Cardiovascular Health

Cardiovascular Health
by Heather Granato

It has been said that blood is life. As such, it is not surprising that one of every 2.6 deaths is attributed to diseases of the cardiovascular system, with its responsibility for moving nutrients and oxygen through the body and removing waste products.

Cardiovascular disease (CVD) is not just one disease, but a host of interrelated conditions affecting the heart, blood vessels and blood cells. Degenerative conditions include atherosclerosis, congestive heart failure (CHF), coronary heart disease (CHD) and hypertension (high blood pressure). These are contributing factors to other acute events including stroke and myocardial infarction. It is estimated that one in five Americans has one or more types of CVD, including 50 million with hypertension, 13.2 million with CHD and 5 million with CHF.

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

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

In addition, consuming certain specialty foods appears to further lower the risk of CVD.The National Cholesterol Education Program and the AHA suggest the use of viscous fibers, plant sterols, soy protein and nuts; a study in 46 hyperlipidemic adults found the combination reduced lowdensity lipoprotein (LDL or “bad”) cholesterol by 30 percent, significantly reducing CHD risk.³ In fact, the diet lowered LDL as effectively as the use of the pharmaceutical lovastatin. Similar results were reported in a study of 25 hyperlipidemic subjects following the portfolio diet or a control, low saturated fat diet.⁴ The portfolio diet reduced LDL by 35 percent and also significantly improved the ratio of LDL-to-HDL (high-density lipoprotein, the “good” cholesterol that removes plaque from arteries).

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

Researchers have also investigated the impact of adding certain foods to the diet with the goal of reducing CVD risk. For example, nuts are drawing a great deal of interest of late for their beneficial effects. A review from the Bundaberg Specialist Centre in Australia noted 1 oz. of daily nut ingestion may reduce the risk of fatal CHD by 45 percent when substituted for saturated fat, and by 30 percent when substituted for carbohydrate intake.⁷ The author pointed out nuts are a good source of arginine, vitamin E, folate, fiber, potassium, magnesium, tannins and polyphenols, and may also have a satiating effect in the diet. Nuts’ fatty acid profile is also of interest, as most nuts are high in oleic acid, linoleic acid and linolenic acid, with additional phytosterols and tocopherols.⁸ Dietary intervention studies have found the addition of peanuts (replacing an equal amount of other fat) reduces triacylglycerol and increases serum magnesium levels,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 dietary fiber also appears beneficial. Researchers from Tulane University in New Orleans investigated the relationship between total and soluble fiber intake and the risk of CHD and CVD in 9,776 adults over a 19-year follow up.¹¹ Compared with the lowest quartile of dietary fiber intake, participants in the highest quartile had a 12 percent reduced risk of CHD and an 11 percent reduction in CVD events. Similar results were reported from a population study of 3,588 older men and women, in which subjects in the highest quintile of cereal fiber intake had a 21 percent lower risk of incident CVD compared with those in the lowest quintile.¹² Cereal fiber intake was particularly associated with lower risk of stroke and ischemic heart disease death. A pooled analysis of cohort studies, which included data from 91,058 men and 245,186 women, found each 10 g/d increment of total dietary fiber 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 claim linking higher intake of dietary fiber, particularly soluble fiber, to a reduced risk of heart disease, as well as a separate claim on the relationship between soluble fiber from oats and psyllium seed and a reduced risk of heart disease. Oats as a source of dietary fiber and the soluble fiber betaglucan have been extensively studied for their benefit on heart health. Intervention studies have shown a hypocaloric diet containing oats significantly decreases cholesterol and lowers blood pressure compared to a similar diet without oats,¹⁴ and may even improve blood pressure control to the point that patients can reduce the dosage of antihypertensive medications.¹⁵ To that end, researchers at Tulane recruited 110 subjects with untreated, but higher than optimal blood pressure or stage 1 hypertension to receive 8 g/d of water-soluble fiber from oat bran or a control intervention.¹⁶ Three months of the fiber intervention had a moderate effect on both systolic and diastolic blood pressure.

