Cardiovascular Health

Cardiovascular Health

by HeatherGranato

It has been said that blood is life. As such, it is notsurprising that one of every 2.6 deaths is attributed to diseases of thecardiovascular system, with its responsibility for moving nutrients and oxygenthrough the body and removing waste products.

Cardiovascular disease (CVD) is not just one disease, but ahost of interrelated conditions affecting the heart, blood vessels and bloodcells. Degenerative conditions include atherosclerosis, congestiveheart failure (CHF), coronary heart disease (CHD) and hypertension (high bloodpressure). These are contributing factors to other acute events including strokeand myocardial infarction. It is estimated that one in five Americans has one ormore types of CVD, including 50 million with hypertension, 13.2 million with CHDand 5 million with CHF.

With such prevalence in the population, it is no wonder thatthe costs associated with CVD are staggering. In 2004, the estimated direct andindirect cost of CVD was $368.4 billion, according to the American HeartAssociation (AHA).

As with all disease prevention, ensuring a healthy lifestyleis critical. Researchers suggest incorporating regular physical activity,avoiding smoking, maintaining a healthy body weight and following a diet rich inwhole grains, fruits and vegetables, omega-3 essential fatty acids (EFAs) andunsaturated fats as the predominant form of dietary fat could prevent themajority of CVD in Western populations.¹ Such a diet has shown significantbenefits compared with the more predominant Western pattern dietcharacterized by high intakes of processed meats, eggs, red meats and high-fatdairy products; that Western diet appears to increase inflammation, insulin and glycated hemoglobin, raising CVD risk.²

In addition, consuming certain specialty foods appears tofurther lower the risk of CVD.The National Cholesterol Education Program and theAHA suggest the use of viscous fibers, plant sterols, soy protein and nuts; astudy in 46 hyperlipidemic adults found the combination reduced lowdensitylipoprotein (LDL or bad) cholesterol by 30 percent, significantly reducingCHD risk.³ In fact, the diet lowered LDL as effectively as the use of thepharmaceutical lovastatin. Similar results were reported in a study of 25hyperlipidemic subjects following the portfolio diet or a control, low saturatedfat diet.⁴ The portfolio diet reduced LDL by 35 percent and also significantlyimproved the ratio of LDL-to-HDL (high-density lipoprotein, the goodcholesterol that removes plaque from arteries).

Another well known diet for its cardiovascular benefits is theMediterranean diet, characterized by olive oil as the dominant fat source, ahigh consumption of fruit and vegetables, fiber, fish and legumes, plus winewith meals. Dutch researchers noted the Mediterranean diet is low in saturatedfat and high in monounsaturated fatty acids, antioxidants, fiber and folic acid,and intervention studies support the use of the diet to improve the coronaryrisk profile.⁵ In particular, data from the GISSIPrevenzione clinical trial,which included 11,323 men and women with myocardial infarction, found adherenceto a Mediterranean diet significantly reduced the risk of premature mortality.⁶

Researchers have also investigated the impact of addingcertain foods to the diet with the goal of reducing CVD risk. For example, nutsare drawing a great deal of interest of late for theirbeneficial effects. A review from the Bundaberg Specialist Centre in Australianoted 1 oz. of daily nut ingestion may reduce the risk of fatal CHD by 45percent when substituted for saturated fat, and by 30 percent when substitutedfor carbohydrate intake.⁷ The author pointed out nuts are a good source of arginine, vitamin E, folate, fiber, potassium, magnesium, tannins andpolyphenols, and may also have a satiating effect in the diet. Nuts fattyacid profile is also of interest, as most nuts are high in oleic acid, linoleicacid and linolenic acid, with additional phytosterols and tocopherols.⁸ Dietaryintervention studies have found the addition of peanuts (replacing an equalamount of other fat) reduces triacylglycerol and increases serum magnesiumlevels,⁹ while adding walnuts (in place of other dietary fat) to the diet of hypercholesterolemic subjects can reduce total and LDL cholesterol and improve endothelial function.¹⁰

Increasing the quantity of dietaryfiber also appears beneficial. Researchers from Tulane University in New Orleans investigatedthe relationship between total and soluble fiber intake and the risk of CHD andCVD in 9,776 adults over a 19-year follow up.¹¹ Compared with the lowestquartile of dietary fiber intake, participants in the highest quartile had a 12percent reduced risk of CHD and an 11 percent reduction in CVD events. Similarresults were reported from a population study of 3,588 older men and women, inwhich subjects in the highest quintile of cereal fiber intake had a 21 percentlower risk of incident CVD compared with those in the lowest quintile.¹² Cerealfiber intake was particularly associated with lower risk of stroke and ischemicheart disease death. A pooled analysis of cohort studies, which included datafrom 91,058 men and 245,186 women, found each 10 g/d increment of total dietaryfiber was associated with a 14 percent decrease in risk of all coronary events and a 27 percent decrease in risk of coronary death.¹³

The benefits of fiber intake led FDA to allow a health claimlinking higher intake of dietary fiber, particularly soluble fiber, to a reducedrisk of heart disease, as well as a separate claim on the relationship betweensoluble fiber from oats and psyllium seed and a reduced risk of heart disease. Oatsas a source of dietary fiber and the soluble fiber betaglucanhave been extensively studied for their benefit onheart health. Intervention studies have shown a hypocaloric diet containingoats significantly decreases cholesterol and lowers blood pressure compared to asimilar diet without oats,¹⁴ and may even improve blood pressure control to thepoint that patients can reduce the dosage of antihypertensive medications.¹⁵ Tothat end, researchers at Tulane recruited 110 subjects with untreated, buthigher than optimal blood pressure or stage 1 hypertension to receive 8 g/d ofwater-soluble fiber from oat bran or a control intervention.¹⁶ Three months of the fiberintervention had a moderate effect on both systolic and diastolic bloodpressure.

