla 2009). However, supplemental magnesium and potassium should be avoided in renal insufficiency. Additional studies are needed to improve our understanding of a link between magnesium intake, indicators of magnesium status, and heart disease.
16.2.14. Iron
The importance of iron to health is well known, and there is increasing interest in identifying and treating iron deficiency in cardiac failure. Debate has been going on regarding whether erythropoietin (EPO) is needed in addition to iron to improve symptoms and exercise capacity in anemic heart failure patients. In one study of anemic patients (Hb ≤ 12 g/dL) with stable CHF, intravenous injections of iron sucrose alone over 12 days increased hemoglobin, decreased symptoms, and improved exercise capacity (Bolger et al. 2006). In patients with heart failure of New York Heart Association (NYHA) functional class II or III decreased left ventricular ejection fraction (≤40%) and iron deficiency, treatment with intravenous iron (ferric carboxymaltose) resulted in great improvements in self-reported symptoms and objective assessments of heart failure in the ferric carboxymaltose-treated group (Anker et al. 2009). Results were similar in patients with or without anemia, and mortality, adverse events, and serious adverse events were similar in the active treatment and placebo groups. This trial had several limitations, such as a high dropout rate, and it is not known if oral iron replacement might provide similar benefits or if long-term benefits may be seen (Dec 2009). Nonetheless, it does seem appropriate to assess iron status in patients with CHF and to give some effective form of iron replacement in those with iron deficiency. Conversely, as in patients with thalassemia, excessive iron deposition in the heart can cause cardiomyopathy, heart failure, and cardiac arrhythmias.
16.2.15. Trace Minerals
Trace amounts of cobalt are essential to health and are involved in the formation of vitamin B12 (hydroxocobalamin). Excessive intake can result in thyroid insufficiency, and in 1966 the syndrome “beer drinker’s cardiomyopathy” appeared in Quebec City, Canada, characterized by pericardial effusion, elevated hemoglobin levels, and CHF (Barceloux 1999).
Chromium is important in glucose and lipid metabolism, and it may help in regression of cholesterol-induced atherosclerosis. In a study of 40 hypercholesterolemic patients, a combination of 200 μg of chromium polynicotinate and grape-seed extract (proanthocyanidin) dosed at 100 mg twice daily resulted in decreases in LDL and total cholesterol (Preuss et al. 2000). There was no significant change in either HDL cholesterol or triglyceride levels in the treatment or placebo group. Since insulin resistance may be a major factor in disturbed lipid metabolism, chromium’s favorable action on glucose/insulin metabolism may be a key factor in improving the lipid profile; however, a review of published studies concluded there are benefits to glucose and insulin metabolism only in diabetic patients and there are no overall effects on lipids (Balk et al. 2007). Although no significant adverse reactions have been noted from chromium polynicotinate doses of 400 μg/ day, a high dose of chromium picolinate has been associated with renal failure (Wasser, Feldman, and D’Agati 1997).
Selenium is an essential mineral and an antioxidant with immune-enhancing and anticancer properties. It is a cofactor of the enzyme glutathione peroxidase, an antioxidant found in platelets and the arterial wall. Soil deficiencies of selenium can lead to Keshan disease, a multifocal myocardial necrosis, with cardiomyopathy, CHF, and cardiac arrhythmias. A subsidiary report from the Physician’s Health Study showed no relationship between selenium blood levels and the risk of MI in well-nourished subjects (Salvini et al. 1995). The reliability of plasma selenium level measurements has been questioned, and other more accurate methods have been proposed (Kok et al. 1989). Primary prevention trials and most secondary prevention studies suggest that supplementation does not result in any significant decrease in ischemic CVD events (Hercberg et al. 2004). Current evidence is insufficient to support a beneficial role for selenium in cardiovascular prevention, but it is considered safe at doses below 200 μg, although people living in regions with high selenium intake may be at risk of diabetes and hypercholesterolemia from taking selenium supplements (Navas-Acien, Bleys, and Guallar 2008). Excessive selenium can also result in alopecia, abnormal nails, emotional lability, lassitude, and a garlic odor to the breath (Kendler 1997).
16.2.16. L-Carnitine
In one study, L-carnitine was used as an adjunct therapy to percutaneous coronary intervention (PCI) for non-ST elevation acute coronary syndrome (NSTEMI). This resulted in decreased levels of cardiac markers, suggesting some prevention of cardiac damage, although this result needs to be confirmed (Xue et al. 2007). In a combination with α-lipoic acid, acetyl-L-carnitine was suggested to lower blood pressure (McMackin et al. 2007), but at present, there is no definitive evidence for cardiovascular benefits.
