About this Journal Submit a Manuscript Table of Contents
ISRN Cardiology
Volume 2011 (2011), Article ID 397136, 16 pages
http://dx.doi.org/10.5402/2011/397136
Review Article

Effects of Some Common Food Constituents on Cardiovascular Disease

1Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
2Centre for Clinical Pharmacology, University College London, London WC1E 6JF, UK

Received 14 March 2011; Accepted 19 April 2011

Academic Editors: C. Briguori, E. Z. Fisman, A. Ganau, and A. M. Gerdes

Copyright © 2011 Yaling Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cardiovascular diseases are the major cause of morbidity and mortality worldwide, and there is considerable interest in the role of dietary constituents and supplements in the prevention and treatment of these disorders. We reviewed the major publications related to potential effects on cardiovascular risk factors and outcomes of some common dietary constituents: carotenoids, flavonoid-rich cocoa, tea, red wine and grapes, coffee, omega-3 fatty acids, and garlic. Increased intake of some of these has been associated with reduced all-cause mortality or reduced incidence of myocardial infraction, stroke, and hypertension. However, although the evidence from observational studies is supportive of beneficial effects for most of these foodstuffs taken as part of the diet, potential benefits from the use of supplements derived from these natural products remain largely inconclusive.

1. Introduction

Cardiovascular disease (CVD) has been the major cause of morbidity and mortality in developed countries over the last several decades, and the prevalence is increasing dramatically in China and India and other developing countries. The underlying atheromatous vascular disease manifests as coronary heart disease (CHD), cerebrovascular disease, peripheral vascular disease, and subsequent development of heart failure and cardiac arrhythmias. The major risk factors for these disorders have been recognised for many years and include high levels of low-density lipoprotein (LDL) cholesterol, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, insufficient consumption of fruits and vegetables, excess alcohol, and lack of regular physical activity, and it was reconfirmed recently in the INTERHEART study that these conventional risk factors accounted for over 90% of the population attributable risk for myocardial infarction (MI) [1].

The management of the major risk factors with conventional drugs is effective in reducing cardiovascular events, and this is supported by extensive evidence from clinical trials. Recently, there is growing awareness of the place of dietary factors and herbal medicines in the prevention of CVD and the possibility of their use in treatment. Much of this interest centres on the antioxidant vitamins and the antioxidant properties of food constituents and herbal materials, but some herbal materials may also improve conventional cardiovascular risk factors or have antithrombotic effects. The 2005 US Dietary Guidelines and the American Heart Association have recommended the Diet Approaches to Stop Hypertension (DASH) diet, but most Americans are not following these guidelines and their daily consumption of fruit and vegetables are far short of the recommended targets [1, 2]. In 2009, it was estimated that only 32.5% of adults in the United States consumed fruit two or more times per day and 26.3% consumed vegetables three or more times per day [3]. In this paper we shall focus on some of the common food constituents which have been thought to have beneficial effects on CVD and will discuss some of the potential mechanisms and results from large clinical trials and meta-analyses.

2. Common Potentially Beneficial Food Constituents

Electronic literature searches were performed using MEDLINE, ISI Web of Knowledge, SCOPUS, and Science Direct (published from 1970 to 2010). The search terms used were cardiovascular diseases, clinical trial, meta-analysis, systematic review, carotenoids, cocoa, tea, red wine, grapes, coffee, omega-3 fatty acids, and garlic. A total of 2270 articles were identified. The bibliographies of all articles thus located were also scanned for further relevant references. Three authors (Y. Yang, S. W. Chan, and B. Tomlinson) extracted all articles independently and evaluated the quality of the studies and strength of the evidence of clinical impact using the same standards. Based on the relevance, strength, and quality of the design and methods, only the shortlist of the latest studies or representative findings were discussed below. Where meta-analyses were available, these have been discussed rather than the individual studies included in those analyses. Apart from some important mechanistic studies, in vitro and animal studies were generally excluded, as were articles written in languages other than English.

2.1. Carotenoids

Numerous natural carotenoids are present in fresh fruits and vegetables, and some have been studied extensively in the prevention of CHD. Most carotenoids have free radical scavenging effect [4] and a potential to protect LDL cholesterol against oxidation [5, 6]. Carrots are a primary source of β-carotene. Elevated levels of serum β-carotene were associated with a lower risk of cancer and reduced overall mortality rates [7], and early observational studies reported an association between a high dietary intake of β-carotene and reduced incidence of CVD [8, 9]. In a case-control study, the risk of nonfatal acute MI in women was inversely associated with daily intake of 𝛽 -carotene-containing diet [10]. In the Rotterdam study, a population-based cohort study in the elderly, dietary intake of 𝛽 -carotene was inversely associated with the risk of MI [11]. Interestingly, in the American Health Professional’s Study conducted in 39,910 US males, carotene intake was associated with a lower risk of CHD among current smokers but not nonsmokers [12].

Although many epidemiologic studies have reported an association between 𝛽 -carotene and the risk of CVD, several large randomized trials did not reveal any reduction in CVD with 𝛽 -carotene consumption. For instance, the MRC/BHF Heart Protection Study showed no benefit from 𝛽 -carotene 20 mg daily, in combination with vitamin E 600 mg and vitamin C 250 mg, on morbidity or mortality in high-risk individuals [13]. In the 𝛼 -tocopherol and 𝛽 -carotene (ATBC) study conducted in 1,862 male smokers who had a previous MI, there were no significant differences in the number of major coronary events between any supplementation group and the placebo group. Moreover, the risk of fatal CHD was increased in the 𝛽 -carotene and combined 𝛼 -tocopherol and 𝛽 -carotene groups compared to the placebo group [14]. Likewise, the Women’s Antioxidant Cardiovascular Study (WACS) found no CVD risk reduction in women at high risk with 𝛽 -carotene 50 mg every other day, or with vitamin C 500 mg daily or vitamin E 600 IU every other day [15]. The prospective 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 [16], but after 12 years of followup there was no impact from supplementation of 𝛽 -carotene 50 mg alternate days on CVD, cancer, or overall mortality among primarily nonsmokers [17].

Lycopene, one of the most common carotenoids in the human diet, has twice the antioxidant activity of 𝛽 -carotene [18]. Tomatoes are the best source of lycopene, which is the focus of research as a precursor to vitamin A. A diet rich in tomatoes, tomato products, and lycopene is associated with a lower risk of CHD [19]. Epidemiological studies and supplementation clinical trials suggested a reduction in CVD risk but not all studies have confirmed this. A multicentre case-control study suggested that lycopene may contribute to the protective effect of vegetable consumption on MI risk [20]. The Kuopio Ischaemic Heart Disease Risk Factor Study conducted in 1,028 middle-aged men in eastern Finland showed that subjects with low concentration of serum lycopene concentration had a significantly higher mean intima-media thickness of the common carotid artery (CCA-IMT) and higher maximal CCA-IMT than did the other men [21]. Conversely, in the Physicians’ Health Study, no association between increasing concentrations of plasma lycopene and the risk of CVD was found [22]. A recent review of the controlled clinical studies with lycopene in well-defined subject populations found no definite evidence for CVD prevention [23]. Representative observational and intervention studies on the association of carotenoids with the risk of CVD are summarized in Table 1.

tab1
Table 1: Observational and intervention studies of the association of carotenoids with the risk of cardiovascular disease.

Apart from carotenoids and lycopene, many fruits and vegetables are also rich in glutathione. Glutathione and glutathione-1 peroxidase provide important antioxidant effects that may prevent CVD. A prospective study conducted in 636 patients with suspected coronary artery disease (CAD), with a median followup period of 4.7 years (maximum, 5.4), suggested that increasing glutathione-1 peroxidase activity might lower the risk of cardiovascular events [24]. A thorough review on the relations between plasma glutathione levels and CVD suggested that reduced plasma total glutathione levels are a risk factor for CVD especially for cerebral small vessel disease [25].

Currently, it seems logical that a higher dietary intake of fruit and vegetables rich in carotenoids may play a role in the prevention of morbidity and mortality associated with CVD. However, the evidence that specific supplements are beneficial is controversial, and the underlying mechanisms are not clear. Further studies are in progress to determine the usefulness of the consumption of carotenoids in the prevention and treatment of CVD.

2.2. Flavanol-Rich Cocoa

Flavanol-rich foods are common in the spectrum of the human diet and flavanols are present in items such as wine, tea, various fruits, and certain vegetables. Among these, cocoa and cocoa-derived products, such as cocoa powder and chocolate, are representative foods containing natural flavanols that have received much attention. Cocoa and cocoa-derived products are derived from the fermented, roasted, and industrially processed seed of the Theobroma cacao tree. The Kuna Indians in Panama have a very high intake of flavanol-rich cocoa, which may be related to them having low blood pressure levels, reduced frequency of cardiovascular events, and longer life expectancy than other Panamanians [26]. In cocoa and cocoa products, the flavanols include monomeric forms (catechins) and polymer forms (procyanidins). Monomers bind together by links between C4 and C8 and form dimers, and oligomers even up to decamers [27]. Procyanidins, also known as condensed tannins, combine with salivary proteins which cause the bitterness of cocoa as well as the astringent character of some fruits [28]. The major cocoa catechins include ( + ) -catechin, ( ) -epicatechin, ( + ) -gallocatechin, and ( ) -epigallocatechin. These monomers bind together to form procyanidin B1, procyanidin C1, procyanidin D, and so forth.