On the cholesterol side, oat bran and other sources of dietaryfiber appear to lower total and LDL cholesterol. A randomized study in 235 malepatients with hypercholesterolemia found the administration of a fatmodifieddiet with 35 g/d to 50 g/d of oat bran significantly decreased total and LDLcholesterol, as well as apolipoprotein B (apoB).¹⁷ And a study in 36 overweightmen who received oat or wheat cereal (each providing 14 g/d of dietary fiber),found only the oat diet produced lower concentrations of the moreatherosclerotic small, dense LDL and LDL particle number, while improving the HDL-to-LDL ratio.¹⁸

Another FDA health claim in the heart health arena linksconsumption of soy with hearthealth. Approved in 1999 after a petition from the Solae Co., the claim linksthe intake of 25 g/d of soy protein with a reduced risk of CHD. A review fromthe University of Illinois noted soy consumption appears to improve plasmalipids, reduce LDL oxidation and improve vascular reactivity.¹⁹ Further reviewssuggest the benefits of soy include its vegetable protein, high soluble fibercontent, absence of saturated fat with high levels of polyunsaturated fats, and major phytoestrogencontent.²⁰

A great deal of the initial work in the soy field was done inAsian populations, which generally have a much greater intake of soy foods thanWestern cultures. Researchers at Vanderbilt University examined the relationshipbetween soy food intake and incidence of CHD among 64,900 Chinese women participating in the Shanghai Womens HealthStudy.²¹ There was a dose-response relationship between soy food intakeand risk of total CHD, with an adjusted relative risk of 0.25 observed for womenin the highest versus the lowest quartile of total soy protein intake. A laterEuropean study in 1,033 pre- and postmenopausal women included 361nonvegetarians, 570 vegetarians and 102 vegans; soy protein intake was inverselyassociated with total and LDL cholesterol concentrations, and with the ratio of total-to-HDL cholesterol.²²

Intervention diet studies have found relatively positiveresults on CVD risk factors. A randomized, placebo-controlled crossover trialcomparing soy-based milk and yogurt with equivalent dairy products for fiveweeks each in 26 mildly hypercholesterolemic and/or hypertensive subjects foundsoy intake significantly improved total cholesterol and LDL cholesterol inequol-positive subjects.²³ Another study in 61 men with relatively higher bloodpressure and/or total cholesterol found 20 g/d of soy protein in the dietreduced both systolic and diastolic blood pressure and total cholesterol.²⁴ Anda three-month study comparing the impact of soy milk (500 mL twice daily) onblood pressure found chronic soy milk ingestion had modest but significanthypotensive action in hypertensive men and women.²⁵

Isolated soy protein has also netted good results. Researchersat the University of Illinois at Urbana-Champaign investigated the impact of 0.5g/kg/d isolated soy protein consumption on serum lipids in 14 Type II diabeticmen.²⁶ Over the course of the study, which included two eightweek interventionperiods and two four-week washout periods, isolated soy protein consumptionsignificantly improved the total-to-HDL ratio and HDL cholesterol levels.Another study found the use of 30 g/d or 50 g/d of isolated soy protein in 130subjects significantly reduced LDL cholesterol concentrations.²⁷ And when usedin place of animal protein in the diet of 42 subjects with moderatehypercholesterolemia, 25 g of soy protein appears to modestly reduce LDL andtotal cholesterol to more normal levels.²⁸

One pending question remains the significance of soys isoflavoneson cardiovascular risk factors. A recent Canadianstudy involved 20 hyperlipidemic subjects who underwent a four-phase,randomized, crossover trial using diets with isolated soy protein or animalprotein (25 g/1,000 kcal), with or without isoflavones.²⁹ Soy protein reducedtriglycerides by 12 percent, total cholesterol by 4 percent and LDL by 5 percentcompared to animal protein; isoflavones had no significant effect ontriglyceride, HDL or LDL levels, though there was a slight reduction in totalcholesterol associated with isoflavone intake. Another Canadian study involved41 hyperlipidemic men and women following three different diets for one montheach: low fat dairy (control), high-isoflavone (50 g soy protein with 73 mgisoflavones daily) and low-isoflavone (52 g soy protein and 10 mg isoflavonesdaily).³⁰ Both soy diets resulted in significantly lower total cholesterol andestimated CHD risk, and positive changes in the ratio of LDL-to-HDL cholesterol,with no significant differences between the isoflavone groups. However, ameta-analysis from Tokyo University of Agriculture involving eight studiescomparing high- and low-isoflavone comparisons found with identical soy proteinintake, higher levels of isoflavone led to greater decreases in LDL levels.³¹

This is supported by data from the Framingham Offspring Study,analyzed by researchers from the University Medical Center in Utrecht, TheNetherlands, who examined the association between dietary phytoestrogen intakeand metabolic CVD risk factors in 939 postmenopausal women.³² Higher intake of isoflavones and lignans were associated with lower triglyceride levels, as wellas a reduced cardiovascular risk factor metabolic score. Another review ofdietary phytoestrogen intake in 403 postmenopausal women found increasing isoflavone intake was associated with decreased aorticstiffness.³³

Animal research has suggested soy isoflavones may havespecific benefits in the cardiovascular system. An isoflavone-rich soysupplement provided to mice slightly mitigated the plasma cholesterol increasesassociated with adding cholesterol to the diet, and also appeared to keep plasmatriglycerides lower.³⁴ Soy isoflavones were also found in a diabetic rat modelto reduce the atherosclerotic index and inhibit lipid peroxidation compared tocontrol rats that did not receive added isoflavones.³⁵ Also, 5 mg/kg body weightof soy isoflavones caused significant decreases in the concentrations of freeradicals in the bodies of male New Zealand white rabbits, and decreased levelsof plasma total lipids, total cholesterol, triglycerides, LDL, very low-densitylipoprotein (VLDL) and the LDL-to-HDL ratio.³⁶

Isoflavones are not only consumed through soy. Supplementaldosages of red clover appearto have effects on plasma lipid levels as well. A 12-week, randomized, doubleblind, placebo-controlled trial in 252 menopausal women investigated the impactof two different red clover dietary supplements (Promensil, 82 mg totalisoflavones, and Rimostil, 57.2 mg total isoflavones) or placebo on lipids and boneturnover.³⁷ Women taking the red clover supplements had greater meanincreases in HDL cholesterol and a significant decrease in triglyceride levels.Another study using a supplement with 43.5 mg isoflavones or placebo in 177women found supplementation in perimenopausal women reduced triglycerides, totalcholesterol and LDL cholesterol, suggesting menopausal status may impactefficacy of the supplement.³⁸ However, red clover supplements may also benefitmen, as a study in 46 middle-aged men and 34 postmenopausal women foundadministration of 40 mg/d of red clover isoflavones for six weeks reduced LDL inthe men but not in the women.³⁹

Another source of dietary phytoestrogens as lignans is flaxseed.A review from the University of Pennsylvania, Philadelphia, noted flaxseed maymodestly reduce serum total and LDL cholesterol and decrease some markers ofinflammation.⁴⁰ Researchers from Oklahoma State University, Stillwater,investigated the impact of flaxseed on the prevention of ovariectomy-inducedrise in total cholesterol and atherosclerotic lesions in hamsters.⁴¹ Over fourmonths, the three doses of flaxseed (7.5 percent, 15 percent or 22.5 percent ofthe diet) significantly reduced the fatty acid streak area, and prevented the ovariectomy-induced rise in total cholesterol seen in the control animals. Thesame researchers investigated the impact of 40 g/d of ground flaxseed oncholesterol levelsin postmenopausal women not on hormone therapy.⁴²Flaxseed significantly lowered serum total cholesterol and non-HDL cholesterol.