16.2.17. Omega-3 Polyunsaturated Fatty Acids
Ever since a very low incidence of CHD in Greenland Eskimos was reported (Bang, Dyerberg, and Nielsen 1971), which was believed to be related to the high intake of seafood containing long-chain omega (n)-3 polyunsaturated fatty acids (n-3 PUFAs), many studies in other populations have supported the theory that marine n-3 PUFAs protect against thrombosis, atherosclerosis, and CHD. Some prospective cohort studies and randomized control trials (RCTs) in secondary prevention have indicated that consuming fish or fish oil containing the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is associated with decreased cardiovascular death rate, whereas consumption of the vegetable oil-derived n-3 fatty acid a-linolenic acid is not as effective (Breslow 2006); however, the results of studies are not all consistent. One systematic analysis concluded that long-chain and short-chain omega-3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer (Hooper et al. 2006). Various studies show that doses >3 g/day of EPA plus DHA can improve many CVD risk factors, including lowering of plasma triglycerides, blood pressure, platelet aggregation, and inflammation, and improvement of vascular reactivity, but it has been considered that the therapeutic effects are more likely due to suppression of fatal arrhythmias than due to stabilization of atherosclerotic plaques (Breslow 2006).
A recent systematic review and meta-analysis on the effects of fish oil DHA and EPA on mortality and arrhythmias, which examined 12 studies totaling 32,779 patients, concluded that fish oil supplementation was associated with a significant decrease in deaths from cardiac causes, although it had no effect on arrhythmias or all-cause mortality (Leon et al. 2008). The optimal formulations for EPA and DHA remain unclear (Leon et al. 2008). Most recently, a large study from Denmark that followed 57,053 middle-aged men and women for 7.6 years found that a modest intake of fatty fish was associated with a lower risk of acute coronary syndrome (ACS) with benefits seen for intakes >6 g of fatty fish per day; but no obvious additional benefit for higher intakes and no benefit from intake of lean fish were seen (Bjerregaard et al. 2010). There were fewer cases of ACS in women and no consistent associations with fish intake were observed. Current recommendations from the American Heart Association are that everyone should eat oily fish twice a week for primary prevention and that people with established CHD should take 1 g/day of EPA and DHA from oily fish or supplements (Pearson et al. 2002; Smith et al. 2006).
16.2.18. Coenzyme Q10
Coenzyme Q10 (ubiquinone) has a number of important physiological functions and has been used in oral forms to treat various cardiovascular disorders including angina pectoris, hypertension, and CHF; but the evidence to support beneficial effects of this coenzyme is still not available (Greenberg and Frishman 1990). It may have a role in the myalgia or myopathy associated with statin treatment or in cardiomyopathy with or without statins. However, this assumption remains to be confirmed (Silver et al. 2003; Wolinsky 2007; Chatzizisis, Vaklavas, and Giannoglou 2008; Joy and Hegele 2009).
16.2.19. Summary
Despite the extensive literature suggesting the benefits of antioxidant vitamins in observational studies, the results of interventional studies have largely been disappointing. There may still be a role for supplementation with folic acid, vitamin B12, and vitamin B6 to decrease homocysteine levels in stroke prevention, and recent data with vitamin D and CVD provides new opportunities for further research. Niacin clearly has beneficial effects on plasma lipids when given in pharmacological doses, and although n-3 PUFAs are suggested to have various benefits, their exact role in prevention and treatment of CVD still needs to be defined more clearly. Flavonoids such as resveratrol and flavanol-rich cocoa and chocolate appear to have beneficial effects that may be through specific mechanisms rather than a general antioxidant activity, and these merit further investigations. Other herbal medicines also have ingredients with specific pharmacologic effects that influence CVD, and these are discussed in Sections 16.3.1 through 16.3.9.
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16.3. HERBAL MEDICINES AND CARDIOVASCULAR DISEASE
A wide variety of plant extracts have been used in traditional medicine over the centuries and some, such as digoxin, have been adopted in conventional medicine. In this section, we concentrate on those plants and herbs for which there is some evidence, if not final proof, supporting their value in the prevention or treatment of CVD. More detailed reviews can be found elsewhere in the literature (Mashour, Lin, and Frishman 1998; Frishman, Beravol, and Carosella 2009).