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

Another FDA health claim in the heart health arena links consumption of soy with heart health. Approved in 1999 after a petition from the Solae Co., the claim links the intake of 25 g/d of soy protein with a reduced risk of CHD. A review from the University of Illinois noted soy consumption appears to improve plasma lipids, reduce LDL oxidation and improve vascular reactivity.¹⁹ Further reviews suggest the benefits of soy include its vegetable protein, high soluble fiber content, absence of saturated fat with high levels of polyunsaturated fats, and major phytoestrogen content.²⁰

A great deal of the initial work in the soy field was done in Asian populations, which generally have a much greater intake of soy foods than Western cultures. Researchers at Vanderbilt University examined the relationship between soy food intake and incidence of CHD among 64,900 Chinese women participating in the Shanghai Women’s Health Study.²¹ There was a dose-response relationship between soy food intake and risk of total CHD, with an adjusted relative risk of 0.25 observed for women in the highest versus the lowest quartile of total soy protein intake. A later European study in 1,033 pre- and postmenopausal women included 361 nonvegetarians, 570 vegetarians and 102 vegans; soy protein intake was inversely associated with total and LDL cholesterol concentrations, and with the ratio of total-to-HDL cholesterol.²²

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

Isolated soy protein has also netted good results. Researchers at the University of Illinois at Urbana-Champaign investigated the impact of 0.5 g/kg/d isolated soy protein consumption on serum lipids in 14 Type II diabetic men.²⁶ Over the course of the study, which included two eightweek intervention periods and two four-week washout periods, isolated soy protein consumption significantly 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 130 subjects significantly reduced LDL cholesterol concentrations.²⁷ And when used in place of animal protein in the diet of 42 subjects with moderate hypercholesterolemia, 25 g of soy protein appears to modestly reduce LDL and total cholesterol to more normal levels.²⁸

One pending question remains the significance of soy’s isoflavones on cardiovascular risk factors. A recent Canadian study involved 20 hyperlipidemic subjects who underwent a four-phase, randomized, crossover trial using diets with isolated soy protein or animal protein (25 g/1,000 kcal), with or without isoflavones.²⁹ Soy protein reduced triglycerides by 12 percent, total cholesterol by 4 percent and LDL by 5 percent compared to animal protein; isoflavones had no significant effect on triglyceride, HDL or LDL levels, though there was a slight reduction in total cholesterol associated with isoflavone intake. Another Canadian study involved 41 hyperlipidemic men and women following three different diets for one month each: low fat dairy (control), high-isoflavone (50 g soy protein with 73 mg isoflavones daily) and low-isoflavone (52 g soy protein and 10 mg isoflavones daily).³⁰ Both soy diets resulted in significantly lower total cholesterol and estimated CHD risk, and positive changes in the ratio of LDL-to-HDL cholesterol, with no significant differences between the isoflavone groups. However, a meta-analysis from Tokyo University of Agriculture involving eight studies comparing high- and low-isoflavone comparisons found with identical soy protein intake, 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, The Netherlands, who examined the association between dietary phytoestrogen intake and metabolic CVD risk factors in 939 postmenopausal women.³² Higher intake of isoflavones and lignans were associated with lower triglyceride levels, as well as a reduced cardiovascular risk factor metabolic score. Another review of dietary phytoestrogen intake in 403 postmenopausal women found increasing isoflavone intake was associated with decreased aortic stiffness.³³

Animal research has suggested soy isoflavones may have specific benefits in the cardiovascular system. An isoflavone-rich soy supplement provided to mice slightly mitigated the plasma cholesterol increases associated with adding cholesterol to the diet, and also appeared to keep plasma triglycerides lower.³⁴ Soy isoflavones were also found in a diabetic rat model to reduce the atherosclerotic index and inhibit lipid peroxidation compared to control rats that did not receive added isoflavones.³⁵ Also, 5 mg/kg body weight of soy isoflavones caused significant decreases in the concentrations of free radicals in the bodies of male New Zealand white rabbits, and decreased levels of plasma total lipids, total cholesterol, triglycerides, LDL, very low-density lipoprotein (VLDL) and the LDL-to-HDL ratio.³⁶

Isoflavones are not only consumed through soy. Supplemental dosages of red clover appear to have effects on plasma lipid levels as well. A 12-week, randomized, double blind, placebo-controlled trial in 252 menopausal women investigated the impact of two different red clover dietary supplements (Promensil, 82 mg total isoflavones, and Rimostil, 57.2 mg total isoflavones) or placebo on lipids and bone turnover.³⁷ Women taking the red clover supplements had greater mean increases in HDL cholesterol and a significant decrease in triglyceride levels. Another study using a supplement with 43.5 mg isoflavones or placebo in 177 women found supplementation in perimenopausal women reduced triglycerides, total cholesterol and LDL cholesterol, suggesting menopausal status may impact efficacy of the supplement.³⁸ However, red clover supplements may also benefit men, as a study in 46 middle-aged men and 34 postmenopausal women found administration of 40 mg/d of red clover isoflavones for six weeks reduced LDL in the 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 may modestly reduce serum total and LDL cholesterol and decrease some markers of inflammation.⁴⁰ Researchers from Oklahoma State University, Stillwater, investigated the impact of flaxseed on the prevention of ovariectomy-induced rise in total cholesterol and atherosclerotic lesions in hamsters.⁴¹ Over four months, the three doses of flaxseed (7.5 percent, 15 percent or 22.5 percent of the diet) significantly reduced the fatty acid streak area, and prevented the ovariectomy-induced rise in total cholesterol seen in the control animals. The same researchers investigated the impact of 40 g/d of ground flaxseed on cholesterol levels in postmenopausal women not on hormone therapy.⁴² Flaxseed significantly lowered serum total cholesterol and non-HDL cholesterol.