In addition to its lignan component, flaxseed is a rich sourceof the omega-3 fatty acid alpha-linolenic acid (ALA),which may alter the generation of eicosanoids and procoagulant activity, andexert antiatherosclerotic and antiarrhythmic effects.⁴³ When fed to rats,flaxseed increases the serum levels of both ALA and the longer-chain eicosapentaenoicacid (EPA), which is produced through an enzymaticconversion of ALA.⁴⁴ Human studies have shown beneficial effects of ALA on CVDrisk factors. A study in 23 hypercholesterolemic subjects who received a controldiet or a diet high in ALA and linoleic acid found the high- ALA diet decreasedvascular cell adhesion molecule-1, inhibiting vascularinflammation and endothelial activation.⁴⁵ Similarly, hypercholesterolemic men and women who received amargarine enriched with ALA showed lower levels of C-reactive protein (CRP), amarker of inflammation, but did not prevent progression of atherosclerosis,hardening of the arteries that can lead to heart attack, compared to a control group.⁴⁶

However, there has been debate over the efficiency of theprocess by which the body converts ALA into the longer-chain omega-3s. Researchers from Pennsylvania State University, UniversityPark, noted conversion of ALA to EPA and docosahexaenoicacid (DHA) is inefficient, with less than 10 percentconversion to EPA and less than 5 percent to DHA.⁴⁷ A clinical trial in 150 hyperlipidemic subjects who received 0.8 g/d of EPA+DHA, 1.7g/d EPA+DHA, 4.5 g/d ALA, 9.5 g/d ALA or a control oil sought to determine thedifferent impacts of ALA and the longer-chain omega-3s.⁴⁸ The 1.7 g/d EPA+DHAintervention significantly reduced fasting triacylglycerols while the 9.5 g/dALA intervention increased the levels. The EPA+DHA intervention also increased ex vivo LDL oxidationsusceptibility compared to the ALA intervention.

Another consideration in the omega-3 puzzle is the balancebetween intake of omega-3s and omega-6s, including linoleic acid (LA). While LAregulates LDL metabolism and enhances its clearance, the omega-3s are criticalfor endothelial function and platelet sensitivity.⁴⁹

Recently, researchers from the University of Missouri-KansasCity proposed a new risk factor called the omega-3 index, which they suggest canindicate risk for CHD death.⁵⁰ The researchers proposed content of EPA and DHAin cardiac membranes is related to CHD mortality, and reviewed studies thatindicate an omega-3 index of greater than 8 percent, is associated with thehighest level of cardioprotection. Similarly, researchers from the University ofKuopio, Finland, found CHD patients with the highest proportions of omega-3s inserum lipids had the least incidence of early mortality related to myocardial infarction and stroke.⁵¹

The greatest attention in the area of omega-3s and CVD relatesto the role of fish oil,which is a rich source of preformed DHA and EPA. The original link betweenmarine omega-3 fatty acids and heart health came from observational studies ofJapanese and Eskimo populations, in which diets rich in fatty fish protectedagainst CHD. Population-based cohorts have examined fish intake and incidence ofcardiovascular events, including CHD, myocardial infarction and hypertension. Apopulation study in 4,815 adults assessed long-term fish intake, and foundconsumption of tuna or other broiled or baked fish was inversely related withincidence of atrial fibrillation, with risk inversely related to higherconsumption.⁵² Another study, this one in 229 postmenopausal women with CHD,found consumption of two or more servings of fish, or one or more servings of tuna or dark fish, significantly reduced progression ofatherosclerosis.⁵³ And a cohort study of 79,839 women in the Nurses HealthStudy found consumption of fish significantly reduced therisk of stroke, with women in the highest quintile of intake of long-chainomega-3s with a 28 percent reduced risk of stroke and a 33 percent reduced riskof thrombotic infarction compared with the lowest quintile.⁵⁴

These findings have led researchers to suggest marine-sourceomega-3 fatty acids protect against CHD through several mechanisms of action,including antiarrhythmic, antithrombotic, antiatherosclerotic andanti-inflammatory activities, lowering blood pressure, lowering triglycerideconcentrations and improving endothelial function.⁵⁵ To further the link, therehave been a host of intervention studies, in which patients have takenmarine-source omega-3 EFAs, and the risk of CVD was assessed. The best-known is possibly the GISSI-Prevenzione trial, inwhich 11,324 patients surviving recent myocardial infarction received eithermarine n-3 EFAs (1 g/d), 300 mg/d of vitamin E, both or neither, for 3.5years.⁵⁶ Treatment with omega-3s significantly lowered the risk ofoverall, cardiovascular and sudden death, as well as incidence of non-fatalmyocardial infarction and stroke. The findings led researchers to call forfurther study into the mechanism of action and efficacy of omega-3 EFAs.

In a recent study from the Royal Veterinary and AgriculturalUniversity in Frederiksberg, Denmark, researchers randomly assigned 79 healthymen to receive 12 g/d of fish oil, 33 g/d of fat from partially hydrogenated soyoil, or control fat (fats supplied by Pronova Biocare, Norway, and Aarhus Olie,Denmark).⁵⁷ After eight weeks, the trans fat group had decreases in HDL, whilethe n-3 EFAs decreased triglycerides and mean arterial blood pressure. Theimpact on atherosclerosis is unclear, as a trial in 171 patients with CHD taking1.65 g/d of omega-3s found no difference in progression of atherosclerosiscompared to placebo,⁵⁸ while a controlled trial in 170 patients awaiting carotid endarterectomy found fish oil supplementation enhanced the stability ofatherosclerotic plaques, possibly reducing CVD events.⁵⁹

Omega-3s have also been studied in the areas of inflammationand endothelial function. Contrasting results were found in two studiesinvestigating the impact of fish oil on CRP levels. A study in 88 older men andwomen found CRP levels were unchanged by 3.5 g/d of fish oil for 12 weekscompared to placebo;⁶⁰ however, a study in 30 healthy women on hormonereplacement who took 14 g/d of fish oil showed significantly decreased CRP andIL-6 levels, compared to women taking 14 g/d of safflower oil.⁶¹ Studies havealso shown the benefit of fish oil supplementation on reducing thrombingeneration⁶² and collagen aggregation,⁶³ and on enhancing endothelial function,even in healthy subjects.⁶⁴