16.3.1. Hawthorn (Crataegus Species)
Crataegus encompasses many species believed to be valuable in treating CVDs, particularly angina, heart failure, and hyperlipidemia (Chang et al. 2002). The leaves, flowers, and fruits of Crataegus species contain varying amounts of a number of biologically active substances, such as oligomeric procyanins, flavonoids, and catechins. The extract is suggested to have antioxidant properties, and inhibits the formation of thromboxane (Bahorun et al. 1994; Vibes et al. 1994). In traditional Chinese medicine (TCM), the fruit of the hawthorn (usually Crataegus pinnatifida; known as shanzha) is widely used for many indications, including digestive disorders and for lowering cholesterol and blood pressure (Chang et al. 2002). C. oxyacantha berry extract antagonized dietary-induced increases in cholesterol, triglycerides, and phospholipid levels in LDL fractions and very-low-density lipoprotein fractions in rats (Shanthi et al. 1994). Thus, it could inhibit the progression of atherosclerosis. This hypocholesterolemic action may be due to an upregulation of hepatic LDL receptors resulting in a greater influx of plasma cholesterol into the liver. A similar extract also increased degradation of cholesterol to bile acids and suppressed cholesterol biosynthesis (Rajendran et al. 1996). Extracts of Crataegus have been reported to have cardioprotective effects without affecting coronary blood flow in isolated perfused hearts; they have also been reported to have simultaneous positive cardiac inotropic and vasodilator actions (Blesken 1992; Nasa et al. 1993). A multicenter, placebo-controlled, double-blind study of Crataegus special extract WS 1442 was found to improve cardiac performance determined by heart rate product (systolic blood pressure × heart rate) in patients with NYHA class II heart failure (Weikl et al. 1996). One possible mechanism of action of flavonoids from Crataegus is the inhibition of 3′,5′-cyclic adenosine monophosphate phosphodiesterase (Schussler, Holzl, and Fricke 1995).
Hawthorn is relatively free from adverse effects (Daniele et al. 2006). In comparison with other inotropic agents such as epinephrine, amrinone, milrinone, and digoxin, Crataegus has the potential to lower arrhythmogenic risk because it prolongs the effective refractory period (Joseph, Zhao, and Klaus 1995; Popping et al. 1995). The concomitant use of hawthorn with cardiac glycosides can markedly enhance their activity; therefore, care must be taken (Mashour, Lin, and Frishman 1998). The use of Crataegus in CVD may seem promising, but more studies are needed to confirm the efficacy and safety of hawthorn extracts. However, some recent studies performed on the effects of C. oxycantha special extract WS 1442 in patients with heart failure, including the Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in CHF (SPICE) trial, showed no significant benefits (Holubarsch et al. 2008; Zick, Gillespie, and Aaronson 2008).
16.3.2. Garlic (Allium sativum)
For centuries, garlic has been valued for its medicinal properties. As an herbal medicine, it has been more closely examined than many other herbs. Research focuses on garlic for preventing atherosclerosis. Multiple beneficial cardiovascular effects have been found, including lowering of blood pressure, inhibition of platelet aggregation, enhancement of fibrinolytic activity, lowering of cholesterol and triglyceride levels, and protection of the elastic properties of the aorta (Rahman and Lowe 2006).
The intact cells of garlic bulbs contain an odorless sulfur-containing amino acid, allinin. When garlic is crushed, allinin comes into contact with allinase, which converts allinin to allicin. This has potent antibacterial properties and is highly odoriferous and unstable. Ajoenes are the self-condensation products of allicin and are suggested to be responsible for garlic’s antithrombotic action. Most authorities now agree that allicin and its derivatives are the bioactive constituents of garlic. Fresh garlic releases allicin in the mouth while chewing. Dried garlic preparations lack allicin but contain both allinin and allinase. Since allinase is inactivated in the stomach, dried garlic preparations should have an enteric coating so that they pass unaltered through the stomach to the small intestine, where allinin is enzymatically converted to allicin. Only a few commercially available garlic preparations are standardized for their yield of allicin based on the allinin content (Mashour, Lin, and Frishman 1998).