In addition to its lignan component, flaxseed is a rich source of the omega-3 fatty acid alpha-linolenic acid (ALA), which may alter the generation of eicosanoids and procoagulant activity, and exert antiatherosclerotic and antiarrhythmic effects.⁴³ When fed to rats, flaxseed increases the serum levels of both ALA and the longer-chain eicosapentaenoic acid (EPA), which is produced through an enzymatic conversion of ALA.⁴⁴ Human studies have shown beneficial effects of ALA on CVD risk factors. A study in 23 hypercholesterolemic subjects who received a control diet or a diet high in ALA and linoleic acid found the high- ALA diet decreased vascular cell adhesion molecule-1, inhibiting vascularinflammation and endothelial activation.⁴⁵ Similarly, hypercholesterolemic men and women who received a margarine enriched with ALA showed lower levels of C-reactive protein (CRP), a marker 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 the process by which the body converts ALA into the longer-chain omega-3s. Researchers from Pennsylvania State University, University Park, noted conversion of ALA to EPA and docosahexaenoic acid (DHA) is inefficient, with less than 10 percent conversion 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, 1.7 g/d EPA+DHA, 4.5 g/d ALA, 9.5 g/d ALA or a control oil sought to determine the different impacts of ALA and the longer-chain omega-3s.⁴⁸ The 1.7 g/d EPA+DHA intervention significantly reduced fasting triacylglycerols while the 9.5 g/d ALA intervention increased the levels. The EPA+DHA intervention also increased ex vivo LDL oxidation susceptibility compared to the ALA intervention.

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

Recently, researchers from the University of Missouri-Kansas City proposed a new risk factor called the omega-3 index, which they suggest can indicate risk for CHD death.⁵⁰ The researchers proposed content of EPA and DHA in cardiac membranes is related to CHD mortality, and reviewed studies that indicate an omega-3 index of greater than 8 percent, is associated with the highest level of cardioprotection. Similarly, researchers from the University of Kuopio, Finland, found CHD patients with the highest proportions of omega-3s in serum 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 relates to the role of fish oil, which is a rich source of preformed DHA and EPA. The original link between marine omega-3 fatty acids and heart health came from observational studies of Japanese and Eskimo populations, in which diets rich in fatty fish protected against CHD. Population-based cohorts have examined fish intake and incidence of cardiovascular events, including CHD, myocardial infarction and hypertension. A population study in 4,815 adults assessed long-term fish intake, and found consumption of tuna or other broiled or baked fish was inversely related with incidence of atrial fibrillation, with risk inversely related to higher consumption.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 of atherosclerosis.⁵³ And a cohort study of 79,839 women in the Nurses’ Health Study found consumption of fish significantly reduced the risk of stroke, with women in the highest quintile of intake of long-chain omega-3s with a 28 percent reduced risk of stroke and a 33 percent reduced risk of thrombotic infarction compared with the lowest quintile.⁵⁴

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

In a recent study from the Royal Veterinary and Agricultural University in Frederiksberg, Denmark, researchers randomly assigned 79 healthy men to receive 12 g/d of fish oil, 33 g/d of fat from partially hydrogenated soy oil, 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, while the n-3 EFAs decreased triglycerides and mean arterial blood pressure. The impact on atherosclerosis is unclear, as a trial in 171 patients with CHD taking 1.65 g/d of omega-3s found no difference in progression of atherosclerosis compared to placebo,⁵⁸ while a controlled trial in 170 patients awaiting carotid endarterectomy found fish oil supplementation enhanced the stability of atherosclerotic plaques, possibly reducing CVD events.⁵⁹