Data from cell culture and animals studies suggest that cocoa may have antioxidant and anti-inflammatory effects [37]. An in vitro study examined nitric oxide (NO) levels in human umbilical vein endothelial cells under different treatment conditions. It found that epicatechin, a flavan-3-ol, scavenged free radicals, inhibited NADPH oxidase activity, and preserved the bioavailability of NO [38]. An animal study carried out on rabbit aortic rings showed that polymeric procyanidins derived from cocoa produced an endothelium-dependent relaxation which was mediated by activation of endothelial NO synthase [39]. In another study using cultured endothelial cells, cocoa decreased the activity of arginase which augmented the local levels of L-arginine, the precursor for NO synthesis [40]. It has been demonstrated that oral administration of L-arginine improves endothelium-dependent dilation in the forearm conduit arteries in patient with hypercholesterolemia [41]. In a prospective, double-blind, randomized crossover trial, long-term oral administration of L-arginine improved endothelium-dependent dilation and reduced monocyte adhesion to the endothelium in young men with coronary disease [42].

Accumulating epidemiological evidence suggests that flavanol-rich food such as cocoa has potential cardioprotective effects which might be attributed to improvements of cardiovascular risk factors (Table 2). In healthy male adults, daily intake of flavanol-rich cocoa drink over 1 week produces a sustained increase in FMD [43]. This long-term result on FMD is probably induced by elevated level of endothelial NO synthase (eNOS), which is further corroborated by in vitro data. In a double-blind, randomized study, consumption of chocolate improved coronary vascular function and reduced platelet adhesion, and these beneficial effects were coupled with reduced serum oxidative stress measures and changes in serum epicatechin concentration [44].

tab2
Table 2: Observational studies of the association of flavanol-rich food with the risk of cardiovascular disease.

A prospective cohort study from Sweden with followup of 31,823 women over 9 years concluded that moderate habitual chocolate intake was associated with a lower incidence of heart failure. However, the protective association was not observed with greater intake of chocolate per day [31]. An observational study in a cohort of 19,357 German adults with followup of 8 years revealed that chocolate consumption lowered the risk of the combined outcome of MI and stroke which was partially due to reduced blood pressure [29]. It has also been reported that chocolate consumption is correlated with lower cardiac mortality in patients who survived a previous acute MI [30].

A recent meta-analysis, which included ten controlled studies involving normal adults or patients with hypertension and treated with cocoa products for a short-term ranging from 2 to 18 weeks, concluded that flavanol-rich cocoa products taken for 2–18 weeks reduce both systolic (−4.5 mmHg) and diastolic (−2.5 mmHg) blood pressures [45]. Furthermore, a meta-analysis of randomized controlled trials showed that chocolate or cocoa produced both acute and chronic effects on FMD but not on LDL cholesterol and high-density lipoprotein (HDL) cholesterol concentrations [46]. Several trials indicate that cocoa or chocolate inhibits platelet function [47, 48].

Evidence for cardiovascular benefits of cocoa flavanols has come largely from short-term and uncontrolled studies and, therefore, additional well-designed, long-term clinical trials of cocoa supplementation are required [49]. The mechanisms described above may partially explain the positive effects of flavanol-rich foods on CVD. Whether cocoa may possess antioxidant activity requires further investigation. It is important to consider that many chocolate-containing products also contain large amounts of fat and sugar which might negate any potential benefit from the flavanol content of the product.

2.3. Tea

Tea is one of the most popular beverages worldwide. It contains polyphenols in amounts similar to those found in red grapes. Tea is the product of the leaves and leaf buds of Camellia sinensis. Tea can be classified into 3 main categories according to the degree of fermentation: fully-fermented black tea, semifermented Oolong tea, and unfermented green tea. The polyphenolic compounds, mainly catechins, contained in green tea are associated with its cardiovascular protective effect. The major tea catechins include ( ) epicatechin (EC), ( ) -epigallocatechin (EGC), ( ) -epicatechin-3-gallate (ECG), and ( ) -epigallocatechin-3-gallate (EGCG). Catechins inhibit the expression of inducible NO synthase (iNOS) [50, 51] and reduce inflammation and ROS-generating enzymes [52, 53]. They also induce apoptosis of monocytes [54], lower lipids levels [55], reduce oxidative stress [50], inhibit platelet aggregation [56], and decrease apolipoprotein (Apo) B levels and increase the ratio of ApoA-1/ApoB [57]. The galloyl group may also exert cardiovascular protective effects via multiple cellular pathways and transcriptional factors involved in the cardiovascular system [58].

The association of green tea consumption with cardiovascular protection has been well documented in observational studies (see Table 2). A long-term study performed in Japan showed that daily consumption of 10 cups green tea was associated with a reduction in cardiovascular mortality in men [33]. In the Ohsaki study, a population-based prospective cohort study, green tea consumption was associated with a reduction in CVD mortality [32]. A prospective cohort study in 6,358 Japanese followed up for 5 years revealed an inverse correlation of green tea consumption and the risk of stroke incidence [34]. This association was further confirmed by a meta-analysis on 9 studies involving 4,378 individuals from different countries [59]. However, in a study of 2,855 Japanese, no association between green tea consumption and cardiovascular mortality was observed [60]. In a review of randomized controlled trials on the association between green tea and CVD risk profiles, only 17 out of 30 studies have reported beneficial effects of green tea, 11 studies showed neutral effects whereas 2 studies concluded harmful effects [61].

The increase in blood pressure shortly (30–90 minutes) after green tea consumption has been examined in several studies [6264]. It is noteworthy that the increase in blood pressure is even greater than that produced by the same amount of caffeine administered alone [64]. Conversely, long-term consumption of tea may have a beneficial effect on blood pressure. In a cross-sectional study of 218 Australian women over 70 years old, long-term regular consumption of tea was associated with a lower systolic blood pressure and lower diastolic blood pressure [65]. In a cohort study conducted in 1,507 Chinese over 20 years old in which the mean blood pressure was carefully multiadjusted, daily consumption of 123–599 mL or over 600 mL green or oolong tea reduced the risk of developing hypertension by 46% and 65%, respectively, compared with non-habitual tea drinkers [35]. However, a larger cross-sectional study conducted in 3,336 Japanese males showed that green tea consumption failed to alter blood pressure [66].

Consumption of green tea has also been associated with lower levels of total cholesterol and LDL cholesterol [46], but without effects on serum HDL cholesterol and triglycerides [67]. A double-blind, randomized, controlled study conducted in 40 overweight Japanese children suggested that 24-week consumption of a drink made from green tea effectively reduced the LDL cholesterol level although the effect may have been related to weight loss [68]. A randomized, double-blind, placebo-controlled study in 111 healthy adult volunteers revealed that consumption of green tea (standardized and defined decaffeinated) for 3 weeks reduced LDL cholesterol levels [69]. However, several studies failed to find a significant correlation between green tea consumption and HDL cholesterol levels [6971].

The majority of studies with tea have used green tea, but a few studies have been done using black tea and oolong tea. Short- and long-term consumption of black tea was shown to reverse endothelial vasomotor dysfunction but did not reduce ex vivo platelet aggregation in patients with CHD [72, 73]. Potential protective effects of green tea and black tea against CVD and cancer were attributed to the polyphenolic compounds, particularly the catechin, epigallocatechin gallate (EGCG) in green tea, and theaflavins in black tea. The processing of tea to produce black tea results in the conversion of catechins into theaflavins and thearubigins, but these also appear highly potent in NO production and vasorelaxation [74]. The concentrations of catechins including EGCG in black tea are much lower than that in green tea [75] but the theaflavins in black tea also provide an antioxidant effect which in some studies is similar to that of green tea [76]. In an epidemiological study on 17,228 subjects (mean age, 59.5 years) initially free of CVD and cancer from the College Alumni Health Study, black tea consumption was not associated with a reduced risk of CVD [77]. In a prospective study of 76,979 healthy individuals aged 40–79 years in Japan, consumption of coffee, green tea, and oolong tea and total caffeine intake were all associated with reduced risks of mortality from CVD [78]. A small study performed in The Netherlands, which studied the use of dietary bioflavonoids, phenolic acids, and quercetin, showed that there was a reduction in the incidence of heart attack and sudden death in the elderly men aged 65–84 years with a higher flavonoid intake and one of the major sources of flavonoid intake (61%) was from tea [79].

2.4. Red Wine and Grapes

The traditional French diet is high in saturated fats, but residents of France have a lower incidence of CAD than Americans, the so-called French paradox [80]. The typical French diet includes regular intake of fresh fruit and vegetables that contain phytonutrients which have antioxidant effects and may retard atherogenesis and thrombosis. However, consumption of red wine may be another protective factor. The rich polyphenolic content of red wine has made it a popular subject for consideration in the possible prevention of cancer and CVD [81]. Daily consumption of mild to moderate (1-2 drinks) amounts of red wine is thought to produce beneficial effects on CVD, which have been considered by some to provide the basis for the French paradox.

Red wine contains many polyphenolic compounds including nonflavonoids and flavonoids [82]. These compounds have antioxidant, anti-inflammatory, and potential antiatherogenic effects. A study of the antioxidant activity of red wine in volunteers showed that two glasses of red wine before food had antioxidant activity lasting for at least 4 hours [83]. Red wine increases antioxidant activity through the flavonoid-polyphenol effect. Grapes and wines also contain catechol compounds which possess antioxidative effects.

