Nutritional Ingredients to Prevent, Recover from Heart Attack, Stroke

In the United States, more than 80.7 million adults have one or more types of cardiovascular disease (CVD), according to the American Heart Association (AHA). The association reported there are 8.1 million incidents of myocardial infarction (MI), also known as heart attack, and 5.8 million stroke incidents reported annually. Further, while men have a higher incidence of MI and women a higher incidence of stroke, women are more likely to die from a heart attack within a few weeks of occurrence, in part because women tend to suffer MI at older ages than men.

At the core of these conditions is ischemia, a situation in which the flow of blood to a part of the body is restricted. This is often the result of coronary heart disease (CHD), in which atherosclerotic plaques have narrowed the arterial walls, thereby setting the stage for ruptures and clots that can impede blood flow. Cardiac ischemia refers to a lack of blood flow and oxygen to the heart muscle, while a restriction of blood flow and oxygen to the brain results in ischemic stroke. Ischemic stroke accounts for approximately 87 percent of stroke incidence; hemorrhagic stroke results from ruptured blood vessels in the brain, and has a significantly higher fatality rate than ischemic stroke.

There are several basic tips provided by organizations like AHA to reduce the risk of suffering a heart attack or stroke. Primary among them is to stop smoking. Further suggestions include engaging in physical activity, maintaining or reducing weight, controlling blood pressure, controlling blood sugar, limiting alcohol intake and following a healthy diet. Some healthy diets have been examined for their ability to stave off incidence of heart attack or stroke, or to increase survival rates after incidence.

The Mediterranean diet, for example, emphasizes fruits and vegetables, lean protein, fish, whole grains and healthy fats such as olive oil. A review from Ontario’s Robarts Research Institute noted adherence to such a diet has been shown to reduce stroke and MI by 60 percent compared to following even the AHA recommended diet, an effect the researchers noted was twice that of studies investigating the impact of statin intervention on MI incidence.¹ Further, French researchers reported MI patients who followed a Mediterranean diet compared to a “prudent” Western diet significantly increased quality-adjusted life years in a cost-effective way, representing an “exceptional return on investment.”²

Population studies support the recommendation. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study found increased adherence to a Mediterranean diet among 2,671 adults with MI lowered mortality rate by 18 percent.³ Similar findings were reported by Dutch researchers, who found among adults with previous MI, following a Mediterranean diet, along with moderate alcohol consumption and not smoking, lowered all-cause mortality by 40 percent.⁴ And the GISSI-Prevenzione investigators noted following such a diet could halve mortality, leading them to urge clinicians to advise MI patients to follow a Mediterranean-style diet, regardless of any drug treatment prescribed.⁵

The DASH diet (Dietary Approaches to Stop Hypertension) may also have a beneficial effect on MI and stroke incidence. Researchers from Boston’s Brigham & Women’s Hospital recently reported on the results of a prospective cohort study assessing the association between adherence to a DASH-style diet and risk of CHD and stroke in women.⁶ The quintile with the highest adherence had a 24 percent reduction in relative risk of nonfatal MI and fatal CHD, and a 18 percent lower risk of stroke. Results in the three lowest quintiles were fairly similar, a result seen as well in a study out of the University of Minnesota, Minneapolis, in which only the highest quintile of adherence to a DASH-style diet had a significant impact on MI and stroke incidence.⁷

One commonality between these dietary approaches is the emphasis on including fish as a primary protein source. Research suggests greater intake of long-chain omega-3 fatty acids, as found in fish, may help to reduce CVD end points including fatal and non-fatal MI and stroke.⁸ In fact, a meta-analysis out of Chicago’s Northwestern University found fish consumption even as seldom as one to three times per month could have a protective effect against ischemic stroke.⁹

Austrian researchers have noted the use of standardized omega-3 supplements may make the most sense for MI patients hoping to realize a reduction in sudden cardiac deaths, as the level of essential fatty acids (EFAs) needed and the standardization of dosage may be easier to comply within a supplemental form.¹⁰ For example, researchers from Kobe University, Japan, examined whether the use of eicosapentaenoic acid (EPA) supplements (1,800 mg/d) could prevent major (fatal and non-fatal) coronary events in hypercholesterolemic patients (n=18,645) when given with a statin.¹¹ EPA helped reduce major coronary events in patients with a history of CHD; among patients without CHD, there was a non-significant reduction seen, particularly among non-fatal coronary events.