Omega-3s have also been studied in the areas of inflammation and endothelial function. Contrasting results were found in two studies investigating the impact of fish oil on CRP levels. A study in 88 older men and women found CRP levels were unchanged by 3.5 g/d of fish oil for 12 weeks compared to placebo;⁶⁰ however, a study in 30 healthy women on hormone replacement who took 14 g/d of fish oil showed significantly decreased CRP and IL-6 levels, compared to women taking 14 g/d of safflower oil.⁶¹ Studies have also shown the benefit of fish oil supplementation on reducing thrombin generation⁶² 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 levels of monounsaturated fatty acids as well as a host of phytochemicals. Spanish researchers noted olive oil contains antioxidants that may protect against peroxidation, while it can also decrease the plasmatic levels of LDL cholesterol and increase those of HDL cholesterol.⁶⁵ In addition, data from the Greek arm of the European Prospective Investigation into Cancer and Nutrition study found olive oil had a beneficial effect on systolic and diastolic blood pressure.⁶⁶ Similarly, a study in 31 hypertensive patients and 31 normotensive patients found diets enriched in virgin olive oil normalized systolic blood pressure in the hypertensive patients.⁶⁷ And a study in 24 hypertensive patients, administration of an onion-olive oil maceration product significantly decreased systolic blood pressure and showed a trend toward decreasing diastolic blood pressure.⁶⁸

The oleic acid in olive oil further appears to interfere with the inflammatory response, as incorporation of oleic acid into cell lipids decreases expression of a number of pro-inflammatory proteins associated with atherosclerosis.⁶⁹ A study in spontaneously hypertensive and Wistar-Kyoto rats compared the impact of a diet rich in virgin olive oil and a diet rich in high-oleic acid sunflower oil on vascular response and lipid composition.⁷⁰ Both oleic acid-rich diets decreased contraction of aortic rings; however, only the olive oil diet attenuated the vascular response, leading researchers to suggest the olive oil contains additional beneficial compounds beyond the oleic acid, such as polyphenols.

These polyphenols in olive oil include hydroxytyrosol, which has been shown to be dose-dependently absorbed and increases the plasma antioxidant capacity in animal studies.⁷¹ Isochromans isolated from hydroxytyrosol have similarly been found to be effective free radical scavengers that can inhibit platelet aggregation in vitro.⁷² Recent cell-free models on the antioxidant capacity of a combination of olive oil antioxidants (as OleaSelect™ from Indena) including both verbascoside and hydroxytyrosol (obtained through a water and ethanol extraction process) had greater free radical scavenging ability compared to the individual constituents.

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

On their own, red wine polyphenols appear to have powerful antioxidant effects, strongly inhibiting LDL.⁷⁵ In an Italian study of 15 healthy volunteers, 250 mL of red wine was found to reduce the oxidative stress seen in plasma after a high fat meal.⁷⁶ Researchers from the University of Western Australia, Perth, conducted a study of atherosclerosis progression in apolipoprotein E-deficient mice, examining the impact of red wine.⁷⁷ While the supplementation to the high fat, high cholesterol diet had no impact on lipid peroxidation, lipid deposition in the aorta was significantly inhibited by the red wine, suggesting activity beyond just antioxidant ability.Even dealcoholized red wine appears to contain the polyphenolic compounds necessary to decrease atherosclerosis progression.⁷⁸

These polyphenols can also be delivered in grape seed extract, where their antioxidant activity significantly reduces LDL oxidation.⁷⁹ In addition, phenolic-rich extracts from grape seeds were shown in an animal model to prevent the development of aortic atherosclerosis without impacting plasma antioxidant capacity.⁸⁰ A human study conducted by the Free Radical Research Group in Rome found supplementing a meal rich 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, enhancing vasorelaxation.⁸² Researchers at the Dunedin School of Medicine, New Zealand, administered red and white wine with a light meal to 14 subjects with proven CHD, and found the wine improved nearly threefold flow-mediated dilation of the brachial artery.⁸³ And in a study at Creighton University, Omaha, Neb., researchers investigated the effects of grape seed extract (as ActiVin® from San Joaquin Valley) with and without niacin-bound chromium (as ChromeMate® from InterHealth Nutraceuticals) on blood pressure in normotensive and hypertensive rats.⁸⁴ The compounds, both individually and in combination, significantly lowered systolic blood pressure in both types of rats.