Part of the benefit of red wine may be from the alcohol content. The INTERHEART study, a very large case-control study conducted in 15,152 patients who had experienced an acute MI and 14,820 age- and sex-matched controls, has shown that regular consumption of alcohol (3 or more times a week) had a cardioprotective effect against MI [1]. However, in the prospective Copenhagen Heart study, low to moderate consumption of wine was associated with lower mortality from CVD and cerebrovascular disease and other causes whereas beer consumption failed to affect mortality and a similar intake of spirits appeared to increase the risk [36] (Table 2). In a meta-analysis including 13 studies and 209,418 participants, moderate red wine intake reduced the atherosclerotic risk by 37% and there was a similar, but smaller, association with reduced risk in beer consumption studies, again suggesting that red wine may have an additional benefit beyond the alcohol content [84].

Moderate red wine consumption has beneficial effects on some cardiovascular risk factors, particularly HDL cholesterol and possibly fibrinogen, which are not seen with red grape extract so those benefits may be attributed to the alcohol content and it has been suggested that any beneficial effect of red wine compared to other alcoholic beverages may be related to other life-style confounders rather than the nonalcohol components of red wine [85]. Several small studies have shown beneficial effects from the other components of red wine. A double-blind, cross-over study conducted in 15 CAD patients showed that acute consumption of either 250 mL regular or alcohol-free red wine significantly improved the arterial stiffness and wave reflections [86]. Interestingly, administration of alcohol-free red wine produces an improvement in various CVD risk parameters in some other studies. In line with these results, two studies showed that acute consumption of alcohol-free red wine caused an improvement of brachial artery flow-mediated vasodilation [87, 88]. However, some studies failed to show any additional protective effects of red wine consumption compared with other types of alcoholic beverages [89, 90].

Several studies have examined the potential benefits of specific components in red wine such as resveratrol and oligomeric proanthocyanidins in reducing CVD risk. Resveratrol is mainly found in grape skin, and, thus, significant amounts of resveratrol are present in red wine. It has been suggested that it has cardioprotective effect since it activates platelet NO synthetase [91] and inhibits LDL oxidation [9294], inflammation [95], production of reactive oxygen species [96], and platelet aggregation [97]. Evidence from animal studies suggests that resveratrol exerts it cardioprotective effect by attenuating the proinflammatory effects invoked by platelet-activating factor [98] and upregulating the expression for iNOS, eNOS, VEGF, and KDR [99]. The beneficial effects of moderate wine intake on ischaemic CVD may be explained by this [100]. Many studies on resveratrol have been conducted in cultured cells and animal models. However, there is currently no definite evidence that resveratrol has cardioprotective effects in humans, and as the oral bioavailability of resveratrol in man is extremely low it is difficult to assess the true physiological significance of resveratrol [101].

Oligomeric proanthocyanidins are free radical scavengers [102] which inhibit lipid peroxidation [103] and have anti-inflammatory and antiallergenic properties [104]. Like carotenoids, they are found predominantly in brightly coloured fruits and vegetables and represent a safe source of polyphenols and quercetin, the latter being believed to be particularly active in preventing LDL oxidation [105]. In a placebo-controlled cross-over study with quercetin 150 mg daily supplementation for 6 weeks in overweight or obese subjects with metabolic syndrome traits, there was a decrease in systolic blood pressure by 2.6 mmHg, a decrease in plasma concentrations of atherogenic oxidised LDL, and a small but significant decrease in serum HDL cholesterol concentrations, although the ratio of LDL : HDL-cholesterol was unchanged [106].

The Physician’s Health Study did not show any association between intake of flavonoids and all CAD events [107]. The Kuopio Ischaemic Heart Disease Risk Factor Study concluded that a high intake of flavonols and the mean CCA-IMT were negatively associated [108]. The optimal amount and form of flavonoids in the diet are not known, and some of these compounds have rather low bioavailability. In spite of the uncertainties, many flavonoids are available as food supplements in doses as high as 500 and 1000 mg, an amount 10 to 20 times the daily intake of a typical vegetarian diet. With the currently available information, patients with CAD and those at risk of CVD may be encouraged to include moderate red wine intake in their diet, but current research findings do not support the use of supplemental flavonoids derived from grapes or red wine, and further prospective controlled studies are needed to identify whether such supplements may be beneficial.

2.5. Coffee

Coffee from the seeds of plants of the Coffea genus is the most important overall source of caffeine in adults although caffeine is also present in tea, chocolate, and certain soft drinks [109]. Coffee also contains other biologically active compounds, including chlorogenic acid, and the diterpene alcohols cafestol and kahweol, which may have long-term effects on risk factors for CHD. Acute intake of coffee has a number of unfavorable cardiovascular effects, including increases in blood pressure, circulating catecholamines, arterial stiffness, and impairment of endothelium-dependent vasodilation which are probably attributable to caffeine [110]. However, studies examining the association between coffee consumption and CHD have been inconclusive, which may reflect the complex mixture of compounds that may have either beneficial or harmful effects on the cardiovascular system [111].

Acute intake of coffee raises systolic and diastolic blood pressure and slightly reduces heart rate, which is probably due to the effect of caffeine antagonizing the adenosine A1 and A2A receptors [112]. Coffee also has a cholesterol-raising effect which appears to be related to diterpenes present in boiled coffee, and this may contribute to the risk of CHD associated with unfiltered coffee consumption [113]. Coffee consumption is associated with higher plasma total homocysteine concentrations which may increase the risk of CVD, and it was shown that caffeine was only partly responsible for the homocysteine-raising effect of coffee [114]. However, several studies have shown that coffee intake, including decaffeinated coffee, was inversely associated with the risk of developing type 2 diabetes mellitus [115], and another study showed that potentially black tea, but not green tea, in addition to coffee may also reduce the risk of type 2 diabetes mellitus [116].

A study of the association between coffee consumption and risk of acute nonfatal MI found that the polymorphism in the cytochrome P450 1A2 (CYP1A2) enzyme resulting in the variant C Y P 1 A 2 1F with “slow” caffeine metabolism modified the association so that increased intake of coffee was only associated with an increased risk of nonfatal MI among individuals with slow caffeine metabolism, suggesting that caffeine was a major factor in the association [117]. Several studies have examined the relationship between coffee intake and cardiovascular events and mortality with conflicting results. A recent long-term followup of participants in the Health Professionals Followup Study and Nurses' Health Study found that regular coffee consumption was not associated with an increased mortality rate in either men or women and there appeared to be a modest benefit of coffee consumption on all-cause and CVD mortality [118]. A lower risk of CHD among moderate coffee drinkers might be due to antioxidants found in coffee.

2.6. Omega-3 Poly-Unsaturated Fatty Acids

Early reports of the very low incidence of CHD in Greenland Eskimos [124] which was believed to be related to the high intake of seafood containing long-chain omega (n)-3 polyunsaturated fatty acids (n-3 PUFA) prompted many studies in other populations that have supported the theory that marine n-3 PUFAs protect against thrombosis, atherosclerosis, and CHD. The 3 major dietary n-3 PUFAs include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and 𝛼 -linolenic acid (ALA). Some prospective cohort studies and randomized control trials in secondary prevention have found that consuming fish or fish oil containing EPA and DHA was associated with a decreased cardiovascular death rate, whereas the consumption of vegetable oil-derived ALA may not be as effective [125], but not all studies results are consistent. One systematic analysis concluded that long-chain and shorter-chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer [126].

Various studies show that doses >3 g/d, EPA plus DHA can improve many CVD risk factors, including reducing plasma triglycerides, blood pressure, platelet aggregation, and inflammation, along with improving vascular reactivity. A recent review considered the possible difference between whole fish and fish oil supplements and concluded that there was an association between dietary intake of n-3 PUFAs or fish with a reduced risk of subclinical atherosclerosis [127]. A randomized controlled trial of patients awaiting carotid endarterectomy indicated that n-3 PUFAs from fish oil enhanced the stability of atherosclerotic plaques [128]. However, it has been suggested that the therapeutic effects on CVD mortality could be attributed to a suppression of fatal arrhythmias rather than stabilization of atherosclerotic plaques [125, 129].

A meta-analysis on the effect of n-3 PUFAs in fish oil on blood pressure, which examined 31 controlled trials, concluded that greater consumption of n-3 PUFAs was associated with greater reduction in blood pressure, particularly in hypertensive subjects and those with clinical atherosclerotic disease or hypercholesterolemia [130]. In a randomized open-label, blinded endpoint study, which evaluated 18,645 patients with a total cholesterol of 6.5 mmol/L or above, daily consumption of 1800 mg EPA reduced posttreatment LDL cholesterol, unstable angina, and nonfatal coronary events [123]. A systematic review of 47 studies concluded that daily consumption of EPA and/or DHA (average 3.25 g) produces a significant reduction of triglycerides levels but not total, HDL, or LDL cholesterol in hyperlipidemic subjects [131].

Accumulating evidence has suggested that consumption of n-3 PUFAs decreases the risk of cardiovascular mortality and sudden cardiac death especially in patients with a history of MI. In the diet and reinfarction trial (DART), which involved 2,033 men recovered from MI, there was a significant reduction of total mortality in subjects who consumed 2-3 portions of fatty fish daily [132]. The GISSI-Prevenzione trial, which examined 11,323 patients who had experienced MI within 3 months, showed that daily intake of 1 g n-3 PUFA supplementation was associated with a significant reduction in all-cause and cardiovascular mortality, especially risk of sudden cardiac death [119]. The subsequent analysis to assess the time course of the benefit of n-3 PUFAs in the GISSI-Prevenzione trial found the survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment suggesting that this early benefit supported the hypothesis of an antiarrhythmic effect [120]. In the GISSI-HF trial, patients with chronic heart failure of New York Heart Association class II-IV receiving n-3 PUFA 1 g daily showed small but significant reductions in all-cause mortality and hospital admissions for cardiovascular reasons [122].