The consumption of large quantities of fresh garlic (0.25-1.0 g/kg or about 5-20 average-sized 4 g cloves) has been found to produce the aforementioned beneficial effects (Kleijnen, Knipschild, and ter Riet 1989). In support of this, a double-blind, crossover study of moderately hypercholesterolemic men, which compared the effects of 7.2 g of aged garlic extract with placebo on blood lipid levels, found a maximal decrease of 6.1% in total serum cholesterol levels and 4.6% in LDL cholesterol levels with garlic (Steiner et al. 1996). However, despite the positive evidence from a number of trials, full endorsement of garlic for CVD prevention is not currently possible. Many published studies have methodological shortcomings (Kendler 1987; Kleijnen, Knipschild, and ter Riet 1989; Jain et al. 1993; Silagy and Neil 1994b; Neil et al. 1996; Isaacsohn et al. 1998). Trials were small, lacked statistical power, had inappropriate methods of randomization, lacked dietary run-in periods, were of short duration, or failed to undertake intention-to-treat analysis. This has led to a cautious approach to previous meta-analyses (Neil et al. 1996). One more recent meta-analysis concludes that garlic decreases total cholesterol to a modest extent, an effect driven mostly by the modest decreases in triglycerides, with no appreciable effect on LDL or HDL cholesterol (Reinhart et al. 2009).
Garlic has also been studied in hypertension with no conclusive result (Simons, Wollersheim, and Thien 2009). A meta-analysis of eight trials suggested some clinical value in patients with mild hypertension, but the evidence was insufficient to recommend garlic for routine clinical therapy (Silagy and Neil 1994a). Garlic has been reported to show antiplatelet stickiness activity. This has been documented in vitro (Bordia, Verma, and Srivastava 1996), and another study examined the effect of consuming a clove of fresh garlic on platelet thromboxane production. After 26 weeks, serum thromboxane levels were lowered by about 80% (Ali and Thomson 1995). Thus, garlic may prove to be of benefit in the prevention of thrombosis. Another trial showed that long-term intake of standardized garlic powder at 300 mg daily for more than 2 years improved the elastic properties of the aorta (Breithaupt-Grogler et al. 1997). In these ways, garlic is beneficial to cardiovascular health, and these effects need further study. Moderate garlic consumption causes few adverse effects other than bad odor. However, with consumption of more than five cloves daily, heartburn, flatulence, and other gastrointestinal disturbances have been reported. Allergic contact dermatitis was also reported, and patch testing is available when garlic allergy is suspected (Delaney and Donnelly 1996). Due to its antithrombotic activity, garlic should be taken with caution by people on oral anticoagulants (Rose et al. 1990).
16.3.3. Danshen (Salvia miltiorrhiza)
The dried root of S. miltiorrhiza, known as danshen in TCM, is widely used in China for the treatment of angina pectoris, hyperlipidemia, and acute ischemic stroke (Zhou, Zuo, and Chow 2005). It has a range of potentially beneficial effects, including improving microcirculation, causing coronary vasodilatation, suppressing the formation of thromboxane, inhibiting platelet adhesion and aggregation, and protecting against myocardial ischemia. Danshen is widely used either alone or in combination with other herbal ingredients for patients with CAD and other CVDs (Cheng 2007). Clinical studies in ischemic stroke have various methodological problems and, therefore, reliable conclusions cannot be drawn from them (Wu, Liu, and Zhang 2007). Further high-quality randomized controlled trials should be performed. A more recent review of randomized controlled trials of danshen in ischemic vascular disease published in mainland China identified 150 trials from 1998 to 2007, but concluded that the quality of these trials has not improved significantly over recent years and the overall quality is still poor (Yu et al. 2009). Thus, although the mechanistic studies look promising, better clinical trials are needed to assess the efficacy and safety of this herb.
It has been demonstrated that there is an interaction between S. miltiorrhiza and warfarin in rats (Chan et al. 1995), and there are several case reports of increased anticoagulation or hemorrhage (Chan 2001). The interaction seems to be mainly due to an inhibitory effect of danshen on warfarin metabolism through cytochrome P450 (CYP) 2C9 (Tomlinson et al. 2000), but there may also be a pharmacodynamic interaction.