Polyphenols are not the only type of flavonoid with application in the heart health arena. In fact, more than 4,000 different flavonoids have been described, with ongoing research investigating antioxidant potential and impact on CHD.⁸⁵ A review from Vanderbilt University Medical Center in Nashville, Tenn., noted flavonoids appear to have several mechanisms by which they confer cardiovascular protection, including inhibiting LDL oxidation, reducing thrombosis, improving endothelial function and reducing inflammation.⁸⁶

Tea is one of the most prevalent sources of flavonoids in the human diet, and researchers note tea drinkers appear to have lower risk of conditions such as CHD and stroke.⁸⁷ In evaluating the effect of a high intake of catechins—the primary flavonoids in tea, researchers at the Dutch National Institute of Public Health 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 underwent coronary angiography, those consuming green tea had a significantly lower incidence of CHD.⁸⁹ In addition, a Taiwanese study in 1,507 subjects found habitual consumption of green or oolong tea for more than one year significantly reduced the risk of developing hypertension; the risk was reduced by 65 percent in those who drank more than 600 mL/d or more.⁹⁰

Tea’s flavonoids’ mechanisms of action have been suggested to be functioning as direct and indirect antioxidants, improving the resistance of lipoproteins to oxidation, while also inhibiting atherogenesis.⁹¹ A Chinese study using rat aortic vascular smooth muscle cells (VSMCs) found green tea polyphenols dose-dependently inhibited proliferation of the VSMCs in response to cholesterol 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. Researchers at the University of California, Los Angeles, evaluated the impact of EGCG on evolving and established atherosclerotic lesions in hypercholesterolemic mice.⁹⁴ EGCG treatment for 21 and 42 days increased antioxidant capacity in vascular tissue and circulation, and reduced evolving atherosclerotic plaque size by 55 percent and 73 percent, respectively. However, there was no impact on established lesions. A study from the University of Scranton, Pa., used a hamster model of atherosclerosis to investigate effects of long-term supplementation with green or black tea on atherosclerosis.⁹⁵ There was a dose-response effect by which both teas inhibited development 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 cocoa flavonoids may serve as antioxidants, improve endothelial function, lower blood pressure and decrease platelet activation and function.⁹⁶ In a study of 30 healthy volunteers in England who received 100 g/d of white, milk or dark chocolate, collagen-induced platelet aggregation was inhibited by dark chocolate, indicating a possible role in prevention of thrombus formation.⁹⁷ In the United States, a six-week study in 25 healthy subjects in Texas found administration of 36.9 g/d of a dark chocolate bar and 30.95 g/d of a cocoa drink lowered the oxidizability of LDL cholesterol;⁹⁸ similarly, a two-week study in California in 21 healthy adults who consumed high-flavonoid or low-flavonoid dark chocolate bars found the flavonoid-rich chocolate improved endothelial function and increased plasma antioxidant concentrations.⁹⁹

Citrus is another powerhouse of nutrients of interest in the cardiovascular area. A review from Indonesia noted citrus fruits contain 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 type of citrus.¹⁰¹ Studies in rabbits on a high cholesterol diet found those receiving supplementation with the citrus bioflavonoid naringin increased plasma antioxidant capacity similar to that of two cholesterol-lowering drugs.^102,103 Naringin has also been found to reduce the aortic fatty streak areas in rabbits fed a high cholesterol diet.¹⁰⁴

Another citrus flavonoid, hesperidin, was studied in spontaneously hypertensive rats and normotensive rats, with animals given diets containing 30 mg/d/kg body weight for 25 weeks.¹⁰⁵ Hypertensive rats that received the hesperidin had decreased blood pressure and heart rate, suggesting anti-hypertensive effects of the compound. The flavonoid nobiletin, isolated from tangerines, was found in macrophage studies to reduce plasma concentrations 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 treating hypertriglyceridemia.¹⁰⁷ A review from KGK (supplier of Sytrinol®) examined research on formulations containing citrus flavonoids including tangeretin, hesperidin and naringin, and noted supplementation in the diet appears to significantly 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 in Haifa, Israel, suggest pomegranate polyphenols protect LDL against oxidation both through direct interaction with the lipoprotein and through accumulation in arterial macrophages.¹⁰⁹ They also noted pomegranate polyphenols may prevent the development of atherosclerotic lesions, possibly due to the protection of LDL against oxidation. A study in healthy male volunteers found pomegranate juice consumption for two weeks decreased LDL susceptibility to aggregation and increased antioxidant enzyme activity; a second leg in animals further showed pomegranate juice supplementation in mice reduced the size of established atherosclerotic 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 the plasma.¹¹² A human study conducted at Shaheed Beheshti University of Medical Sciences in Tehran, Iran, included 22 Type II diabetic patients who received 40 g/d of concentrated pomegranate juice for eight weeks.¹¹³ Treatment significantly reduced total cholesterol, LDL cholesterol and the LDL-to-HDL ratio. Similar results were reported in a study from Israel, in which administration of pomegranate juice to 10 patients for up to three years resulted in significant reductions in carotid intima-media thickness (IMT) and serum lipid peroxidation.¹¹⁴