In a randomized, double-blind, placebo-controlled study which was conducted in patients treated with chronic haemodialysis, consumption of n-3 PUFAs did not reduce the risk of cardiovascular event and death [121]. However, some clinical trials with increased consumption of fish oil showed an increase in sudden death in men [133, 134]. A review on the pro- and antiarrhythmic properties of n-3 PUFAs suggested that n-3 PUFAs may be antiarrhythmic under conditions that favour triggered activity but may also facilitate reentrant arrhythmias leading to sudden death and advice to increase intake of n-3 PUFA supplements or fatty fish should be tailored to individual patients with respect to the arrhythmogenic mechanisms associated with the underlying pathology [135]. However, a recent systematic review and meta-analysis on the effects of fish oil DHA and EPA on mortality and arrhythmias, which examined 12 studies totalling 32,779 patients, concluded that fish oil supplementation was associated with a significant reduction in deaths from cardiac causes but had no effect on arrhythmias or all-cause mortality and the optimal formulations for EPA and DHA remain unclear [136].

Most recently, a large study from Denmark following 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 [137]. There were few cases of ACS in women and no consistent associations with fish intake were observed in the women. Studies pertaining to the effects of n-3 PUFA supplements on cardiovascular risks are summarized in Table 3. Current recommendations from the American Heart Association are that everyone should eat oily fish twice per week for primary prevention and that people with established CHD should take 1 g/d of EPA and DHA from oily fish or supplements [138, 139].

tab3
Table 3: Intervention studies of the association of omega-3 poly-unsaturated fatty acids consumption with the risk of cardiovascular disease.
2.7. 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 others. Much research has focused 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, reduction in cholesterol and triglyceride, and protection of the elastic properties of the aorta [140].

The intact cells of garlic bulbs contain an odourless, sulphur-containing amino acid allinin. When garlic is crushed, allinin comes into contact with allinase which converts allinin to allicin. Fresh garlic releases allicin in the mouth during chewing. This has potent antibacterial properties is highly odoriferous and unstable. Ajoenes are the self-condensation products of allicin and appear to be responsible for garlic’s antithrombotic action. It is generally considered that allicin and its derivatives are the active constituents of garlic’s physiological activity. Dried garlic preparations lack allicin but contain both allinin and allinase. Since allinase is inactivated in the stomach, dried garlic preparations should have enteric coating so they pass unaltered through the stomach to the small intestine where allinin is enzymatically converted to allicin. Only few commercially available garlic preparations are standardised for their yield of allicin based on the allinin content [141].

The consumption of large quantities of fresh garlic (0.25 to 1.0 g/kg or about 5–20 average sized 4 g cloves) has been shown to produce certain beneficial effects [142]. In support of this, a recent double-blind, cross-over study in moderately hypercholesterolemic men comparing the effects of 7.2 g of aged garlic extract with placebo on blood lipid levels found a maximal reduction of 6.1% in total serum cholesterol levels and 4.6% in LDL cholesterol levels with garlic compared with placebo [143]. However, despite positive evidence from a number of trials, full endorsement of garlic for CVD is not forthcoming and many published studies have methodological shortcomings [142, 144149]. Some of the problems were that trials were small, they lacked statistical power, they had inappropriate methods of randomization, they lacked dietary run-in periods, they were of short duration, or they failed to undertake intention-to-treat analysis. This has led to a cautious approach in the interpretation of previous meta-analyses [147]. One recent meta-analysis found that garlic reduces total cholesterol to a modest extent, an effect driven mostly by the modest reductions in triglycerides and there was no appreciable effect on LDL or HDL cholesterol [150].

Garlic has also been studied in hypertension, with no conclusive result [151]. A meta-analysis of 8 trials suggested some clinical value in patients with mild hypertension, but the evidence was insufficiently good to commend garlic for routine clinical therapy [149]. Garlic has been shown to have antiplatelet stickiness activity. This has been documented in vitro [152], and a new study examined the effect of consuming a clove of fresh garlic on platelet thromboxane production. After 26 weeks, serum thromboxane levels were reduced by about 80% [153]. Thus it may prove to be of benefit in the prevention of thrombosis. Another trial showed that long-term intake of 300 mg daily of standardised garlic powder for more than 2 years improved the elastic properties of the aorta [154]. In these ways garlic has shown several benefits to cardiovascular health and needs further study. Moderate garlic consumption causes few adverse effects other than bad odour. However, with more than 5 cloves daily, heartburn, flatulence, and other gastrointestinal disturbances have been reported. Allergic contact dermatitis has occurred, and patch testing is available when garlic allergy is suspected [155]. Due to its antithrombotic activity, garlic should be taken with caution in people on oral anticoagulants [156].

3. Research Needs

The clinical studies reviewed above are generally not supportive of the use of supplements of these food constituents although guidelines generally recommend increasing intake of fruits and vegetables which are rich in some of these materials. Omega-3 poly-unsaturated fatty acids may be one exception where supplements appear to be useful in people with established CHD. With the other dietary constituents which may have benefits in the prevention or treatment of CVD, the evidence from intervention trials is mostly not sufficient to support any definitive recommendations. Many of the trials have been too small, and different trials have often used different supplements with variable composition so the meta-analyses of such interventions may not always be considering the same active compounds. Many of these food substances do have ingredients with demonstrable pharmacological effects, but larger clinical trials with properly standardized materials are needed before any clear conclusions can be drawn. In addition, the potential interaction of some chemical components, especially flavonoids, with conventional drugs through mechanisms such as modulating ABC transporter expression may affect the absorption, distribution, and excretion of drugs. For instance, catechins, found in tea and red wine, may alternatively inhibit or enhance P-glycoprotein (ABCB1) function [157], and some of these compounds such as quercetin found in tea and red wine are substrates of P-glycoprotein [158]. These interactions could improve absorption of poorly absorbed drugs, but they could also lead to drug intoxication and interfere with drug excretion process so it is important to consider potential drug interactions if large doses of these materials are given as supplements.

4. Conclusions

Several common food constituents are thought to influence the development and progression of CVD, and this is supported by evidence of potentially beneficial biological actions and analyses from some observational studies. However, the evidence of beneficial effects in studies involving supplementation is generally inconclusive, apart from the use of omega-3 PUFA in patients with established CAD. Furthermore, excessive intake of some of the components which may be taken with these items, such as alcohol, saturated fat, and glucose, is likely to have harmful effects which may offset any benefit from the other active ingredients. Until more definitive results become available, the best approach is to recommend a well-balanced diet that includes adequate fruit and vegetables with moderate amounts of the food constituents discussed here. A summary of recommended lifestyle advice for primary and secondary prevention based on CVD risk groups is showed in Table 4. It is important to recognize that the current worldwide epidemic of obesity, diabetes and resulting CVD is related to excessive intake of calories and animal fats along with reduced physical activity and supplementation with any additional beneficial food material is unlikely to overcome these problems unless the underlying causes are addressed directly.

tab4
Table 4: Summary of recommended lifestyle advice based on cardiovascular risk groups.

Conflict of Interests

The authors have no conflict of interests in relation to this paper.