16.3.4. Lingzhi (Ganoderma lucidum)
G. lucidum, or lingzhi, is a woody mushroom and a popular medicinal herb that is widely used in China and many other Asian countries to promote good health and longevity (Yuen and Gohel 2005; see also Chapter 9 on lingzhi). Many potential beneficial effects, including immunomodulation and anticancer activity, have been attributed to lingzhi (Boh et al. 2007). The active constituents include polysaccharides and oxygenated triterpenoids, which have a broad range of biological activities and pharmacological functions (Shiao 2003). Although it is not typically used for treating CVD, it does appear to have some benefits on the cardiovascular system. In vitro studies with certain extracts have reported effects including inhibition of cholesterol synthesis (Komoda et al. 1989), lowering of blood pressure by reducing sympathetic outflow from the central nervous system (Lee and Rhee 1990), and antioxidant effects (Zhu et al. 1999; Lee et al. 2001; Lai et al. 2006). Animal studies also suggest it may have hypoglycemic effects (Hikino et al. 1989; Zhang and Lin 2004; Seto et al. 2009).
16.3.5. Maidenhair Tree (Ginkgo biloba)
The Ginkgo species of tree has existed on Earth for over 200 million years. The root and kernels of G. biloba are widely used in TCM. A concentrated extract of G. biloba leaves was developed in the West in the 1960s. G. biloba extract (GBE) contains flavonoids that decrease capillary permeability and fragility and are free-radical scavengers, and terpenes (i.e., ginkgolides) that inhibit platelet-activating factors and decrease vascular resistance, thereby improving circulatory flow without appreciably affecting blood pressure (McKenna, Jones, and Hughes 2001; Koch 2005). There has been some support for the use of GBE in treating cerebral insufficiency and its symptoms of vertigo, tinnitus, memory loss, and mood disorder, but a recent placebo-controlled study of GBE administered at 120 mg twice daily found no effect on cognitive decline in older adults with normal cognition or with mild cognitive impairment (Snitz et al. 2009). Peripheral vascular disease and diabetic retinopathy are also potential conditions for treatment, but most recent reviews suggest the evidence for potential benefits is inconclusive (Birks and Grimley Evans 2009; Nicolai et al. 2009; Perez 2009; Snitz et al. 2009). Some early studies suggest beneficial effects in intermittent claudication for the standardized extract of G. biloba, EGb 761, (Mouren, Caillard, and Schwartz 1994), but the most recent analysis of the Cochrane database of systematic reviews found no evidence that G. biloba has a clinically significant benefit for patients with peripheral arterial disease (Nicolai et al. 2009).
The bioequivalence of various GBE products has not been established. Adverse effects with GBE are rare but have included gastrointestinal disturbances, headache, and allergic skin rash (Mahadevan and Park 2008). Although there is some concern that GBE may potentiate the effects of anticoagulant or antiplatelet drugs, there is very little evidence to support this assumption (Bone 2008).
16.3.6. Foxglove (Digitalis purpurea/lanata)
Potent cardioactive glycosides (digitalis, digitoxin, and digoxin) have been used in CHF for many years. Their treatment value is limited by a low therapeutic index, that is, the dose needing careful adjustment for each patient. Standardization of powdered digitalis, digitoxin, or digoxin is essential for safe and effective use. There are many other plant sources of cardiac glycosides, including Convallaria majalis (lily of the valley, convallaria), Helleborus niger (black hellebore), Nerium oleander (oleander), Plumeria rubra (frangipani), Strophanthus hispidus and S. kombe (strophanus), Thevetia peruviana (yellow oleander), and Urginea maritima (squill), to name but a few, and the venom of the cane toad (Bufo marinus) also contains cardiac glycosides (Mashour, Lin, and Frishman 1998). The skin and venom glands of the Chinese toads Bufo gargarizans and B. melanostictus is used in a TCM called chansu and a proprietary Chinese medicine called Lu Shen Wan. These contain bufotoxins, which have a digoxin-like effect and may cause toxicity when taken in excessive doses (Tomlinson et al. 2000). Some other herbal remedies such as Siberian ginseng (Eleutherococcus senticosus) may cause apparent increases in digoxin levels (McRae 1996). Reports of accidental poisonings and even suicide attempts with cardiac glycosides are frequent, and oleander species are often involved (Safadi et al. 1995; Eddleston and Warrell 1999; Davies and Mayne 2001; Fonseka et al. 2002; Rajapakse 2009). The use of digoxin in heart failure has gradually declined since the Digitalis Investigation Group study showed that digoxin did not reduce overall mortality in heart failure patients (The Digitalis Investigation Group 1997). However, it is still commonly used to control the heart rate in atrial fibrillation.