Another beneficial fat is olive oil,which plays a key role in the Mediterranean diet. Olive oil contains high levelsof monounsaturated fatty acids as well as a host of phytochemicals. Spanishresearchers noted olive oil contains antioxidants that may protect againstperoxidation, while it can also decrease the plasmatic levels of LDL cholesteroland increase those of HDL cholesterol.⁶⁵ In addition, data from the Greek arm ofthe European Prospective Investigation into Cancer and Nutrition study foundolive oil had a beneficial effect on systolic and diastolic blood pressure.⁶⁶Similarly, a study in 31 hypertensive patients and 31 normotensive patientsfound diets enriched in virgin olive oil normalized systolic blood pressure inthe hypertensive patients.⁶⁷ And a study in 24 hypertensive patients,administration of an onion-olive oil maceration product significantly decreasedsystolic blood pressure and showed a trend toward decreasing diastolic blood pressure.⁶⁸

The oleic acid inolive oil further appears to interfere with the inflammatory response, asincorporation of oleic acid into cell lipids decreases expression of a number ofpro-inflammatory proteins associated with atherosclerosis.⁶⁹ A study inspontaneously hypertensive and Wistar-Kyoto rats compared the impact of a dietrich in virgin olive oil and a diet rich in high-oleic acid sunflower oil onvascular response and lipid composition.⁷⁰ Both oleic acid-rich diets decreasedcontraction of aortic rings; however, only the olive oil diet attenuated thevascular response, leading researchers to suggest the olive oil containsadditional beneficial compounds beyond the oleic acid, such as polyphenols.

These polyphenols inolive oil include hydroxytyrosol,which has been shown to be dose-dependently absorbed and increases the plasmaantioxidant capacity in animal studies.⁷¹ Isochromans isolated fromhydroxytyrosol have similarly been found to be effective free radical scavengersthat can inhibit platelet aggregation in vitro.⁷² Recent cell-free models on theantioxidant capacity of a combination of olive oil antioxidants (as OleaSelectfrom Indena) including both verbascoside and hydroxytyrosol (obtained through awater and ethanol extraction process) had greater free radical scavengingability compared to the individual constituents.

Olive oil also appears to work synergistically with theantioxidant polyphenols found in red wine,another beneficial component of the Mediterranean diet. Researchers from the CNRInstitute of Clinical Physiology in Lecce, Italy, found in studies usingendothelial cells that phytochemicals including oleuropein,hydroxytyrosol and resveratrol hadmarked antioxidant activity and reduced cell adhesion of the endothelium.⁷³Similarly, researchers from the Universite de Montpellier in France foundpolyphenols from grapes and grape seeds and olives showed strong activity against LDL oxidation.⁷⁴

On their own, red wine polyphenols appear to have powerfulantioxidant effects, strongly inhibiting LDL.⁷⁵ In an Italian study of 15 healthy volunteers, 250 mL of red wine was found to reduce theoxidative stress seen in plasma after a high fat meal.⁷⁶ Researchers from theUniversity of Western Australia, Perth, conducted a study of atherosclerosisprogression in apolipoprotein E-deficient mice, examining the impact of redwine.⁷⁷ While the supplementation to the high fat, high cholesterol diet had noimpact on lipid peroxidation, lipid deposition in the aorta was significantlyinhibited by the red wine, suggesting activity beyond just antioxidantability.Even dealcoholized red wine appears to contain the polyphenoliccompounds necessary to decrease atherosclerosis progression.⁷⁸

These polyphenols can also be delivered in grapeseed extract, where their antioxidant activitysignificantly reduces LDL oxidation.⁷⁹ In addition, phenolic-rich extracts fromgrape seeds were shown in an animal model to prevent the development of aorticatherosclerosis without impacting plasma antioxidant capacity.⁸⁰ A human studyconducted by the Free Radical Research Group in Rome found supplementing a mealrich in oxidizable lipids with grape seed proanthocyanidins prevented LDL from increased susceptibility to oxidation.⁸¹

Red wine polyphenols further have action in endothelial cells, increasing nitric oxide synthase expression, enhancingvasorelaxation.⁸² Researchers at the Dunedin School of Medicine, New Zealand,administered red and white wine with a light meal to 14 subjects with provenCHD, and found the wine improved nearly threefold flow-mediated dilation of thebrachial artery.⁸³ And in a study at Creighton University, Omaha, Neb.,researchers investigated the effects of grape seed extract (as ActiVin® fromSan Joaquin Valley) with and without niacin-bound chromium (as ChromeMate® fromInterHealth Nutraceuticals) on blood pressure in normotensive and hypertensiverats.⁸⁴ The compounds, both individually and in combination, significantlylowered systolic blood pressure in both types of rats.

Polyphenols are not the only type of flavonoidwith application in the heart health arena. In fact,more than 4,000 different flavonoids have been described, with ongoing researchinvestigating antioxidant potential and impact on CHD.⁸⁵ A review fromVanderbilt University Medical Center in Nashville, Tenn., noted flavonoidsappear to have several mechanisms by which they confer cardiovascularprotection, including inhibiting LDL oxidation, reducing thrombosis, improvingendothelial function and reducing inflammation.⁸⁶

Tea

is one of the most prevalent sources offlavonoids in the human diet, and researchers note tea drinkers appear to havelower risk of conditions such as CHD and stroke.⁸⁷ In evaluating the effect of ahigh intake of catechinstheprimary flavonoids in tea, researchers at the Dutch National Institute of PublicHealth and the Environment looked at data from a cohort study of 806 men.⁸⁸ Catechin intake was inversely associated with ischemic heart disease mortality,though not with stroke. And a Chinese study found in 203 patients who underwentcoronary angiography, those consuming green tea had a significantly lowerincidence of CHD.⁸⁹ In addition, a Taiwanese study in 1,507 subjects foundhabitual consumption of green or oolong tea for more than one year significantlyreduced the risk of developing hypertension; the risk was reduced by 65 percent in those who drank more than 600 mL/d ormore.⁹⁰

Teas flavonoids mechanisms of action have been suggestedto be functioning as direct and indirect antioxidants, improving the resistanceof lipoproteins to oxidation, while also inhibiting atherogenesis.⁹¹ A Chinesestudy using rat aortic vascular smooth muscle cells (VSMCs) found green teapolyphenols dose-dependently inhibited proliferation of the VSMCs in response tocholesterol administration.⁹² Another study, conducted in Berlin, found epigallocatechin-3-gallate(EGCG) reduced adhesion of leukocytes to the vascular endothelium.⁹³

Similar results were reported in animal studies. Researchersat the University of California, Los Angeles, evaluated the impact of EGCG onevolving and established atherosclerotic lesions in hypercholesterolemic mice.⁹⁴ EGCG treatment for 21 and 42 days increased antioxidant capacity in vasculartissue and circulation, and reduced evolving atherosclerotic plaque size by 55percent and 73 percent, respectively. However, there was no impact on established lesions. A studyfrom the University of Scranton, Pa., used a hamster model of atherosclerosis toinvestigate effects of long-term supplementation with green or black tea onatherosclerosis.⁹⁵ There was a dose-response effect by which both teas inhibiteddevelopment of atherosclerosis by 26 percent to 63 percent.