That said, some caution may be needed in the area of EFA intake. A review of the Diet and Reinfarction Trial (DART) and DART-2 trials noted in the DART trial, increasing fish intake reduced all-cause mortality among men recovering from MI; however, increasing fish intake in DART-2 by men with stable angina did not affect mortality.¹² In fact, in DART-2, men taking fish oil capsules had an increase in sudden cardiac death, which the reviewer noted conflicts with other studies. There have also been some concerns that fish oil may be pro-arrythmic in some patient populations, leading researchers from the University of Amsterdam, The Netherlands, to encourage patients to discuss their use with health care providers.¹³

Also in the protein arena are the amino acids, several of which have a role to play in supporting heart health, including possible prevention of infarction. L-arginine, for example, enhances blood flow and improves endothelial activity; when L-arginine circulates in the bloodstream, the endothelial cells convert it to nitric oxide (NO) via an enzymatic reaction. L-citrulline is a byproduct of this process, and can be converted back into L-arginine and then into NO. There has been work suggesting oral supplementation with L-citrulline is more effective at raising NO and plasma levels of L-arginine compared to supplementation with L-arginine.¹⁴

In 2004, the Journal of Nutrition published the Proceedings of the Symposium on Arginine, which was supported in part by a grant from Ajinomoto USA Inc. “Arginine Metabolism: Enzymology, Nutrition and Clinical Significance” (134(10S)) covers the basics of arginine metabolism and its pathophysiology. A review out of the Boston University School of Medicine on L-arginine and atherothrombosis noted the amino acid has several mechanisms by which it improves endothelial function, preventing the earliest pathologic process of atherothrombosis and related infarction.¹⁵ These mechanisms include increased intracellular transport and levels of NO, an antioxidant effect, competitive antagonism of asymmetric dimethylarginine (an inhibitor of NO), and altered intracellular signaling. Additional insights from a review out of Brigham & Women’s Hospital included L-arginine’s ability to help treat coronary artery disease and peripheral artery disease, and regulation of vascular tone.¹⁶

Animal trials have shown L-arginine protects the heart in models of MI, helping balance energy demands,¹⁷ and preventing myocardial and endothelial dysfunction.¹⁸ In a human study out of Grochowski Hospital, Warsaw, Poland, 792 men with MI, admitted within 24 hours after onset of symptoms, received oral L-arginine or placebo for 30 days.¹⁹ Supplementation was well tolerated and a non-significant beneficial trend toward reduction of major clinical events such as reinfarction or CVD death was seen. Similarly, Turkish researchers found adding L-arginine to a cardioplegia solution for MI patients increased NO levels and attenuated free-radical-mediated myocardial injury.²⁰

Two more important amino acids in this arena are L-taurine and L-carnitine. L-taurine comprises more than 50 percent of the total free amino acids in the heart; it has been shown to strengthen the heart muscle and may lower blood pressure. Japanese researchers recently reported administering taurine before or after inducing ischemia in rat hearts could prevent infarction and reduce myocardial injury; given after reperfusion, it significantly enhanced functional recovery.²¹

L-carnitine transports fatty acids into the mitochondria, supporting energy production; the heart is particularly rich in mitochondria and has very high energy demands. Researchers who provided L-carnitine or exogenous NO to rats subjected to ischemia-reperfusion found both interventions worked to protect the heart from myocardial damage.²² The acetylated form, acetyl-L-carnitine (ALC), is of particular interest in the stroke arena. Studies have shown ALC may have the ability to reduce neuronal damage, possibly due in part to activating the choline uptake system.²³ It also appears to restore mitochondrial function in aged rats, which can protect against ischemic damage.²⁴

Combination formulas may be particularly beneficial. A study out of St. Michael’s Hospital, Toronto, evaluated the impact of a combination of L-carnitine, L-taurine and coenzyme Q10 (CoQ10) vs. carnitine alone or placebo on survival, infarct size and cardiac function in a rat MI model.²⁵ The combination supplement significantly improved survival (60 percent vs. 34 percent of control animals) and cardiac function, and reduced infarct size (30 percent vs. 42 percent of control). Carnitine improved survival in a similar manner to the combination, but did not reduce infarct size. On its own, CoQ10 administered prior to²⁶ or during MI²⁷ can improve the survival of myocardial cells and limit postinfarct myocardial remodeling. A review out of Duke University, Durham, N.C., further noted CoQ10’s antioxidant activity may make it a neuroprotectant in stroke cases.²⁸

Antioxidants may work to prevent free radical damage that can result during MI or stroke. Vitamin E, on its own or in combination, has been studied for its ability to decrease oxidative damage. In particular, the tocotrienol isomers appear to have efficacy preventing neuronal and cardiovascular damage induced by ischemia. Researchers from the University of Connecticut School of Medicine, Farmington, used natural palm tocotrienol complex and individual tocotrienol isomers (as Tocomin®, from Carotech Inc.) to study the effects and mechanisms of tocotrienol’s cardioprotective function.²⁹ Results showed all forms of tocotrienols could improve postischemic ventricular function, reduce myocardial infarct size, reduce the percentage of apoptotic cardiomyocytes and partially protect the proteasome during ischemia. Gamma-tocotrienol had the highest cardioprotective activity, followed by alpha-tocotrienol and, with the lowest level, delta-tocotrienol.