16.3.7. Ginseng (Panax Species)
Ginseng has been used medicinally in East Asian countries for thousands of years as an adaptogen and a tonic (see also Chapter 8 on ginseng). The two species that have been the most extensively researched are Panax ginseng (Asian ginseng) and P. quinquefolius (American ginseng). The name Panax is derived from the Latin word “panacea,” which illustrates the usage of this herb for a wide range of conditions. P. ginseng and P. notoginseng are used in TCM for hemostasis and the treatment of patients with angina and CAD (Mashour, Lin, and Frishman 1998). The mode of action here may be as a calcium ion channel antagonist in vascular tissues, which may result in a lowering of blood pressure (Kwan 1995). In vitro studies of P. notoginseng show an enhancement of blood fibrinolytic parameters (Zhang, Wojta, and Binder 1994). Inhibition of atherogenesis by P. notoginseng saponins through decreased proliferation of smooth muscle cells (Lin et al. 1993), and dilatation of coronary arteries in rabbit tissue in vivo (Han 1992) suggest its possible use in angina. However, a systematic review of ginseng treatment in CVD concluded that there is insufficient evidence for this herb’s efficacy (Buettner et al. 2006). The evidence for its benefits in treating diabetes is more convincing (Vuksan and Sievenpiper 2005; Xie, McHendale, and Yuan 2005; Ma et al. 2008; Vuksan et al. 2008). American ginseng (P. quinquefolius) appears to attenuate hyperglycemia by a variety of mechanisms that are not yet fully understood (Luo and Luo 2009).
16.3.8. Other Herbal Medicines
Many other herbal materials have been used for treating cardiovascular conditions. They have not been studied to the same extent as the ones listed here, although some did show demonstrable effects. For hyperlipidemia, the herbal extract from the resin of the Commiphora mukul or mukul myrrh tree, known as guggul, is widely used in Asia based on Indian Ayurvedic medicine. The presumed bioactive compounds, guggulsterones, are suggested to antagonize the farnesoid X receptor (FXR) involved in controlling cholesterol metabolism (Deng 2007). A short-term safety and efficacy study of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia showed no improvement of serum lipids, and there was a dermatologic hypersensitivity reaction in some patients (Szapary et al. 2003). More promising effects were seen in rats with diabetes induced by a high-fat diet (Sharma et al. 2009).
Extracts of Chinese red yeast rice (Monascus purpureus) contain several active ingredients, including lovastatin, which can lower LDL cholesterol (Lin, Li, and Lai 2005; Huang et al. 2007; Gheith et al. 2009). These preparations appear to be safe in moderate doses, but they may not be standardized well and are likely to have the same side effects and drug interactions as lovastatin when taken in large amounts.
As suggested with ginkgo, extracts of rosemary may have benefits in attenuating cognitive decline from cerebral insufficiency, but this remains unproved (Kennedy and Scholey 2006). Extracts of rosemary (Rosmarinus officinalis) do appear to have antiproliferative, antioxidant, and anti-inflammatory properties in various cell line studies (Cheung and Tai 2007).
The component tetrandrine isolated from Stephania tetrandra has antihypertensive and antiarrhythmic effects that have been demonstrated in experimental hypertensive animals and in hypertensive patients (Qian 2002). These effects come to action mainly through a calcium antagonistic effect, but other pharmacological mechanisms may also be involved. Rauwolfia preparations and veratrum alkaloids are mainly of historical interest in hypertension treatment (Moser 1986).
Extracts of horse chestnut (Aesculus hippocastanum) have been used in the treatment of chronic venous insufficiency, and they were found to be safe and well tolerated, with some beneficial effects in one study (Dickson et al. 2004). Extracts from Butcher’s broom rhizome (Ruscus aculeatus) have also been widely used for the treatment of chronic venous insufficiency with some favorable reports (Vanscheidt et al. 2002).
16.3.9. Summary
Overall, many of the herbal medicines discussed here do appear to have pharmacological effects in vitro and in animal studies, which may influence CVD (Table 16.2). However, the evidence from properly conducted clinical trials is generally insufficient to draw definitive conclusions. The problems with standardization of herbal preparations and performance of properly controlled clinical trials to acceptable international standards need to be addressed before the true clinical value of these herbs can be defined.
TABLE 16.2
Potential applications for therapy in cardiovascular conditions of some common Herbal Medicines.