Another dietary source of these beneficial flavonoids is cocoa.A review from the University of California, San Francisco, suggested cocoaflavonoids may serve as antioxidants, improve endothelial function, lower bloodpressure and decrease platelet activation and function.⁹⁶ In a study of 30healthy volunteers in England who received 100 g/d of white, milk or darkchocolate, collagen-induced platelet aggregation was inhibited by darkchocolate, indicating a possible role in prevention of thrombus formation.⁹⁷ Inthe United States, a six-week study in 25 healthy subjects in Texas foundadministration of 36.9 g/d of a dark chocolate bar and 30.95 g/d of a cocoa drink lowered the oxidizability of LDLcholesterol;⁹⁸ similarly, a two-week study in California in 21 healthy adultswho consumed high-flavonoid or low-flavonoid dark chocolate bars found theflavonoid-rich chocolate improved endothelial function and increased plasma antioxidant concentrations.⁹⁹

Citrus

is another powerhouse of nutrients ofinterest in the cardiovascular area. A review from Indonesia noted citrus fruitscontain an array of bioactive compounds including vitamin C, beta-carotene,flavonoids and limonoids;¹⁰⁰ however, the quantity and quality of polyphenols, and their activity, varies depending on the typeof citrus.¹⁰¹ Studies in rabbits on a high cholesterol diet found thosereceiving supplementation with the citrus bioflavonoid naringinincreased plasma antioxidant capacity similar to that of twocholesterol-lowering drugs.^102,103 Naringin has also been found to reduce the aortic fatty streakareas in rabbits fed a high cholesterol diet.¹⁰⁴

Another citrus flavonoid, hesperidin,was studied in spontaneously hypertensive rats and normotensive rats, withanimals given diets containing 30 mg/d/kg body weight for 25 weeks.¹⁰⁵Hypertensive rats that received the hesperidin had decreased blood pressure andheart rate, suggesting anti-hypertensive effects of the compound. The flavonoid nobiletin,isolated from tangerines, was found in macrophage studies to reduce plasmaconcentrations of LDL, and to inhibit macrophage foam-cell formation.¹⁰⁶ And tangeretin,a polymethoxylated flavone from citrus, was found in a study headed by London,Ontario-based KGK Synergize to modulate apoB-containing lipoprotein metabolism,including reducing apoB secretion, suggesting a role in treatinghypertriglyceridemia.¹⁰⁷ A review from KGK (supplier of Sytrinol®) examinedresearch on formulations containing citrus flavonoids including tangeretin,hesperidin and naringin, and noted supplementation in the diet appears tosignificantly reduce total and LDL cholesterol, with a tendency to further reduce serum triacylglycerols.¹⁰⁸

Another powerful fruit is pomegranate,which is also rich in polyphenols. Researchers from Rambam Medical Center inHaifa, Israel, suggest pomegranate polyphenols protect LDL against oxidationboth through direct interaction with the lipoprotein and through accumulation inarterial macrophages.¹⁰⁹ They also noted pomegranate polyphenols may prevent thedevelopment of atherosclerotic lesions, possibly due to the protection of LDLagainst oxidation. A study in healthy male volunteers found pomegranate juiceconsumption for two weeks decreased LDL susceptibility to aggregation andincreased antioxidant enzyme activity; a second leg in animals further showedpomegranate juice supplementation in mice reduced the size of establishedatherosclerotic lesions by 44 percent as well as the number of foam cells.¹¹⁰

In vitro work suggests the flavonoids in pomegranate,including delphinidin, cyanidin,pelargonidin and punicalagin,exhibit scavenging activity against free radicals¹¹¹ and are taken up into theplasma.¹¹² A human study conducted at Shaheed Beheshti University of MedicalSciences in Tehran, Iran, included 22 Type II diabetic patients who received 40 g/d of concentrated pomegranate juice for eightweeks.¹¹³ Treatment significantly reduced total cholesterol, LDLcholesterol and the LDL-to-HDL ratio. Similar results were reported in a studyfrom Israel, in which administration of pomegranate juice to 10 patients for upto three years resulted in significant reductions in carotid intima-mediathickness (IMT) and serum lipid peroxidation.¹¹⁴

French maritime pine bark extract

may also supportcardiovascular health. A review of studies on pine bark extract (asPycnogenol®, supplied in the United States by Natural Health Sciences) notedthe extract protects against oxidative stress directly and indirectly, and alsoappears to prevent platelet aggregation.¹¹⁵ The extract was also shown in humansubjects to reduce LDL cholesterol and increase HDL cholesterol.¹¹⁶

Further, Pycnogenol appears to enhance production ofvasodilatory endothelial nitric oxide, lowering high blood pressure, relaxingartery constriction and improving blood circulation.¹¹⁷ In a double blind, placebocontrolled study conducted at the Chinese Medical Science ResearchInstitute, 58 patients with hypertension were given 100 mg/d of Pycnogenol for12 weeks.¹¹⁸ Supplementation helped reduce the dose of hypertensive medication,and also increased endothelin-1 concentrations.