Carotech has supported research efforts at the Ohio State University Medical Center, Columbus, since 2000 looking at the effect of Tocomin and Tocomin SupraBio™ in reducing stroke-induced neurodegeneration. The researchers have reported alpha-tocotrienol from Tocomin is significantly more potent than alpha-tocopherol in protecting neurons from glutamate-induced toxicity,³⁰ and has the ability to cross the blood-brain barrier to protect neurons from glutamate-induced neurodegeneration as seen in stroke.³¹ When Tocomin was given to spontaneously hypertensive rats (SHR), the levels of tocotrienols in the brain increased significantly, and exerted protection against stroke-induced brain injury.³²

Combining vitamin E with vitamin C may work to improve recovery from MI, reducing oxidative damage and supporting ventricular remodeling.³³ A randomized pilot trial out of Warsaw, Poland, involving 800 patients with acute MI found providing 1,000 mg of vitamin C for a 12 hour infusion plus 1,200 mg/24 hours orally with 600 mg/24 hours of vitamin E reduced non-fatal new MI and cardiac mortality.³⁴ Similarly, when a team at the University of Sheffield, England, started acute ischemic stroke patients on 800 IU/d vitamin E, 500 mg/d vitamin C and B vitamins (5 mg folic acid, 5 mg B2, 50 mg B6 and 0.⁴ mg B12) within 12 hours of symptom onset, oral supplementation was found to increase plasma antioxidant concentrations, mitigate oxidative damage and reduce inflammatory markers.³⁵

Another fat-soluble antioxidant, the carotenoid astaxanthin, may also play a role in preventing stroke-induced damage. Researchers at the International Research Center for Traditional Medicine, Toyama, Japan, investigated whether long-term administration of astaxanthin could protect against hypertension and stroke.³⁶ Their study compared stroke-prone SHR, given 50 mg/kg of astaxanthin (as AstaReal®, from Fuji Chemical Industry), and normotensive rats. Two weeks of supplementation significantly reduced blood pressure in SHR; the researchers also found astaxanthin exerted neuroprotective effects in ischemic mice. A review from the same research team noted astaxanthin has been shown to exert anti-inflammatory and antioxidant activity.³⁷ Interestingly, pharmaceutical-grade astaxanthin is now being commercialized as a drug, Cardax™, from Cardax Pharmaceuticals. In vitro and animal trials have shown treatment with Cardax prior to ischemia induction can reduce infarct size and support myocardial salvage.^38,39

The plant kingdom also offers a range of antioxidants, often attributed to their flavonoid components. Data from the Kuopio Ischemic Heart Disease Risk Factor Study illustrated the association between intake of different classes of flavonoids and CVD, with men in the highest quartile of flavonol and flavan-3-ol intakes reducing the risk of ischemic stroke by 45 and 41 percent, respectively, compared to the lowest quartiles.⁴⁰ Italian researchers conducted an eight-year study among older adults and found those in the highest quintile of anthocyanidins had a 55 percent reduction in acute MI risk; the highest quintile of intake of flavonols dropped the risk by 35 percent.⁴¹ And a Japanese study linked higher intake of isoflavones by women—particularly postmenopausal women—to a reduced risk of cerebral and myocardial infarctions.⁴²

Polyphenols, as found in grape seed extract (GSE) and red wine, may exert a powerful antioxidant effect and protect blood vessel function, as well as increasing fibrinolysis.⁴³ In vitro work at the University of California, Davis, has shown GSE (as MegaNatural™ BP, from Polyphenolics) can cause endothelium-dependent relaxation of blood vessels.⁴⁴

Providing GSE either before or after induced stroke may reduce oxidative and neuronal damage. Researchers out of the University of Debrecen, Hungary, reported rats treated with 50 and 100 mg of grape seed proanthocyanidins/kg had significantly reduced ventricular fibrillation when ischemia was induced; the researchers suggested GSE exerted its effects by direct and indirect antioxidant activity in the myocardium.⁴⁵ Providing GSE to animals after induction of forebrain ischemia appears to have neuroprotective effects by inhibiting DNA damage⁴⁶ and suppressing lipid peroxidation and proapoptotic protein expression.⁴⁷