References

  1. S. Yusuf, S. Hawken, S. Ôunpuu et al., “Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study,” Lancet, vol. 364, no. 9438, pp. 937–952, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. S. T. Chen, N. M. Maruthur, and L. J. Appel, “The effect of dietary patterns on estimated coronary heart disease risk results from the dietary approaches to stop hypertension trial,” Circulation: Cardiovascular Quality and Outcomes, vol. 3, no. 5, pp. 484–489, 2010. View at Publisher · View at Google Scholar · View at PubMed
  3. “State-specific trends in fruit and vegetable consumption among adults—United States, 2000–2009,” Morbidity and Mortality Weekly Report, vol. 59, no. 35, pp. 1125–1130, 2010.
  4. P. Di Mascio, S. Kaiser, and H. Sies, “Lycopene as the most efficient biological carotenoid singlet oxygen quencher,” Archives of Biochemistry and Biophysics, vol. 274, no. 2, pp. 532–538, 1989. View at Scopus
  5. A. Bub, B. Watzl, L. Abrahamse et al., “Moderate intervention with carotenoid-rich vegetable products reduces lipid peroxidation in men,” Journal of Nutrition, vol. 130, no. 9, pp. 2200–2206, 2000. View at Scopus
  6. S. Agarwal and A. V. Rao, “Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study,” Lipids, vol. 33, no. 10, pp. 981–984, 1998. View at Scopus
  7. E. R. Greenberg, J. A. Baron, M. R. Karagas et al., “Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation,” Journal of the American Medical Association, vol. 275, no. 9, pp. 699–703, 1996. View at Publisher · View at Google Scholar · View at Scopus
  8. K. F. Gey and P. Puska, “Plasma vitamins E and A inversely correlated to mortality from ischemic heart disease in cross-cultural epidemiology,” Annals of the New York Academy of Sciences, vol. 570, pp. 268–282, 1989. View at Scopus
  9. A. F. M. Kardinaal, F. J. Kok, J. Ringstad et al., “Antioxidants in adipose tissue and risk of myocardial infarction: the EURAMIC study,” Lancet, vol. 342, no. 8884, pp. 1379–1384, 1993. View at Publisher · View at Google Scholar · View at Scopus
  10. A. Tavani, E. Negri, B. D'Avanzo, and C. La Vecchia, “Beta-carotene intake and risk of nonfatal acute myocardial infarction in women,” European Journal of Epidemiology, vol. 13, no. 6, pp. 631–637, 1997. View at Publisher · View at Google Scholar · View at Scopus
  11. K. Klipstein-Grobusch, J. M. Geleijnse, J. H. den Breeijen et al., “Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam study,” American Journal of Clinical Nutrition, vol. 69, no. 2, pp. 261–266, 1999. View at Scopus
  12. E. B. Rimm, M. J. Stampfer, A. Ascherio, E. Giovannucci, G. A. Colditz, and W. C. Willett, “Vitamin E consumption and the risk of coronary heart disease in men,” New England Journal of Medicine, vol. 328, no. 20, pp. 1450–1456, 1993. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. Heart Protection Study Collaborative Group, “MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial,” Lancet, vol. 360, no. 9326, pp. 23–33, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. J. M. Rapola, J. Virtamo, S. Ripatti et al., “Randomised trial of α-tocopherol and β-carotene supplements on incidence of major coronary events in men with previous myocardial infarction,” Lancet, vol. 349, no. 9067, pp. 1715–1720, 1997. View at Publisher · View at Google Scholar · View at Scopus
  15. N. R. Cook, C. M. Albert, J. M. Gaziano et al., “A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the women's antioxidant cardiovascular study,” Archives of Internal Medicine, vol. 167, no. 15, pp. 1610–1618, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. S. Liu, I. M. Lee, U. Ajani, S. R. Cole, J. E. Buring, and J. E. Manson, “Intake of vegetables rich in carotenoids and risk of coronary heart disease in men: the physicians' health study,” International Journal of Epidemiology, vol. 30, no. 1, pp. 130–135, 2001. View at Scopus
  17. C. H. Hennekens, J. E. Buring, J. E. Manson et al., “Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease,” New England Journal of Medicine, vol. 334, no. 18, pp. 1145–1149, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. N. J. Miller, J. Sampson, L. P. Candeias, P. M. Bramley, and C. A. Rice-Evans, “Antioxidant activities of carotenes and xanthophylls,” FEBS Letters, vol. 384, no. 3, pp. 240–242, 1996. View at Publisher · View at Google Scholar · View at Scopus
  19. A. V. Rao and S. Agarwal, “Role of antioxidant lycopene in cancer and heart disease,” Journal of the American College of Nutrition, vol. 19, no. 5, pp. 563–569, 2000. View at Scopus
  20. L. Kohlmeier, J. D. Kark, E. Gomez-Gracia et al., “Lycopene and myocardial infarction risk in the EURAMIC study,” American Journal of Epidemiology, vol. 146, no. 8, pp. 618–626, 1997. View at Scopus
  21. T. H. Rissanen, S. Voutilainen, K. Nyyssönen, R. Salonen, G. A. Kaplan, and J. T. Salonen, “Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study,” American Journal of Clinical Nutrition, vol. 77, no. 1, pp. 133–138, 2003. View at Scopus
  22. H. D. Sesso, J. E. Buring, E. P. Norkus, and J. M. Gaziano, “Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men,” American Journal of Clinical Nutrition, vol. 81, no. 5, pp. 990–997, 2005. View at Scopus
  23. G. Riccioni, B. Mancini, E. Di Ilio, T. Bucciarelli, and N. D'Orazio, “Protective effect of lycopene in cardiovascular disease,” European Review for Medical and Pharmacological Sciences, vol. 12, no. 3, pp. 183–190, 2008. View at Scopus
  24. S. Blankenberg, H. J. Rupprecht, C. Bickel et al., “Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease,” New England Journal of Medicine, vol. 349, no. 17, pp. 1605–1613, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. H. Shimizu, Y. Kiyohara, I. Kato et al., “Relationship between plasma glutathione levels and cardiovascular disease in a defined population: the Hisayama study,” Stroke, vol. 35, no. 9, pp. 2072–2077, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. N. K. Hollenberg, N. D. Fisher, and M. L. McCullough, “Flavanols, the Kuna, cocoa consumption, and nitric oxide,” Journal of the American Society of Hypertension, vol. 3, no. 2, pp. 105–112, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. J. F. Hammerstone, S. A. Lazarus, A. E. Mitchell, R. Rucker, and H. H. Schmitz, “Identification of procyanidins in cocoa (Theobroma cacao) and chocolate using high-performance liquid chromatography/mass spectrometry,” Journal of Agricultural and Food Chemistry, vol. 47, no. 2, pp. 490–496, 1999. View at Publisher · View at Google Scholar · View at Scopus
  28. C. Manach, A. Scalbert, C. Morand, C. Rémésy, and L. Jiménez, “Polyphenols: food sources and bioavailability,” American Journal of Clinical Nutrition, vol. 79, no. 5, pp. 727–747, 2004. View at Scopus
  29. B. Buijsse, C. Weikert, D. Drogan, M. Bergmann, and H. Boeing, “Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults,” European Heart Journal, vol. 31, no. 13, pp. 1616–1623, 2010. View at Publisher · View at Google Scholar · View at PubMed
  30. I. Janszky, K. J. Mukamal, R. Ljung, S. Ahnve, A. Ahlbom, and J. Hallqvist, “Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program,” Journal of Internal Medicine, vol. 266, no. 3, pp. 248–257, 2009. View at Publisher · View at Google Scholar
  31. E. Mostofsky, E. B. Levitan, A. Wolk, and M. A. Mittleman, “Chocolate intake and incidence of heart failure a population-based prospective study of middle-aged and elderly women,” Circulation: Heart Failure, vol. 3, no. 5, pp. 612–616, 2010. View at Publisher · View at Google Scholar · View at PubMed
  32. S. Kuriyama, T. Shimazu, K. Ohmori et al., “Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study,” Journal of the American Medical Association, vol. 296, no. 10, pp. 1255–1265, 2006. View at Publisher · View at Google Scholar · View at PubMed
  33. K. Nakachi, S. Matsuyama, S. Miyake, M. Suganuma, and K. Imai, “Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention,” BioFactors, vol. 13, no. 1–4, pp. 49–54, 2000.
  34. N. Tanabe, H. Suzuki, Y. Aizawa, and N. Seki, “Consumption of green and roasted teas and the risk of stroke incidence: results from the Tokamachi-Nakasato cohort study in Japan,” International Journal of Epidemiology, vol. 37, no. 5, pp. 1030–1040, 2008. View at Publisher · View at Google Scholar · View at PubMed
  35. Y. C. Yang, F. H. Lu, J. S. Wu, C. H. Wu, and C. J. Chang, “The protective effect of habitual tea consumption on hypertension,” Archives of Internal Medicine, vol. 164, no. 14, pp. 1534–1540, 2004. View at Publisher · View at Google Scholar · View at PubMed
  36. M. Gronbaek, A. Deis, T. I. A. Sorensen, U. Becker, P. Schnohr, and G. Jensen, “Mortality associated with moderate intakes of wine, beer, or spirits,” British Medical Journal, vol. 310, no. 6988, pp. 1165–1169, 1995.
  37. R. di Giuseppe, A. Di Castelnuovo, F. Centritto et al., “Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy italian population,” Journal of Nutrition, vol. 138, no. 10, pp. 1939–1945, 2008.
  38. Y. Steffen, T. Schewe, and H. Sies, “(-)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase,” Biochemical and Biophysical Research Communications, vol. 359, no. 3, pp. 828–833, 2007. View at Publisher · View at Google Scholar · View at PubMed
  39. M. Karim, K. McCormick, and C. T. Kappagoda, “Effects of cocoa extracts on endothelium-dependent relaxation,” Journal of Nutrition, vol. 130, no. 8, pp. 2105S–2108S, 2000.