While flavonoids are water-soluble antioxidants, carotenoidsare fatsoluble compounds that also serve a protectiverole in the body. Carotenoids appear particularly adept at scavenging singletoxygen and peroxyl radicals generated in the process of lipid peroxidation.¹¹⁹Data from a prospective, nested, case-control analysis of 297 participants inthe Physicians Health Study found plasma levels of alpha-carotene,betacarotene and lycopenewere inversely related to risk of ischemic stroke,¹²⁰while findings from a cohort of 573 women and men in a study at the Universityof Southern California, Los Angeles, found higher plasma levels ofalpha-carotene, lutein, beta-cryptoxanthinand zeaxanthinreduced atherosclerotic progression, as measured by IMT.¹²¹

Particular attention has been paid to lycopene, the primarycarotenoid in tomatoes. It is suggested lycopene may work not only as anantioxidant, but also impact LDL degradation and particle size, as well asaltering endothelial function.¹²² Several researchers suggest lycopeneseffects may be enhanced when delivered with the additional nutrients intomatoes, while processing may also increase the bioavailability of lycopene intomato products.¹²³ For example, a study at Japan Womens University in Tokyofound ingestion of tomato juice, compared to a control drink, increased levelsof lycopene in LDL and HDL cholesterol and protected the lipids fromoxidation.¹²⁴ Dietary intake of tomato-based products was found to protectagainst CVD progression in 39,876 women participating in a study at Brigham andWomens Hospital in Boston, whereas serum lycopene levels were not stronglyassociated with the risk of CVD; researchers concluded the combination oflycopene and other phytochemicals produced the cardiovascular benefits.¹²⁵

Serum levels of lycopene appear linked to increased risk ofcardiovascular effects. Data from 725 men participating in the Kuopio IschaemicHeart Disease Risk Factor Study in Finland suggested men in the lowest quarterof serum lycopene levels had a 3.3-fold risk of acute coronary events or strokecompared with others.¹²⁶ Data from the same cohort also found men in the lowestquarter of serum lycopene concentration had a significantly higher IMT of the carotidartery.¹²⁷

The carotenoid astaxanthin hasbeen used in the food and feed industry, and its profile in the nutraceuticalarena has been increasing, given its potential as an antioxidant impacting several healthconditions.¹²⁸ Japanese researchers investigated the in vitro and ex vivoeffects of astaxanthin on LDL oxidation.¹²⁹ They found astaxanthin significantlyprolonged the oxidation lag time in vitro, with similar results reported on LDLtaken from human subjects after astaxanthin supplementation. Another animal study, conducted at the Medical College ofWisconsin, Milwaukee, found pre-treatment of rats with disodium disuccinateastaxanthin (as Cardax from Hawaii Biotech) prior to myocardial infarction significantly reduced the area of infarct.¹³⁰

Despite these beneficial findings for many other types ofantioxidant compounds, the antioxidant vitamins have garnered mixed results inclinical trials. A systematic review of the effects of antioxidant vitamins inprevention of CVD found while observational studies showed a link between intakeof antioxidant vitamins in the diet and reduced risk of CVD, randomizedcontrolled trials have shown no beneficial effects in primary prevention ofmyocardial infarction and stroke.¹³¹ Another meta-analysis reviewed sevenrandomized trials of vitamin E treatment(50 IU/d to 800 IU/d) and eight separate trials of beta-carotene treatment (15mg/d to 50 mg/d); all trials included at least 1,000 patients.¹³²Vitamin E did not benefit mortality nor significantly decrease risk ofcardiovascular death, suggesting routine use of vitamin E for heart health doesnot appear beneficial.

Recent clinical studies have shown some benefits of vitamin Esupplementation. A placebo-controlled, double blind study at the University ofCambridge, England, investigated the impact of 500 IU/d of alphatocopherol(one of the eight vitamin E isomers, and the one mostcommonly used in intervention trials) on lipid oxidation and atherosclerosisdevelopment in 104 carotid endarectomy patients.¹³³ Supplementation increasedplasma vitamin E and decreased the susceptibility of LDL cholesterol tooxidation; arterial lesions showed increases in alphatocopherol concentrations,though no decrease in lesion size. A longerterm (three year) study at theUniversity of Southern California, Los Angeles, investigated the impact of 400IU/d DL-alpha-tocopherol or placebo on subjects with high cholesterol but no clinicalsigns of CVD.¹³⁴ Compared to placebo, alpha-tocopherol supplementationsignificantly increased plasma vitamin E levels, reduced circulating oxidizedLDL and reduced LDL oxidative susceptibility. However, treatment did not reducethe progression of atherosclerosis development.

While animal studies and some human studies have shownbeneficial effects of alpha-tocopherol on oxidative stress, a review from theUniversity of Pennsylvania, Philadelphia, noted long-term supplementation trialsdo not show whether that translates into protection against CVD.¹³⁵ Theresearcher suggested future trials in the area of antioxidant vitaminsupplementation be directed at patients with high levels of oxidative stressand/or depletion of natural antioxidant defense systems who may be most likelyto benefit from such intervention.

An additional question in the literature is whether the typeof vitamin E used in the trials influenced the outcome. Most supplementationtrials have used alpha-tocopherol, a single isomer of vitamin E, rather than anyof the tocotrienol isomers ora full spectrum incorporating all eight isomers. Research appears to indicate tocotrienol is a powerfulantioxidant in its own right, reducing LDL oxidation and endothelial cellproliferation.¹³⁶ A four-week study in hamsters receiving a high fat diet foundadministration of mixed tocotrienols or gamma-tocotrienol decreased totalcholesterol levels and LDL cholesterol levels.¹³⁷

One of the richest dietary sources of tocotrienols is palmfruit; its vitamin E content is approximately 30percent tocopherols and 70 percent tocotrienols. Researchers from the MalaysianPalm Oil Board noted health properties associated with palm vitamin E, includingcholesterol lowering and protection against atherosclerosis, have been largelyattributed to the tocotrienol content.¹³⁸ Interesting results were posted from astudy in the Ivory Coast, which compared the antioxidant capacity of subjectsliving in a selenium deficient region who consume a vegetarian diet rich incrude palm oil with the capacity of subjects in a coastal region consuming a fishbased diet with refined palm oil.¹³⁹ While the subjects in the seleniumdeficient region had a higher exposure risk to oxidative stress, there was noapparently oxidative damage, which the researchers suggested was related to thecrude palm oil supplying full spectrum vitamin E.

A newer supplemental form of vitamin E is vitamin E phosphate(Ester- E®, developed by Zila Nutraceuticals). While alpha-tocopherol is anactive form of vitamin E, the monophosphate ester of alpha-tocopherol is awater-soluble form of vitamin E that may be converted by the body as needed intoalpha-tocopherol.¹⁴⁰ Swiss researchers investigated the effect of a mixture ofalpha-tocopheryl phosphate and di-alpha-tocopheryl phosphate (as Ester-E) on twocell lines, rat aortic smooth muscle cells and human monocytic leukemiacells.¹⁴¹ The compound inhibited cell proliferation in both lines, and inhibitedoxidized LDL surface binding and uptake, inhibiting the major elements involvedin the progression of atherosclerosis. In addition, Dutch researchers comparedthe ability of several types of vitamin E isomers to inhibit LDL oxidation, andfound vitamin E phosphate (as Ester-E) was a potent antioxidant withoutconversion to vitamin E by esterases, and reduced membrane fluidity, inhibiting the transfer of free radicals between cells.¹⁴²

Studies on vitamin E have often used it in combination with vitaminC to provide both lipid-soluble and water-solubleantioxidants. A study in Slovakia investigated the impact of a mixture ofantioxidants (100 mg/d vitamin E, 100 mg/d vitamin C, 6 mg/d beta-carotene and50 mcg/d selenium) on men who had survived a heart attack, and foundsupplementation increased the antioxidant capacity of plasma and reduced theproducts of lipid peroxidation.¹⁴³ A longer-term study in Finland examined theimpact of twice daily supplementation with 136 IU of vitamin E and 250 mg ofvitamin C in 520 men and postmenopausal women with high cholesterol.¹⁴⁴ Aftersix years, supplementation reduced IMT of the carotid artery, slowing theprogression of atherosclerosis.