French maritime pine bark extract may also support cardiovascular health. A review of studies on pine bark extract (as Pycnogenol®, supplied in the United States by Natural Health Sciences) noted the extract protects against oxidative stress directly and indirectly, and also appears to prevent platelet aggregation.¹¹⁵ The extract was also shown in human subjects to reduce LDL cholesterol and increase HDL cholesterol.¹¹⁶

Further, Pycnogenol appears to enhance production of vasodilatory endothelial nitric oxide, lowering high blood pressure, relaxing artery constriction and improving blood circulation.¹¹⁷ In a double blind, placebocontrolled study conducted at the Chinese Medical Science Research Institute, 58 patients with hypertension were given 100 mg/d of Pycnogenol for 12 weeks.¹¹⁸ Supplementation helped reduce the dose of hypertensive medication, and also increased endothelin-1 concentrations.

While flavonoids are water-soluble antioxidants, carotenoids are fatsoluble compounds that also serve a protective role in the body. Carotenoids appear particularly adept at scavenging singlet oxygen and peroxyl radicals generated in the process of lipid peroxidation.¹¹⁹ Data from a prospective, nested, case-control analysis of 297 participants in the Physicians’ Health Study found plasma levels of alpha-carotene, betacarotene and lycopene were inversely related to risk of ischemic stroke,¹²⁰ while findings from a cohort of 573 women and men in a study at the University of Southern California, Los Angeles, found higher plasma levels of alpha-carotene, lutein, beta-cryptoxanthin and zeaxanthin reduced atherosclerotic progression, as measured by IMT.¹²¹

Particular attention has been paid to lycopene, the primary carotenoid in tomatoes. It is suggested lycopene may work not only as an antioxidant, but also impact LDL degradation and particle size, as well as altering endothelial function.¹²² Several researchers suggest lycopene’s effects may be enhanced when delivered with the additional nutrients in tomatoes, while processing may also increase the bioavailability of lycopene in tomato products.¹²³ For example, a study at Japan Women’s University in Tokyo found ingestion of tomato juice, compared to a control drink, increased levels of lycopene in LDL and HDL cholesterol and protected the lipids from oxidation.¹²⁴ Dietary intake of tomato-based products was found to protect against CVD progression in 39,876 women participating in a study at Brigham and Women’s Hospital in Boston, whereas serum lycopene levels were not strongly associated with the risk of CVD; researchers concluded the combination of lycopene and other phytochemicals produced the cardiovascular benefits.¹²⁵

Serum levels of lycopene appear linked to increased risk of cardiovascular effects. Data from 725 men participating in the Kuopio Ischaemic Heart Disease Risk Factor Study in Finland suggested men in the lowest quarter of serum lycopene levels had a 3.3-fold risk of acute coronary events or stroke compared with others.¹²⁶ Data from the same cohort also found men in the lowest quarter of serum lycopene concentration had a significantly higher IMT of the carotid artery.¹²⁷

The carotenoid astaxanthin has been used in the food and feed industry, and its profile in the nutraceutical arena has been increasing, given its potential as an antioxidant impacting several health conditions.¹²⁸ Japanese researchers investigated the in vitro and ex vivo effects of astaxanthin on LDL oxidation.¹²⁹ They found astaxanthin significantly prolonged the oxidation lag time in vitro, with similar results reported on LDL taken from human subjects after astaxanthin supplementation. Another animal study, conducted at the Medical College of Wisconsin, Milwaukee, found pre-treatment of rats with disodium disuccinate astaxanthin (as Cardax™ from Hawaii Biotech) prior to myocardial infarction significantly reduced the area of infarct.¹³⁰

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

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

While animal studies and some human studies have shown beneficial effects of alpha-tocopherol on oxidative stress, a review from the University of Pennsylvania, Philadelphia, noted long-term supplementation trials do not show whether that translates into protection against CVD.¹³⁵ The researcher suggested future trials in the area of antioxidant vitamin supplementation be directed at patients with high levels of oxidative stress and/or depletion of natural antioxidant defense systems who may be most likely to benefit from such intervention.