  40. O. Schnorr, T. Brossette, T. Y. Momma et al., “Cocoa flavanols lower vascular arginase activity in human endothelial cells in vitro and in erythrocytes in vivo,” Archives of Biochemistry and Biophysics, vol. 476, no. 2, pp. 211–215, 2008. View at Publisher · View at Google Scholar · View at PubMed
  41. M. A. Creager, S. J. Gallagher, X. J. Girerd, S. M. Coleman, V. J. Dzau, and J. P. Cooke, “L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans,” Journal of Clinical Investigation, vol. 90, no. 4, pp. 1248–1253, 1992.
  42. M. R. Adams, R. McCredie, W. Jessup, J. Robinson, D. Sullivan, and D. S. Celermajer, “Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease,” Atherosclerosis, vol. 129, no. 2, pp. 261–269, 1997. View at Publisher · View at Google Scholar
  43. C. Heiss, D. Finis, P. Kleinbongard et al., “Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week,” Journal of Cardiovascular Pharmacology, vol. 49, no. 2, pp. 74–80, 2007. View at Publisher · View at Google Scholar · View at PubMed
  44. A. J. Flammer, F. Hermann, I. Sudano et al., “Dark chocolate improves coronary vasomotion and reduces platelet reactivity,” Circulation, vol. 116, no. 21, pp. 2376–2382, 2007. View at Publisher · View at Google Scholar · View at PubMed
  45. S. Desch, J. Schmidt, D. Kobler et al., “Effect of cocoa products on blood pressure: systematic review and meta-analysis,” American Journal of Hypertension, vol. 23, no. 1, pp. 97–103, 2010. View at Publisher · View at Google Scholar · View at PubMed
  46. L. Hooper, P. A. Kroon, E. B. Rimm et al., “Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials,” American Journal of Clinical Nutrition, vol. 88, no. 1, pp. 38–50, 2008.
  47. R. R. Holt, D. D. Schramm, C. L. Keen, S. A. Lazarus, and H. H. Schmitz, “Chocolate consumption and platelet function,” Journal of the American Medical Association, vol. 287, no. 17, pp. 2212–2213, 2002.
  48. D. A. Pearson, T. G. Paglieroni, D. Rein et al., “The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function,” Thrombosis Research, vol. 106, no. 4-5, pp. 191–197, 2002. View at Publisher · View at Google Scholar
  49. R. Mehrinfar and W. H. Frishman, “Flavanol-rich cocoa: a cardioprotective nutraceutical,” Cardiology in Review, vol. 16, no. 3, pp. 109–115, 2008. View at Publisher · View at Google Scholar · View at PubMed
  50. J. B. Paquay, G. R. Haenen, G. Stender, S. A. Wiseman, L. B. Tijburg, and A. Bast, “Protection against nitric oxide toxicity by tea,” Journal of Agricultural and Food Chemistry, vol. 48, no. 11, pp. 5768–5772, 2000. View at Publisher · View at Google Scholar
  51. Y. L. Lin and J. K. Lin, “(-)-epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-κB,” Molecular Pharmacology, vol. 52, no. 3, pp. 465–472, 1997.
  52. K. Takano, K. Nakaima, M. Nitta, F. Shibata, and H. Nakagawa, “Inhibitory effect of (-)-epigallocatechin 3-gallate, a polyphenol of green tea, on neutrophil chemotaxis in vitro and in vivo,” Journal of Agricultural and Food Chemistry, vol. 52, no. 14, pp. 4571–4576, 2004. View at Publisher · View at Google Scholar · View at PubMed
  53. A. Ludwig, M. Lorenz, N. Grimbo et al., “The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells,” Biochemical and Biophysical Research Communications, vol. 316, no. 3, pp. 659–665, 2004. View at Publisher · View at Google Scholar · View at PubMed
  54. K. Kawai, N. H. Tsuno, J. Kitayama et al., “Epigallocatechin gallate induces apoptosis of monocytes,” Journal of Allergy and Clinical Immunology, vol. 115, no. 1, pp. 186–191, 2005. View at Publisher · View at Google Scholar · View at PubMed
  55. S. I. Koo and S. K. Noh, “Green tea as inhibitor of the intestinal absorption of lipids: potential mechanism for its lipid-lowering effect,” Journal of Nutritional Biochemistry, vol. 18, no. 3, pp. 179–183, 2007. View at Publisher · View at Google Scholar · View at PubMed
  56. W. S. Kang, I. H. Lim, D. Y. Yuk et al., “Antithrombotic activities of green tea catechins and (-)-epigallocatechin gallate,” Thrombosis Research, vol. 96, no. 3, pp. 229–237, 1999. View at Publisher · View at Google Scholar
  57. P. T. Chan, W. P. Fong, Y. L. Cheung, Y. Huang, W. K. Ho, and Z. Y. Chen, “Jasmine green tea epicatechins are hypolipidemic in hamsters (Mesocricetus auratus) fed a high fat diet,” Journal of Nutrition, vol. 129, no. 6, pp. 1094–1101, 1999.
  58. A. Sachinidis, R. A. Skach, C. Seul et al., “Inhibition of the PDGF beta-receptor tyrosine phosphorylation and its downstream intracellular signal transduction pathway in rat and human vascular smooth muscle cells by different catechins,” The FASEB Journal, vol. 16, no. 8, pp. 893–895, 2002.
  59. L. Arab, W. Liu, and D. Elashoff, “Green and black tea consumption and risk of stroke: a meta-analysis,” Stroke, vol. 40, no. 5, pp. 1786–1792, 2009. View at Publisher · View at Google Scholar · View at PubMed
  60. N. Iwai, H. Ohshiro, Y. Kurozawa et al., “Relationship between coffee and green tea consumption and all-cause mortality in a cohort of a rural Japanese population,” Journal of Epidemiology, vol. 12, no. 3, pp. 191–198, 2002.
  61. S. Kuriyama, “The relation between green tea consumption and cardiovascular disease as evidenced by epidemiological studies,” Journal of Nutrition, vol. 138, no. 8, pp. 1548S–1553S, 2008.
  62. N. Alexopoulos, C. Vlachopoulos, K. Aznaouridis et al., “The acute effect of green tea consumption on endothelial function in healthy individuals,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 15, no. 3, pp. 300–305, 2008. View at Publisher · View at Google Scholar · View at PubMed
  63. C. Vlachopoulos, N. Alexopoulos, I. Dima, K. Aznaouridis, I. Andreadou, and C. Stefanadis, “Acute effect of black and green tea on aortic stiffness and wave reflections,” Journal of the American College of Nutrition, vol. 25, no. 3, pp. 216–223, 2006.
  64. J. M. Hodgson, I. B. Puddey, V. Burke, L. J. Beilin, and N. Jordan, “Effects on blood pressure of drinking green and black tea,” Journal of Hypertension, vol. 17, no. 4, pp. 457–463, 1999. View at Publisher · View at Google Scholar
  65. J. M. Hodgson, A. Devine, I. B. Puddey, S. Y. Chan, L. J. Beilin, and R. L. Prince, “Tea intake is inversely related to blood pressure in older women,” Journal of Nutrition, vol. 133, no. 9, pp. 2883–2886, 2003.
  66. K. Wakabayashi, S. Kono, K. Shinchi et al., “Habitual coffee consumption and blood pressure: a study of self-defense officials in Japan,” European Journal of Epidemiology, vol. 14, no. 7, pp. 669–673, 1998. View at Publisher · View at Google Scholar
  67. S. Tokunaga, I. R. White, C. Frost et al., “Green tea consumption and serum lipids and lipoproteins in a population of healthy workers in Japan,” Annals of Epidemiology, vol. 12, no. 3, pp. 157–165, 2002. View at Publisher · View at Google Scholar
  68. T. Matsuyama, Y. Tanaka, I. Kamimaki, T. Nagao, and I. Tokimitsu, “Catechin safely improved higher levels of fatness, blood pressure, and cholesterol in children,” Obesity, vol. 16, no. 6, pp. 1338–1348, 2008. View at Publisher · View at Google Scholar · View at PubMed
  69. M. P. Nantz, C. A. Rowe, J. F. Bukowski, and S. S. Percival, “Standardized capsule of Camellia sinensis lowers cardiovascular risk factors in a randomized, double-blind, placebo-controlled study,” Nutrition, vol. 25, no. 2, pp. 147–154, 2009. View at Publisher · View at Google Scholar · View at PubMed
  70. S. Inami, M. Takano, M. Yamamoto et al., “Tea catechin consumption reduces circulating oxidized low-density lipoprotein,” International Heart Journal, vol. 48, no. 6, pp. 725–732, 2007. View at Publisher · View at Google Scholar
  71. D. Erba, P. Riso, A. Bordoni, P. Foti, P. L. Biagi, and G. Testolin, “Effectiveness of moderate green tea consumption on antioxidative status and plasma lipid profile in humans,” Journal of Nutritional Biochemistry, vol. 16, no. 3, pp. 144–149, 2005. View at Publisher · View at Google Scholar · View at PubMed
  72. S. J. Duffy, J. F. Keaney Jr., M. Holbrook et al., “Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease,” Circulation, vol. 104, no. 2, pp. 151–156, 2001.
  73. S. J. Duffy, J. A. Vita, M. Holbrook, P. L. Swerdloff, and J. F. Keaney Jr., “Effect of acute and chronic tea consumption on platelet aggregation in patients with coronary artery disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 6, pp. 1084–1089, 2001.
  74. M. Lorenz, J. Urban, U. Engelhardt, G. Baumann, K. Stangl, and V. Stangl, “Green and black tea are equally potent stimuli of NO production and vasodilation: new insights into tea ingredients involved,” Basic Research in Cardiology, vol. 104, no. 1, pp. 100–110, 2009. View at Publisher · View at Google Scholar · View at PubMed
  75. S. M. Henning, C. Fajardo-Lira, H. W. Lee, A. A. Youssefian, V. L. W. Go, and D. Heber, “Catechin content of 18 teas and a green tea extract supplement correlates with the antioxidant capacity,” Nutrition and Cancer, vol. 45, no. 2, pp. 226–235, 2003.
  76. L. K. Leung, Y. Su, R. Chen, Z. Zhang, Y. Huang, and Z. Y. Chen, “Theaflavins in black tea and catechins in green tea are equally effective antioxidants,” Journal of Nutrition, vol. 131, no. 9, pp. 2248–2251, 2001.
  77. H. D. Sesso, R. S. Paffenbarger, Y. Oguma, and I. M. Lee, “Lack of association between tea and cardiovascular disease in college alumni,” International Journal of Epidemiology, vol. 32, no. 4, pp. 527–533, 2003. View at Publisher · View at Google Scholar