Individual trials with vitamin C have shown mixed results.Astudy at the University of Leipzig, Germany, found vitamin C infusion restored peripheral endothelial function in patients with CHD to normalvalues.¹⁴⁵ And low plasma vitamin C levels have been shown tosignificantly increase the risk of stroke in hypertensive men, according to astudy in 2,419 men in Finland.¹⁴⁶ However, Japanese researchers found five yearsof vitamin C supplementation (50 mg/d or 500 mg/d) did not reduce hypertensionin a high-risk population for stroke,¹⁴⁷ and a study from the University ofColorado, Boulder, found neither acute nor chronic (500 mg/d) vitamin Csupplementation affected artery compliance or blood pressure in healthy men.¹⁴⁸

Another antioxidant, alpha-lipoicacid (ALA), is soluble in both the lipid and aqueousportions of the cell, and may modulate blood lipids, protecting against LDLoxidation and hypertension.¹⁴⁹ A rat study at the University of Montrealexamined whether ALA could prevent an increase in formation of advanced glycation end products (AGEs) associated with the development ofhypertension.¹⁵⁰ Chronic administration of glucose increased blood pressure, glycemia, insulineaia and AGE content in the aorta in control rats; theseincreases were prevented in rats given glucose plus ALA, indicating theantioxidants ability to prevent development of hypertension. Similarly,hypertension induced in rats through a high salt diet was also attenuated byadministration of ALA in a study at the Memorial University of Newfoundland.¹⁵¹

In the area of blood lipids, researchers at AnnamalaiUniversity, India, investigated the impact of ALA on lipid metabolism ininsulin-resistant rats fed a high fructose diet.¹⁵² While the high fructose dietdecreased HDL and increased LDL and VLDL in control animals, ALA helped the bodymaintain near-normal levels of lipids, as well as activity of key enzymesinvolved in lipid metabolism.Mexican researchers reported positive results inthe cholesterol area as well, showing both intensive treatment (100 mg/kg ALAand 140 mg/d vitamin E for seven days after ischemia) and prophylactic treatment(20 mg/d ALA and 50 mg/kg vitamin E from 30 days before infarction) reducedserum lipid peroxidation and diminished brain infarct volume after induction of stroke.¹⁵³

Coenzyme Q10

(CoQ10) is another antioxidantcompound with multiple roles to play in the heart health area. A review fromVirginia Commonwealth University, Richmond, noted CoQ10 appears to havefavorable activity on patients with CHF, including increasing cardiac output andreducing stroke volume.¹⁵⁴ And Australian researchers who looked at trials ofCoQ10 in hypertension suggest it may play a role in reducing both systolic anddiastolic blood pressure.¹⁵⁵ Further, a review of a number of nutritionalcompounds and their effect on heart health found CoQ10 has consistentanti-hypertensive effects, and singled out Q-Gel® (from Tishcon Corp.) as thebest-studied and most bioavailable CoQ10 supplement.¹⁵⁶ A bioavailability studyconducted at the University of North Texas Health Science Center in Fort Worthfound rats that received 150 mg/kg/d of CoQ10 (as Q-Gel) showed uptake into themitochondria of the heart, skeletal muscle, brain, liver and kidney.¹⁵⁷

In the area of atherosclerosis, researchers have examined howCoQ10 may impact its development. In one such study, researchers at the MedicalHospital and Research Centre in Moradabad, India, administered 3 mg/kg/d ofCoQ10 (as Q-Gel) or a placebo for 24 weeks to rabbits consuming a diet rich intrans fats.¹⁵⁸ CoQ10 reduced markers of oxidative damage and atherosclerosisdevelopment scores. Further, a study in Austraila found cosupplementation ofCoQ10 and vitamin E had synergistic activity in reducing atherosclerosis at theaortic root and descending thoracic aorta; further, plasma from CoQ10supplemented animals was more resistant to ex vivo lipid peroxidation, whilevitamin E did not have this effect.¹⁵⁹

A recent human study investigated the impact of supplementalCoQ10 (120 mg/d) for one year on risk factors of atherosclerosis in patientsafter acute myocardial infarction.¹⁶⁰ The CoQ10patients showed increases in plasma vitamin E and HDL, and decreases in dieneconjugates and reactive substances. In addition, approximately half of thepatients were taking a cholesterol-lowering drug (lovastatin, 10 mg/d), whichappeared to lower total and LDL cholesterol levels; however, patients on thedrug who were not taking CoQ10 reported higher incidence of fatigue.

In a review from the University of Southern California, LosAngeles, CoQ10 was suggested as a preventive and treatment for a range of CVDconditions, including hypertension, CHD and hyperlipidemia.¹⁶¹ In addition, thereview noted certain medications including HMG-CoA reductase inhibitors(statins) and beta blockers appear to lower the bodys stores of CoQ10,suggesting CoQ10 may be a necessary adjunct to conventional treatments. In fact,a recent study conducted at Columbia University College in New York foundsubjects taking atorvastatin for 30 days showed a significant decrease in bloodconcentrations of CoQ10, with the fall apparent at only 14 days.¹⁶² The authorssuggested, Widespread inhibition of CoQ10 synthesis could explain the mostcommonly reported adverse effects of statins, especially exercise intolerance,myalgia and myoglobinuria.