An additional question in the literature is whether the type of vitamin E used in the trials influenced the outcome. Most supplementation trials have used alpha-tocopherol, a single isomer of vitamin E, rather than any of the tocotrienol isomers or a full spectrum incorporating all eight isomers. Research appears to indicate tocotrienol is a powerful antioxidant in its own right, reducing LDL oxidation and endothelial cell proliferation.¹³⁶ A four-week study in hamsters receiving a high fat diet found administration of mixed tocotrienols or gamma-tocotrienol decreased total cholesterol levels and LDL cholesterol levels.¹³⁷

One of the richest dietary sources of tocotrienols is palm fruit; its vitamin E content is approximately 30 percent tocopherols and 70 percent tocotrienols. Researchers from the Malaysian Palm Oil Board noted health properties associated with palm vitamin E, including cholesterol lowering and protection against atherosclerosis, have been largely attributed to the tocotrienol content.¹³⁸ Interesting results were posted from a study in the Ivory Coast, which compared the antioxidant capacity of subjects living in a selenium deficient region who consume a vegetarian diet rich in crude 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 selenium deficient region had a higher exposure risk to oxidative stress, there was no apparently oxidative damage, which the researchers suggested was related to the crude 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 an active form of vitamin E, the monophosphate ester of alpha-tocopherol is a water-soluble form of vitamin E that may be converted by the body as needed into alpha-tocopherol.¹⁴⁰ Swiss researchers investigated the effect of a mixture of alpha-tocopheryl phosphate and di-alpha-tocopheryl phosphate (as Ester-E) on two cell lines, rat aortic smooth muscle cells and human monocytic leukemia cells.¹⁴¹ The compound inhibited cell proliferation in both lines, and inhibited oxidized LDL surface binding and uptake, inhibiting the major elements involved in the progression of atherosclerosis. In addition, Dutch researchers compared the ability of several types of vitamin E isomers to inhibit LDL oxidation, and found vitamin E phosphate (as Ester-E) was a potent antioxidant without conversion 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 vitamin C to provide both lipid-soluble and water-soluble antioxidants. A study in Slovakia investigated the impact of a mixture of antioxidants (100 mg/d vitamin E, 100 mg/d vitamin C, 6 mg/d beta-carotene and 50 mcg/d selenium) on men who had survived a heart attack, and found supplementation increased the antioxidant capacity of plasma and reduced the products of lipid peroxidation.¹⁴³ A longer-term study in Finland examined the impact of twice daily supplementation with 136 IU of vitamin E and 250 mg of vitamin C in 520 men and postmenopausal women with high cholesterol.¹⁴⁴ After six years, supplementation reduced IMT of the carotid artery, slowing the progression of atherosclerosis.

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

Another antioxidant, alpha-lipoic acid (ALA), is soluble in both the lipid and aqueous portions of the cell, and may modulate blood lipids, protecting against LDL oxidation and hypertension.¹⁴⁹ A rat study at the University of Montreal examined whether ALA could prevent an increase in formation of advanced glycation end products (AGEs) associated with the development of hypertension.¹⁵⁰ Chronic administration of glucose increased blood pressure, glycemia, insulineaia and AGE content in the aorta in control rats; these increases were prevented in rats given glucose plus ALA, indicating the antioxidant’s ability to prevent development of hypertension. Similarly, hypertension induced in rats through a high salt diet was also attenuated by administration of ALA in a study at the Memorial University of Newfoundland.¹⁵¹

In the area of blood lipids, researchers at Annamalai University, India, investigated the impact of ALA on lipid metabolism in insulin-resistant rats fed a high fructose diet.¹⁵² While the high fructose diet decreased HDL and increased LDL and VLDL in control animals, ALA helped the body maintain near-normal levels of lipids, as well as activity of key enzymes involved in lipid metabolism.Mexican researchers reported positive results in the cholesterol area as well, showing both intensive treatment (100 mg/kg ALA and 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) reduced serum lipid peroxidation and diminished brain infarct volume after induction of stroke.¹⁵³

Coenzyme Q10 (CoQ10) is another antioxidant compound with multiple roles to play in the heart health area. A review from Virginia Commonwealth University, Richmond, noted CoQ10 appears to have favorable activity on patients with CHF, including increasing cardiac output and reducing stroke volume.¹⁵⁴ And Australian researchers who looked at trials of CoQ10 in hypertension suggest it may play a role in reducing both systolic and diastolic blood pressure.¹⁵⁵ Further, a review of a number of nutritional compounds and their effect on heart health found CoQ10 has consistent anti-hypertensive effects, and singled out Q-Gel® (from Tishcon Corp.) as the best-studied and most bioavailable CoQ10 supplement.¹⁵⁶ A bioavailability study conducted at the University of North Texas Health Science Center in Fort Worth found rats that received 150 mg/kg/d of CoQ10 (as Q-Gel) showed uptake into the mitochondria of the heart, skeletal muscle, brain, liver and kidney.¹⁵⁷