  78. Y. Mineharu, A. Koizumi, Y. Wada et al., “Coffee, green tea, black tea and oolong tea consumption and risk of mortality from cardiovascular disease in Japanese men and women,” Journal of Epidemiology and Community Health, vol. 65, no. 3, pp. 230–240, 2011. View at Publisher · View at Google Scholar · View at PubMed
  79. M. G. Hertog, E. J. Feskens, P. C. Hollman, M. B. Katan, and D. Kromhout, “Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly study,” Lancet, vol. 342, no. 8878, pp. 1007–1011, 1993. View at Publisher · View at Google Scholar
  80. J. Ferrières, “The French paradox: lessons for other countries,” Heart, vol. 90, no. 1, pp. 107–111, 2004.
  81. M. F. Ullah and M. W. Khan, “Food as medicine: potential therapeutic tendencies of plant derived polyphenolic compounds,” Asian Pacific Journal of Cancer Prevention, vol. 9, no. 2, pp. 187–195, 2008.
  82. A. L. Waterhouse, “Wine phenolics,” Annals of the New York Academy of Sciences, vol. 957, pp. 21–36, 2002.
  83. S. Maxwell, A. Cruickshank, and G. Thorpe, “Red wine and antioxidant activity in serum,” Lancet, vol. 344, no. 8916, pp. 193–194, 1994.
  84. A. Di Castelnuovo, S. Rotondo, L. Iacoviello, M. B. Donati, and G. De Gaetano, “Meta-analysis of wine and beer consumption in relation to vascular risk,” Circulation, vol. 105, no. 24, pp. 2836–2844, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. A. S. Hansen, P. Marckmann, L. O. Dragsted, I. L. Finné Nielsen, S. E. Nielsen, and M. Grønbæk, “Effect of red wine and red grape extract on blood lipids, haemostatic factors, and other risk factors for cardiovascular disease,” European Journal of Clinical Nutrition, vol. 59, no. 3, pp. 449–455, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. K. N. Karatzi, C. M. Papamichael, E. N. Karatzis et al., “Red wine acutely induces favorable effects on wave reflections and central pressures in coronary artery disease patients,” American Journal of Hypertension, vol. 18, no. 9, part 1, pp. 1161–1167, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. M. Hashimoto, S. Kim, M. Eto et al., “Effect of acute intake of red wine on flow-mediated vasodilatation of the brachial artery,” American Journal of Cardiology, vol. 88, no. 12, article A1459, pp. 1457–1460, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Agewall, S. Wright, R. N. Doughty, G. A. Whalley, M. Duxbury, and N. Sharpe, “Does a glass of red wine improve endothelial function?” European Heart Journal, vol. 21, no. 1, pp. 74–78, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. A. van de Wiel and D. W. de Lange, “Cardiovascular risk is more related to drinking pattern than to the type of alcoholic drinks,” Netherlands Journal of Medicine, vol. 66, no. 11, pp. 467–473, 2008. View at Scopus
  90. K. J. Mukamal, K. M. Conigrave, M. A. Mittleman et al., “Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men,” New England Journal of Medicine, vol. 348, no. 2, pp. 109–118, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. R. Hattori, H. Otani, N. Maulik, and D. K. Das, “Pharmacological preconditioning with resveratrol: role of nitric oxide,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 282, no. 6, pp. H1988–H1995, 2002. View at Scopus
  92. L. Frémont, L. Belguendouz, and S. Delpal, “Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids,” Life Sciences, vol. 64, no. 26, pp. 2511–2521, 1999. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Zou, Y. Huang, Q. Chen, E. Wei, K. Cao, and J. M. Wu, “Effects of resveratrol on oxidative modification of human low density lipoprotein,” Chinese Medical Journal, vol. 113, no. 2, pp. 99–102, 2000. View at Scopus
  94. S. E. Chow, Y. C. Hshu, J. S. Wang, and J. K. Chen, “Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages,” Journal of Applied Physiology, vol. 102, no. 4, pp. 1520–1527, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. S. Das and D. K. Das, “Anti-inflammatory responses of resveratrol,” Inflammation and Allergy—Drug Targets, vol. 6, no. 3, pp. 168–173, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. Z. Ungvari, N. Labinskyy, P. Mukhopadhyay et al., “Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 297, no. 5, pp. H1876–H1881, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. L. M. Szewczuk, L. Forti, L. A. Stivala, and T. M. Penning, “Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic approach to the design of COX-1 selective agents,” Journal of Biological Chemistry, vol. 279, no. 21, pp. 22727–22737, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. S. Shigematsu, S. Ishida, M. Hara et al., “Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants,” Free Radical Biology and Medicine, vol. 34, no. 7, pp. 810–817, 2003. View at Publisher · View at Google Scholar · View at Scopus
  99. S. Das, V. K. Alagappan, D. Bagchi, H. S. Sharma, N. Maulik, and D. K. Das, “Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart,” Vascular Pharmacology, vol. 42, no. 5-6, pp. 281–289, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. P. Gresele, P. Pignatelli, G. Guglielmini et al., “Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production,” Journal of Nutrition, vol. 138, no. 9, pp. 1602–1608, 2008. View at Scopus
  101. T. Walle, F. Hsieh, M. H. DeLegge, J. E. Oatis, and U. K. Walle, “High absorption but very low bioavailability of oral resveratrol in humans,” Drug Metabolism and Disposition, vol. 32, no. 12, pp. 1377–1382, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. D. Bagchi, M. Bagchi, S. J. Stohs et al., “Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention,” Toxicology, vol. 148, no. 2-3, pp. 187–197, 2000. View at Publisher · View at Google Scholar · View at Scopus
  103. D. Bagchi, A. Garg, R. L. Krohn, et al., “Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice,” General Pharmacology, vol. 30, no. 5, pp. 771–776, 1998. View at Publisher · View at Google Scholar
  104. W. G. Li, X. Y. Zhang, Y. J. Wu, and X. Tian, “Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds,” Acta Pharmacologica Sinica, vol. 22, no. 12, pp. 1117–1120, 2001. View at Scopus
  105. F. Natella, F. Belelli, V. Gentili, F. Ursini, and C. Scaccini, “Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans,” Journal of Agricultural and Food Chemistry, vol. 50, no. 26, pp. 7720–7725, 2002. View at Publisher · View at Google Scholar · View at Scopus
  106. S. Egert, A. Bosy-Westphal, J. Seiberl et al., “Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study,” British Journal of Nutrition, vol. 102, no. 7, pp. 1065–1074, 2009. View at Publisher · View at Google Scholar · View at PubMed
  107. E. B. Rimm, M. B. Katan, A. Ascherio, M. J. Stampfer, and W. C. Willett, “Relation between intake of flavonoids and risk for coronary heart disease in male health professionals,” Annals of Internal Medicine, vol. 125, no. 5, pp. 384–389, 1996. View at Scopus
  108. J. Mursu, T. Nurmi, T. P. Tuomainen, A. Ruusunen, J. T. Salonen, and S. Voutilainen, “The intake of flavonoids and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study,” British Journal of Nutrition, vol. 98, no. 4, pp. 814–818, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  109. N. P. Riksen, G. A. Rongen, and P. Smits, “Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease,” Pharmacology and Therapeutics, vol. 121, no. 2, pp. 185–191, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  110. C. M. Papamichael, K. A. Aznaouridis, E. N. Karatzis et al., “Effect of coffee on endothelial function in healthy subjects: the role of caffeine,” Clinical Science, vol. 109, no. 1, pp. 55–60, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. M. C. Cornelis and A. El-Sohemy, “Coffee, caffeine, and coronary heart disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 10, no. 6, pp. 745–751, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. B. B. Fredholm, K. Bättig, J. Holmén, A. Nehlig, and E. E. Zvartau, “Actions of caffeine in the brain with special reference to factors that contribute to its widespread use,” Pharmacological Reviews, vol. 51, no. 1, pp. 83–133, 1999. View at Scopus
  113. R. Urgert and M. B. Katan, “The cholesterol-raising factor from coffee beans,” Annual Review of Nutrition, vol. 17, pp. 305–324, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  114. P. Verhoef, W. J. Pasman, T. Van Vliet, R. Urgert, and M. B. Katan, “Contribution of caffeine to the homocysteine-raising effect of coffee: a randomized controlled trial in humans,” American Journal of Clinical Nutrition, vol. 76, no. 6, pp. 1244–1248, 2002. View at Scopus
  115. M. A. Pereira, E. D. Parker, and A. R. Folsom, “Coffee consumption and risk of type 2 diabetes mellitus: an 11-year prospective study of 28 812 postmenopausal women,” Archives of Internal Medicine, vol. 166, no. 12, pp. 1311–1316, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. A. O. Odegaard, M. A. Pereira, W. P. Koh, K. Arakawa, H. P. Lee, and M. C. Yu, “Coffee, tea, and incident type 2 diabetes: the Singapore Chinese Health study,” American Journal of Clinical Nutrition, vol. 88, no. 4, pp. 979–985, 2008. View at Scopus