Also in the antioxidant arena is the mineral selenium.A review from Saudi Arabia noted selenium deficiency in humans has beenimplicated in the etiology of CVD, but there is only limited data.¹⁶³ A Koreanpopulation study did indicate serum selenium declined in women as they aged, andthat those in the lowest tertile of selenium concentration had significantlyhigher atherogenic indices and lower HDL levels.¹⁶⁴ Similarly, Spanishresearchers reported serum selenium was inversely associated with homocysteinelevels.¹⁶⁵ Chinese researchers associated serum selenium levels and a decreasedrisk of death from heart disease over 15 years in a population of more than1,103 subjects.¹⁶⁶ As the Saudi review indicated, further controlled trials areneeded to further elucidate seleniums role in heart health.¹⁶⁷

Better understood in this area is magnesium,deficiencies of which are associated with hypertension, CHF, arrhythmia andmyocardial infarction.¹⁶⁸ Many of the processes associated with hypertension,including arterial wall thickening and endothelial dysfunction, are influencedby magnesium levels, which impact vascular tone and cardiac function.¹⁶⁹ Frenchresearchers found in spontaneously hypertensive rats, administration of highlevels of magnesium influenced exchangeable cellular magnesium stores,suggesting a magnesium metabolism disturbance in hypertension.¹⁷⁰ And in aGerman study, increasing doses of magnesium administered to piglets induced withhypertension dosedependently benefited circulation and improved heart functionin induced embolism.¹⁷¹

In atherosclerosis, experimentally induced low plasma levelsof magnesium increase LDL concentrations and their modifications, and promoteinflammation.¹⁷² In addition, low magnesium levels promote endothelialdysfunction, further generating a pro-atherogenic environment in the body.¹⁷³ Astudy at Vienna General Hospital, Austria, looked at magnesium levels in 323patients with progressive atherosclerosis over 20 months.¹⁷⁴ Compared withpatients in the highest tertile of magnesium serum levels, patients in thelowest level had three times the risk for neurological events. And in a Greekstudy of patients on hemodialysis, serum magnesium and intracellular magnesiumwere negatively associated with carotid IMT, suggesting magnesium may protectagainst atherosclerosis development in this high-risk population.¹⁷⁵

The amino acid L-carnitine playsa role in heart health, as a review from the University of Florida, Gainesville,noted treatment with carnitine for up to one year results in less heart failurewhen given to patients after myocardial infarction, while also improvingexercise tolerance and reducing angina (a muscle cramp in the heart).¹⁷⁶ Carnitines importance in cardiovascular health is underscored by the factthat one cause of cardiomyopathy is carnitine transport defect, which can be treated with oralcarnitine.¹⁷⁷

Researchers at the University of Seville, Spain, conducted anin vivo study using rat aortic rings to assess the mechanism of the vasodilatoryeffect of carnitine.¹⁷⁸ They found carnitine had a greater relaxation effect inthe aortic rings from spontaneously hypertensive rats compared to normal rats,and the relaxation appeared mediated by endothelial production of nitric oxide.Another study in rat hearts, conducted at the University of Connecticut Schoolof Medicine, Farmington, found infusion of L-carnitine, acetyl-L-carnitineor propionyl-L-carnitine priorto induction of ischemia significantly improved recovery of heart function.¹⁷⁹The carnitine treatments also reduced infarct size and apoptotic cell death.

Another study, conducted at Egypts National CancerInstitute in Cairo, investigated the impact of carnitine in atherosclerosisdevelopment.¹⁸⁰ Hypercholesterolemia and carnitine deficiency was induced inrabbits, which resulted in severe atherosclerotic lesions, intimal plaques andfoam cell formation. Administration of L-carnitine (250 mg/kg-1) for 28 dayscompletely prevented the progression of lesions in both aorta and coronaryarteries.

L-arginine

, another amino acid, also plays a rolein cardiac function, serving as the principal substrate for vascular productionof nitric oxide, with supplementation shown to benefit endothelial function andsystemic blood pressure.¹⁸¹ Japanese researchers found administration of Larginine to spontaneously hypertensive rats reduced blood pressure andthrombotic tendency in cerebral microvessels.¹⁸² A human clinical studyconducted at the University of Colorado, Denver, investigated the impact ofL-arginine (9 g/d) in premenopausal women with or without Type II diabetes.¹⁸³Supplementation significantly increased flow-mediated brachial artery dilationand raised post-ischemic forearm blood flow, improving measures of endothelialfunction, which is commonly impaired in Type II diabetics.

The amino acid taurine hasalso been suggested to prevent progression of atherosclerosis by inhibitinglipid peroxidation, preventing endothelial dysfunction and inhibiting inflammatorymediators.¹⁸⁴ Japanese researchers found administration of taurine to ratsfed a high fat, high cholesterol diet decreased serum LDL and VLDL cholesterol,increased serum HDL cholesterol, and reduced arterial lipid accumulation,compared to rats that did not receive taurine.¹⁸⁵ The scientists suggested taurine may also have stimulated bile acid synthesis to accelerate cholesterolelimination from the body. Another Japanese study in rats fed a 60 percentfructose diet found oral taurine supplementation prevented diet-inducedincreases in systolic blood pressure, possibly by preventing increase inintracellular free calcium concentrations.¹⁸⁶ Similar results were reported byscientists at the University of Florida, Gainesville, in which saltinducedelevations in blood pressure in rats were attenuated by taurine administration, also by preventing an increase in serumcalcium.¹⁸⁷

Endothelial dysfunction has also been linked to increasedlevels of homocysteine, higher levels of which appear to increase the riskfactors of CVD. The B vitamin folicacid is seen as one of the best compounds for loweringlevels of homocysteine, though researchers from the University of Miami noted ina review that it is still unclear whether using folic acid to lower homocysteinelevels actually decreases the risk of CVD.¹⁸⁸ Another review, from EFA SciencesLLC in Norwood, Mass., found folate both reduced plasma homocysteine levels andenhanced nitric oxide synthesis, as well as exhibiting anti-inflammatory activity.¹⁸⁹

Population studies have shown patients with lower intake offolate have higher risk of CVD. A Spanish study in 171 patients with myocardialinfarction and 171 control patients found participants in the lowest dietary quartile of intake of folate had twice the risk of myocardialinfarction.¹⁹⁰ Another study, conducted in China, found CHD patients hadsignificantly higher mean plasma homocysteine concentrations than controlsubjects, while mean serum folate concentrations were significantly lower amongthose patients.¹⁹¹ Additional population studies have shown a higher intake of folate significantly reduced the risk of peripheral arterial disease,¹⁹² and the risk of ischemic stroke.¹⁹³

Promising results from epidemiological reviews have ledresearchers to conduct intervention studies to elucidate the activity of the Bvitamins, including folate. A study conducted at theUniversity of Sheffield, England, involved 48 patients with acute ischemicstroke who received no supplement or a B complex (5 mg/d folate, 5 mg/d vitaminB2, 50 mg/d vitamin B6, 0.4 mg/d vitamin B12) for 14 days.¹⁹⁴ Supplementationsignificantly increased plasma concentrations of the B vitamins and reducedplasma concentrations of inflammatory markers. Another randomized, double blind,placebo-controlled trial at the University Hospital in Bern,