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

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

In a review from the University of Southern California, Los Angeles, CoQ10 was suggested as a preventive and treatment for a range of CVD conditions, including hypertension, CHD and hyperlipidemia.¹⁶¹ In addition, the review noted certain medications including HMG-CoA reductase inhibitors (statins) and beta blockers appear to lower the body’s 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 found subjects taking atorvastatin for 30 days showed a significant decrease in blood concentrations of CoQ10, with the fall apparent at only 14 days.¹⁶² The authors suggested, “Widespread inhibition of CoQ10 synthesis could explain the most commonly 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 been implicated in the etiology of CVD, but there is only limited data.¹⁶³ A Korean population study did indicate serum selenium declined in women as they aged, and that those in the lowest tertile of selenium concentration had significantly higher atherogenic indices and lower HDL levels.¹⁶⁴ Similarly, Spanish researchers reported serum selenium was inversely associated with homocysteine levels.¹⁶⁵ Chinese researchers associated serum selenium levels and a decreased risk of death from heart disease over 15 years in a population of more than 1,103 subjects.¹⁶⁶ As the Saudi review indicated, further controlled trials are needed to further elucidate selenium’s role in heart health.¹⁶⁷

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

In atherosclerosis, experimentally induced low plasma levels of magnesium increase LDL concentrations and their modifications, and promote inflammation.¹⁷² In addition, low magnesium levels promote endothelial dysfunction, further generating a pro-atherogenic environment in the body.¹⁷³ A study at Vienna General Hospital, Austria, looked at magnesium levels in 323 patients with progressive atherosclerosis over 20 months.¹⁷⁴ Compared with patients in the highest tertile of magnesium serum levels, patients in the lowest level had three times the risk for neurological events. And in a Greek study of patients on hemodialysis, serum magnesium and intracellular magnesium were negatively associated with carotid IMT, suggesting magnesium may protect against atherosclerosis development in this high-risk population.¹⁷⁵

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The amino acid L-carnitine plays a 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 failure when given to patients after myocardial infarction, while also improving exercise tolerance and reducing angina (a muscle cramp in the heart).¹⁷⁶ Carnitine’s importance in cardiovascular health is underscored by the fact that one cause of cardiomyopathy is carnitine transport defect, which can be treated with oral carnitine.¹⁷⁷

Researchers at the University of Seville, Spain, conducted an in vivo study using rat aortic rings to assess the mechanism of the vasodilatory effect of carnitine.¹⁷⁸ They found carnitine had a greater relaxation effect in the 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 School of Medicine, Farmington, found infusion of L-carnitine, acetyl-L-carnitine or propionyl-L-carnitine prior to induction of ischemia significantly improved recovery of heart function.¹⁷⁹ The carnitine treatments also reduced infarct size and apoptotic cell death.

Another study, conducted at Egypt’s National Cancer Institute in Cairo, investigated the impact of carnitine in atherosclerosis development.¹⁸⁰ Hypercholesterolemia and carnitine deficiency was induced in rabbits, which resulted in severe atherosclerotic lesions, intimal plaques and foam cell formation. Administration of L-carnitine (250 mg/kg-1) for 28 days completely prevented the progression of lesions in both aorta and coronary arteries.

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

The amino acid taurine has also been suggested to prevent progression of atherosclerosis by inhibiting lipid peroxidation, preventing endothelial dysfunction and inhibiting inflammatory mediators.¹⁸⁴ Japanese researchers found administration of taurine to rats fed 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 cholesterol elimination from the body. Another Japanese study in rats fed a 60 percent fructose diet found oral taurine supplementation prevented diet-induced increases in systolic blood pressure, possibly by preventing increase in intracellular free calcium concentrations.¹⁸⁶ Similar results were reported by scientists at the University of Florida, Gainesville, in which saltinduced elevations in blood pressure in rats were attenuated by taurine administration, also by preventing an increase in serum calcium.¹⁸⁷

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

Population studies have shown patients with lower intake of folate have higher risk of CVD. A Spanish study in 171 patients with myocardial infarction and 171 control patients found participants in the lowest dietary quartile of intake of folate had twice the risk of myocardial infarction.¹⁹⁰ Another study, conducted in China, found CHD patients had significantly higher mean plasma homocysteine concentrations than control subjects, while mean serum folate concentrations were significantly lower among those 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 led researchers to conduct intervention studies to elucidate the activity of the B vitamins, including folate. A study conducted at the University of Sheffield, England, involved 48 patients with acute ischemic stroke who received no supplement or a B complex (5 mg/d folate, 5 mg/d vitamin B2, 50 mg/d vitamin B6, 0.4 mg/d vitamin B12) for 14 days.¹⁹⁴ Supplementation significantly increased plasma concentrations of the B vitamins and reduced plasma concentrations of inflammatory markers. Another randomized, double blind, placebo-controlled trial at the University Hospital in Bern,

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