Another branded standardized GSE (as Leucoselect™, from Indena) has been investigated for its ability to mitigate damage associated with ischemia. Researchers from the University of Milan, Italy, reported Leucoselect could suppress damage to endothelial cells exposed to peroxynitrite generators and also had a vasorelaxant effect.⁴⁸ Work by the same team found perfusing rabbit hearts with Leucoselect (100 or 200 mcg/ml) dose-dependently enhanced postischemic recovery.⁴⁹

One of the major sources of flavonoids in most diets is tea; green tea in particular has been shown to be a potent antioxidant. Green tea catechins’ ability to attenuate oxidative stress and downregulate the inflammatory response may lie at the core of their ability to protect the brain after cerebral ischemia.⁵⁰ Japanese researchers reported providing tea catechins to rats prior to stroke induction could dose-dependently reduce infarct area and volume; plasma concentrations of epigallocatechin gallate (EGCG) were inversely correlated with infarct volume.⁵¹ In their study, catechin ingestion also reduced neurologic deficits.

On the cardiac side, a team from Annamalai University, Tamil Nadu, India, found oral pretreatment of rats with EGCG (10, 20 or 30 mg/kg body weight) had a dose-dependent cardioprotective effect against induced MI.⁵² Also, a specialty green tea extract (Greenselect®, from Indena) specifically appears to protect cardiac myocytes from ischemia-induced apoptotic cell death, while also limiting the extent of infarct size.⁵³ The reduction in cell death was associated with enhance recovery of ventricular function and hemodynamic recovery.

Other dietary compounds have been studied for their role in preventing ischemic damage. Researchers from the National Institute on Drug Abuse, Baltimore, examined whether diets enriched with blueberry, spinach or spirulina could exert neuroprotective effects in focal cerebral ischemia.⁵⁴ Adult rats received equal diets with the different nutrients or a control diet for four weeks, after which the animals’ cerebral artery was ligated and then removed to allow reperfusional injury. The animals that received blueberry-, spinach- or spirulina-enriched diets had significant reductions in volume of infarction and an increase in post-stroke locomotor activity. On their own, blueberries were shown in an animal trial to exert neuroprotective effects in the hippocampus after induced ischemia,⁵⁵ while spirulina’s C-phycocyanin (PC) may attenuate ischemia and reperfusion-induced myocardial injury via antioxidant and anti-apoptotic activity.⁵⁶

The botanical Ginkgo biloba also exerts neuroprotective and cardioprotective effects. Brazilian researchers explored the effects of Ginkgo biloba extract EGb 761 on ischemia-induced memory impairment and hippocampal damage in rats, reporting animals that received the botanical extract had less hippocampal cell loss and related cognitive impairment.⁵⁷ This activity has been linked to its antioxidant properties, which appears to protect against lipoperoxidation.⁵⁸ Additional research, conducted at the University of Leipzig, Germany, examined the impact of EGb 761 on diabetes-induced damage to cardiomyocytes and ischemic injury in spontaneously diabetic rats.⁵⁹ The researchers noted diabetic myocardium is more vulnerable to such damage, but pre-treatment with EGb 761 could significantly improve myocardial recovery.

Complexing Ginkgo biloba extract with phosphatidylcholine (as Ginkgoselect® Phytosome®, from Indena) may enhance its bioavailability and functionality. Researchers at the University of Milan compared antioxidant defense in animals given 300 mg/kg/d of Ginkgo biloba extract or Ginkgoselect, and found the complex had the ability to significantly increase total antioxidant plasma activity.⁶⁰ In addition, animals were subjected to moderate ischemia and reperfusion; recovery was 35 percent of preischemic values in control animals, 50 percent in Gbe animals and 72 percent in rats pre-treated with Ginkgoselect.

Other dietary compounds operate on different parameters than antioxidant protection. For example, studies have shown that lower levels of vitamin B12 and folate increase the risk for cerebral infarction, possibly linked to higher homocysteine levels;⁶¹ and that patients who have suffered ischemic stroke tend to have lower levels of vitamin B6 and higher homocysteine levels.⁶² Additionally, a study out of Cardinal Tien Hospital, Taiwan, assessed circulating levels of homocysteine, folate and B12 in elderly post-stroke patients (n=89) and found folate deficiency and hyperhomocysteinemia were prevalent in the population, and were also strongly, independently associated with the development of brain atrophy.⁶³