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16.4. HERBAL MEDICINE AND DRUG INTERACTIONS
Herbal medicines are frequently used in combination with conventional drugs, and interactions are likely to be more common than those that manifest clinically. Herb-drug interactions have been extensively reviewed in the literature (Hu et al. 2005; Izzo 2005; Izzo and Ernst 2009), and some of the common ones are mentioned in Sections 16.3.1, 16.3.2, 16.3.3, 16.3.5. Pharmacokinetic interactions mediated by drug-metabolizing enzymes or transporters are involved in many herb-drug interactions. Polymorphisms in the genes for these enzymes and transporters may influence the interactions mediated through these pathways (Tomlinson, Hu, and Lee 2008).
Herb–drug interactions are likely to be more serious with drugs having a narrow therapeutic index, such as warfarin or digoxin. Herbs can interact with warfarin in several different ways (Greenblatt and von Moltke 2005). The interaction with danshen is mentioned in Section 16.3.3 and probably occurs by inhibition of warfarin metabolism through CYP2C19. St. John’s wort (Hypericum perforatum; see also Chapter 11 on St. John’s wort) interacts with warfarin and a number of other drugs by inducing the expression of several CYP enzymes and the drug transporter P-glycoprotein (P-gp or ABCB1), resulting in decreased plasma concentrations of the drugs involved and lowered efficacy (Borrelli and Izzo 2009). Digoxin is a substrate for P-gp, and St. John’s wort can lower digoxin levels by increasing the activity of this transporter (Izzo 2004).
The finding that grapefruit juice substantially increased the plasma concentrations of felodipine by decreasing presystemic metabolism through selective post-translational downregulation of CYP3A4 expression in the intestinal wall identified another potential mechanism for drug interactions with natural products (Bailey et al. 1998). This is important with other dihydropyridine calcium-channel blockers and drugs that undergo substantial presystemic metabolism mediated by CYP3A4, including lovastatin and simvastatin in the cardiovascular field. This interaction seems to be most prominent with grapefruit juice and has not been described to date with herbal medicines. Grapefruit juice may also have a small effect on digoxin phamacokinetics, possibly through inhibition of the organic anion transporting polypeptide (OATP) rather than P-gp (Bressler 2006).
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16.5. RESEARCH NEEDS
The evidence from large clinical trials is generally not supportive of the cardiovascular benefits from supplements of antioxidant vitamins or other EMNs, and guidelines generally recommend increasing intake of foods that are rich in these materials rather than using specific supplements. Omega-3 PUFAs may be one exception, and niacin in pharmacological doses clearly has effects on plasma lipids. With the herbal medicines used in the prevention or treatment of CVD, the clinical trial evidence is mostly not sufficient to support any definitive recommendations. Many of the trials have been too small, and different trials have often used different herbal preparations with different standardizations, so the meta-analyses of herbal treatment effects may not always consider the same active compounds. Many herbal medicines do have ingredients with demonstrable pharmacological effects, but larger clinical trials with properly standardized materials are needed before any clear conclusions can be drawn. The potential antihyperglycemic effects of various ginseng preparations and possibly of lingzhi (G. lucidum) are areas for further investigation, and more clinical trials with garlic preparations for treating hyperlipidemia or hypertension are warranted. The role of danshen (S. miltiorrhiza) in treating CVDs can still be defined more clearly with appropriate clinical trials, and although some well-controlled studies with hawthorn extracts in heart failure have not shown significant benefits, there may still be a role for some hawthorn preparations in hyperlipidemia or other areas of CVD prevention.
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16.6. CONCLUSIONS
The cardinal importance of a well-balanced diet that includes adequate fruit and vegetables has been rediscovered after some years of oversight during the era of great pharmaceutical and therapeutic advances. In times of plenty, it is important to control calorie intake and lower the consumption of animal fats and alcohol in association with taking adequate regular physical exercise and mental recreation for the maintenance of good health. A worldwide chronic disease epidemic of obesity, diabetes, and consequent CVDs is replacing the diminished burden of infectious diseases. It is evident that there is a place for the use of EMNs where these are deficient, but their value in treating established CVDs is unproved in most instances. Herbal remedies, although they have a long history of use in traditional medicine and show promising biological actions, remain clinically unproved and are as yet often insufficiently standardized to be recommended as therapy. This situation is likely to change with further research. The evidence to support the use of these alternative therapies from clinical trials is not yet secure, but custom and practice make it likely that they will continue to be used for the prevention or treatment of CVDs, among other indications.