  117. M. C. Cornelis, A. El-Sohemy, E. K. Kabagambe, and H. Campos, “Coffee, CYP1A2 genotype, and risk of myocardial infarction,” Journal of the American Medical Association, vol. 295, no. 10, pp. 1135–1141, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  118. E. Lopez-Garcia, R. M. van Dam, T. Y. Li, F. Rodriguez-Artalejo, and F. B. Hu, “The relationship of coffee consumption with mortality,” Annals of Internal Medicine, vol. 148, no. 12, pp. 904–914, 2008. View at Scopus
  119. F. Valagussa, M. G. Franzosi, E. Geraci, et al., “Dietary supplementation with N-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial,” Lancet, vol. 354, no. 9177, pp. 447–455, 1999. View at Publisher · View at Google Scholar
  120. R. Marchioli, F. Barzi, E. Bomba et al., “Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione,” Circulation, vol. 105, no. 16, pp. 1897–1903, 2002. View at Publisher · View at Google Scholar
  121. M. Svensson, E. B. Schmidt, K. A. Jørgensen, and J. H. Christensen, “N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial,” Clinical Journal of the American Society of Nephrology, vol. 1, no. 4, pp. 780–786, 2006. View at Publisher · View at Google Scholar · View at PubMed
  122. L. Tavazzi, A. P. Maggioni, R. Marchioli, et al., “Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial,” Lancet, vol. 372, no. 9645, pp. 1223–1230, 2008.
  123. M. Yokoyama, H. Origasa, M. Matsuzaki et al., “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis,” Lancet, vol. 369, no. 9567, pp. 1090–1098, 2007. View at Publisher · View at Google Scholar · View at PubMed
  124. H. O. Bang, J. Dyerberg, and A. B. Nielsen, “Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos,” Lancet, vol. 1, no. 7710, pp. 1143–1145, 1971.
  125. J. L. Breslow, “n-3 Fatty acids and cardiovascular disease,” American Journal of Clinical Nutrition, vol. 83, no. 6, pp. 1477S–1482S, 2006.
  126. L. Hooper, R. L. Thompson, R. A. Harrison et al., “Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review,” British Medical Journal, vol. 332, no. 7544, pp. 752–760, 2006. View at Publisher · View at Google Scholar · View at PubMed
  127. K. He, “Fish, long-chain omega-3 polyunsaturated fatty acids and prevention ofcardiovascular disease—eat fish or take fish oil supplement?” Progress in Cardiovascular Diseases, vol. 52, no. 2, pp. 95–114, 2009. View at Publisher · View at Google Scholar · View at PubMed
  128. F. Thies, J. M. Garry, P. Yaqoob et al., “Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial,” Lancet, vol. 361, no. 9356, pp. 477–485, 2003. View at Publisher · View at Google Scholar · View at PubMed
  129. C. Wang, W. S. Harris, M. Chung et al., “n-3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review,” American Journal of Clinical Nutrition, vol. 84, no. 1, pp. 5–17, 2006.
  130. M. C. Morris, F. Sacks, and B. Rosner, “Does fish oil lower blood pressure? A meta-analysis of controlled trials,” Circulation, vol. 88, no. 2, pp. 523–533, 1993.
  131. G. D. Eslick, P. R. Howe, C. Smith, R. Priest, and A. Bensoussan, “Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis,” International Journal of Cardiology, vol. 136, no. 1, pp. 4–16, 2009. View at Publisher · View at Google Scholar · View at PubMed
  132. M. L. Burr, A. M. Fehily, J. F. Gilbert et al., “Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART),” Lancet, vol. 2, no. 8666, pp. 757–761, 1989.
  133. C. M. Albert, C. H. Hennekens, C. J. O'Donnell et al., “Fish consumption and risk of sudden cardiac death,” Journal of the American Medical Association, vol. 279, no. 1, pp. 23–28, 1998. View at Publisher · View at Google Scholar · View at Scopus
  134. C. M. Albert, H. Campos, M. J. Stampfer et al., “Blood levels of long-chain n-3 fatty acids and the risk of sudden death,” New England Journal of Medicine, vol. 346, no. 15, pp. 1113–1118, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  135. H. M. Den Ruijter, G. Berecki, T. Opthof, A. O. Verkerk, P. L. Zock, and R. Coronel, “Pro- and antiarrhythmic properties of a diet rich in fish oil,” Cardiovascular Research, vol. 73, no. 2, pp. 316–325, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  136. H. León, M. C. Shibata, S. Sivakumaran, M. Dorgan, T. Chatterley, and R. T. Tsuyuki, “Effect of fish oil on arrhythmias and mortality: systematic review,” British Medical Journal, vol. 337, p. a2931, 2008.
  137. L. J. Bjerregaard, A. M. Joensen, C. Dethlefsen et al., “Fish intake and acute coronary syndrome,” European Heart Journal, vol. 31, no. 1, pp. 29–34, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  138. T. A. Pearson, S. N. Blair, S. R. Daniels, et al., “AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American heart association science advisory and coordinating committee,” Circulation, vol. 106, no. 3, pp. 388–391, 2002.
  139. S. C. Smith Jr., J. Allen, S. N. Blair et al., “AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update—endorsed by the National Heart, Lung, and Blood Institute,” Circulation, vol. 113, no. 19, pp. 2363–2372, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  140. K. Rahman and G. M. Lowe, “Garlic and cardiovascular disease: a critical review,” Journal of Nutrition, vol. 136, no. 3, pp. 736S–740S, 2006.
  141. N. H. Mashour, G. I. Lin, and W. H. Frishman, “Herbal medicine for the treatment of cardiovascular disease: clinical considerations,” Archives of Internal Medicine, vol. 158, no. 20, pp. 2225–2234, 1998. View at Publisher · View at Google Scholar · View at Scopus
  142. J. Kleijnen, P. Knipschild, and G. ter Riet, “Garlic, onions and cardiovascular risk factors. A review of the evidence from human experiments with emphasis on commercially available preparations,” British Journal of Clinical Pharmacology, vol. 28, no. 5, pp. 535–544, 1989. View at Scopus
  143. M. Steiner, A. H. Khan, D. Holbert, and R. I. Lin, “A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids,” American Journal of Clinical Nutrition, vol. 64, no. 6, pp. 866–870, 1996. View at Scopus
  144. J. L. Isaacsohn, M. Moser, E. A. Stein et al., “Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial,” Archives of Internal Medicine, vol. 158, no. 11, pp. 1189–1194, 1998. View at Publisher · View at Google Scholar · View at Scopus
  145. A. K. Jain, R. Vargas, S. Gotzkowsky, and F. G. McMahon, “Can garlic reduce levels of serum lipids? A controlled clinical study,” American Journal of Medicine, vol. 94, no. 6, pp. 632–635, 1993. View at Publisher · View at Google Scholar · View at Scopus
  146. B. S. Kendler, “Garlic (Allium sativum) and onion (Allium cepa): a review of their relationship to cardiovascular disease,” Preventive Medicine, vol. 16, no. 5, pp. 670–685, 1987. View at Scopus
  147. H. A. Neil, C. A. Silagy, T. Lancaster et al., “Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysis,” Journal of the Royal College of Physicians of London, vol. 30, no. 4, pp. 329–334, 1996. View at Scopus
  148. C. Silagy and A. Neil, “Garlic as a lipid lowering agent—a meta-analysis,” Journal of the Royal College of Physicians of London, vol. 28, no. 1, pp. 39–45, 1994. View at Scopus
  149. C. A. Silagy and H. A. Neil, “A meta-analysis of the effect of garlic on blood pressure,” Journal of Hypertension, vol. 12, no. 4, pp. 463–468, 1994. View at Scopus
  150. K. M. Reinhart, R. Talati, C. M. White, and C. I. Coleman, “The impact of garlic on lipid parameters: a systematic review and meta-analysis,” Nutrition Research Reviews, vol. 22, no. 1, pp. 39–48, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  151. S. Simons, H. Wollersheim, and T. Thien, “A systematic review on the influence of trial quality on the effect of garlic on blood pressure,” Netherlands Journal of Medicine, vol. 67, no. 6, pp. 212–219, 2009. View at Scopus
  152. A. Bordia, S. K. Verma, and K. C. Srivastava, “Effect of garlic on platelet aggregation in humans: a study in healthy subjects and patients with coronary artery disease,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 55, no. 3, pp. 201–205, 1996. View at Publisher · View at Google Scholar
  153. M. Ali and M. Thomson, “Consumption of a garlic clove a day could be beneficial in preventing thrombosis,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 53, no. 3, pp. 211–212, 1995. View at Publisher · View at Google Scholar · View at Scopus
  154. K. Breithaupt-Grögler, M. Ling, H. Boudoulas, and G. G. Belz, “Protective effect of chronic garlic intake on elastic properties of aorta in the elderly,” Circulation, vol. 96, no. 8, pp. 2649–2655, 1997. View at Scopus
  155. T. A. Delaney and A. M. Donnelly, “Garlic dermatitis,” Australasian Journal of Dermatology, vol. 37, no. 2, pp. 109–110, 1996. View at Scopus
  156. K. D. Rose, P. D. Croissant, C. F. Parliament, and M. B. Levin, “Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report,” Neurosurgery, vol. 26, no. 5, pp. 880–882, 1990. View at Scopus
  157. E. J. Wang, M. Barecki-Roach, and W. W. Johnson, “Elevation of P-glycoprotein function by a catechin in green tea,” Biochemical and Biophysical Research Communications, vol. 297, no. 2, pp. 412–418, 2002. View at Publisher · View at Google Scholar · View at Scopus
  158. Y. Wang, J. Cao, and S. Zeng, “Involvement of P-glycoprotein in regulating cellular levels of Ginkgo flavonols: quercetin, kaempferol, and isorhamnetin,” Journal of Pharmacy and Pharmacology, vol. 57, no. 6, pp. 751–758, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  159. New Zealand Guidelines Group, New Zealand Cardiovascular Guidelines Handbook, 2005.