Increasing folate intake appears to help reduce the risk of ischemia. Researchers from the German Institute of Human Nutrition Potsdam-Rehbruecke, Germany, using data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, evaluated the association between folate intake and risk of MI in 22,245 healthy adults.⁶⁴ After 4.6 years of follow-up, higher folate intake was associated with a 43 percent reduction in MI risk. And a report out of Stockholm’s Karolinska Instiutet, using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, found after 13.6 years of follow-up in male smokers, higher folate intake was associated with a statistically significantly lower risk of cerebral infarction.⁶⁵

There has been some controversy surrounding the connection between folate, homocysteine levels and the risk of MI or stroke. A review out of Spedali Civili di Brescia, Italy, noted there is convincing epidemiological evidence on the relation between elevated homocysteine and vascular disease including ischemic stroke; however, the causal relationship has not been proven, and needs further investigation.⁶⁶ For example, nested information from the Nurses Health Study out of Brigham & Women’s Hospital found providing older women (n=5,442) with a combination B vitamin supplement (50 mg B6, 1 mg B12, 2.5 mg folate) lowered homocysteine levels by more than 18 percent, but did not impact the incidence of stroke or MI.⁶⁷ However, folate may well have other mechanisms of action, as Dutch researchers who provided women (n=40) with 10 mg/d of folic acid immediately after acute MI found intervention could improve endothelial function regardless of its impact on homocysteine levels.⁶⁸

Such benefits in recovery are offered by the compound ribose. Ribose is a five-carbon monosaccharide that works to stimulate the metabolic pathway to create purines and pyrimidines, which are essential for producing adenosine triphosphate (ATP)—the “energy currency” of the body. Studies have shown that ribose can help to restore energy and improve function in the heart, particularly in cases of ischemia and heart failure. One study, conducted out of Saddleback Hospital, Laguna Hills, Calif., compared the results of patients with acute myocardial infarction (n=103) given an “off” pump coronary artery bypass (OPCAB) alone, or with oral ribose (as Bioenergy RIBOSE™, from Bioenergy Life Science Inc.), prior to revascularization.⁶⁹ Giving ribose to the patients provided additional functional improvement, compared to OPCAB alone prior to revascularization.

An additional study investigated whether ribose (as Bioenergy Ribose) given to animals in a model of MI could enhance recovery in the animals.⁷⁰ At two and four weeks post-infarction, control animals showed a significant decrease in function of the remote myocardium, which was prevented to a significant degree by ribose infusion. Increasing the myocardial energy levels thereby improved function, which may also delay chronic changes and myocardial remodeling. Similar findings were reported in another animal trial, in which researchers found giving ribose before global MI elevated glycogen stores and reduced injury in normal hearts.⁷¹ In hypertrophied hearts, ribose did not affect ischemic tolerance but it did improve ventricular function.

Another specialty ingredient, aged garlic extract (AGE, as Kyolic®, from Wakunaga) has also been studied for its ability to reduce mortality associated with CVD and stroke. In one trial, S-allyl-L-cysteine (SAC), an active organosulfur compound found in AGE, was found to reduce mortality with lesser incidence of stroke and lower overall stroke-related behavioral score when orally administered to stroke-prone spontaneously hypertensive (SHRSP) rats.⁷² In addition, AGE may help reduce hyperhomocysteinemia and related endothelial dysfunction,⁷³ while it may also increase flow-mediated endothelium-dependent dilation.⁷⁴

In April 2008, Wakunaga presented the results of a recent study from the Los Angeles Biomedical Research Institute of Harbor-UCLA Medical Center, which involved 65 intermediate risk patients who received a placebo or four capsules of 250 mg/d of AGE (as Kyolic), 100 mcg/d of vitamin B12, 300 mcg/d of folic acid, 12.5 mg/d of vitamin B6 and 100 mg/d of L-arginine for one year. The first breakdown of the data showed supplementation with AGE could improve thermal vascular function and reduce coronary artery calcium (CAC) progression in asymptomatic adults with intermediate risk.⁷⁵ The second breakdown of the study showed the ability of AGE, B vitamins, L-arginine and folate to retard progression of CAC and biomarkers of atherosclerosis independent of age, gender and conventional risk factors.⁷⁶

While cholesterol and blood pressure may take center stage in the preventive nutrition arena, awareness of how diet and certain nutritional ingredients can help stave off potentially catastrophic incidents of ischemia can help consumers cover all the bases to increase their years of quality living.

For a list of references, visit NaturalProductsINSIDER.com or e-mail [email protected].

Editor's Note: References start on the next page.

Natural Products INSIDER – June 23, 2008

“Escaping from Ischemia” References

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