Article: Cardiovascular Clues -- April 2009
Cardiovascular disease (CVD) is defined as diseases and injuries of the cardiovascular system: the heart, the blood vessels of the heart and the system of blood vessels (veins and arteries) throughout the body and within the brain. Stroke is the result of a blood flow problem in the brain and is considered a form of CVD.
The U.S. has one of the highest prevalences of CVD globally. Nearly 2,500 Americans die of the disease each day, an average of one death every 35 seconds. Of the over 71 million Americans with one or more types of CVD, 28 million are 65 years or older1. In 2006, the total direct and indirect cost of major CVD and stroke was $403.1 billion2.
As the population ages, the incidences of CVD and stroke will continue to increase, as will the financial impact. With such alarming statistics and consumer concerns escalating, it is no wonder ingredients that favorably impact heart health continue to be a major focus of the research community and, ultimately, the food industry.
Omega-3s, fiber and grains, as well as nut-based ingredients, cocoa flavanols, and other antioxidants and phytosterols are ingredients that continue to garner research attention for the management of CVD.
Omega-3s to C-reactive Protein
Omega-3 fatty acids have been strongly associated with diminished risk of CVD, since the first cross-cultural epidemiologic studies conducted in the 1970s on the Greenland Inuit population revealed low levels of heart disease, despite high animal fat diets. Two of the most popular sources of omega-3s are flaxseed and fish oil, which contain the shorter-chain alpha-linolenic acid (ALA), and the longer-chains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively.
The scientific data on EPA and DHA is impressive, with upward of 8,000 publications to date. Wang, et al., have recently conducted an extensive meta-analysis on omega-3 intakes and CVD outcomes3. Incidences of all-cause mortality, myocardial infarction, cardiac and sudden death, and stroke were all significantly reduced in 14 randomized, controlled trials assessed. Primary prevention of CVD was reported in one randomized, clinical trial, in 25 prospective cohort studies and in seven case-control studies.
An exciting area of new research for omega-3s (and other bioactives) focuses on high sensitivity C-reactive protein (CRP). CRP is a marker of acute inflammation recently recognized as an independent predictor of future CVD. Lowering blood levels of CRP may be as important as reducing LDL cholesterol4. Half of all heart attacks and strokes in the U.S. occur in people with normal cholesterol levels, and 20% of all events occur in people with no major risk factors (such as smoking or obesity). In one study, supplementation with fish oil produces significant reductions in CRP5 and the alleviation of active rheumatoid arthritis. Although, whether CRP is a causative agent in CVD or is just a marker is still under investigation, it is an intriguing area to watch.
Fish oils also decrease the production of inflammatory eicosanoids, reactive oxygen species and the expression of adhesion molecules, which improves vascular function. Omega-3 fatty acids act by replacing arachidonic acid (AA) as an eicosanoid substrate and inhibiting its metabolism. AA produces eicosanoids that stimulate proinflammatory, vasoconstrictive and prothrombotic reactions in the body. Both EPA and DHA have been found to decrease inflammatory cytokine production. In one in vitro study, omega-3 fatty acids (alpha-linolenic) were found to “block” inflammatory metabolites such as protein kinase, COX-2 and PGE6.
EPA and DHA beneficially influence CVD by reducing arrhythmias and, thus, sudden cardiac death7. In clinical studies, dosages of some 4g/day of EPA plus DHA produce reductions in triacylglycerols of 25-30%8. At doses of between 3-5.6g/day, EPA plus DHA has been shown to reduce blood pressure in hypertensive persons by up to 5.5mmHg systolic and 3.4mmHg diastolic pressure9. Doses of EPA plus DHA of about 3g/day have also been shown to decrease platelet aggregation10 and improve vascular reactivity and endothelial function, the later in studies of patients with high cholesterol levels11.
ALA may protect the heart through improvements in abnormal heart rhythms and a reduction in thrombosis. ALA also significantly improves inflammatory responses by lowering CRP in an in vivo study14 and vascular cell adhesion molecules in an in vitro study with cell cultures, thus indicating the potential for improved endothelial health15.
A long-time staple in foods fortified for heart health, fiber has benefitted from decades of clinical research. Using food-frequency questionnaires, a lower risk of CVD was found in subsets of nearly 40,000 females and more than 43,000 males who consumed between 22.9-26.3g/day of fiber, in comparison to lower ranges of 11.5-12.5g/day16, 17, 18.
Fiber is classified as soluble or insoluble. Soluble fiber attracts water during digestion and becomes viscous, trapping lipids and bile acids. Well-controlled intervention studies have shown that for each additional gram of water-soluble fiber (particularly beta-glucan from oats and barley, psyllium, pectin and guar gum) in the diet, serum total and LDL cholesterol concentrations decrease by -0.028mmol/L (-10.83mg/dL) and -0.029mmol/L (-11.21mg/dL), respectively19.
Insoluble fiber is found in foods such as wheat bran, vegetables and whole grains. It appears to speed the passage of foods through the stomach and intestines and adds bulk to the stool. Several studies assessed from 1998-2004 indicated that the consumption of cereal ?bers from bran and whole grains reduced the risk of arterial and peripheral disease 25-35% for the highest whole-grain eaters, in comparison to those eating lower amounts20,21.
Fiber’s potential role as a protective agent in lowering blood pressure (BP) is an interesting area of study. He and coworkers have reported that 8g/day of soluble fiber from oat bran produced a moderate BP (systolic and diastolic) lowering effect in 55 participants aged 30-65 years who had untreated, but higher than optimal, BP or stage-1 hypertension.22 Notably, foods containing beta-glucan from oats have also been shown to significantly reduce both systolic and diastolic blood pressures in obese subjects23 and may control BP to the point where patients can reduce their dosages of hypertensive drugs24.
As with omega-3 fatty acids, the role that fiber may play in influencing serum CRP is of scientific interest. In recent cross-sectional and longitudinal analyses in 524 subjects, the likelihood of elevated CRP concentrations was 63% lower in participants in the highest quartile of total fiber intake than in participants in the lowest quartile. These results suggest that dietary fiber is protective against high CRP levels25.
A recent American Dietetic Association position paper on dietary fiber and health suggests that the benefits of fiber on the cardiovascular system appear to be due to its interference with cholesterol and bile acid absorption, thus lowering blood cholesterol and low-density lipoprotein (LDL) cholesterol. Another proposed mechanism is a delayed absorption of fat and carbohydrate, which leads to increased insulin sensitivity and decreased levels of circulating triglycerides. In addition and as noted, fiber shows a beneficial effect on BP and may reduce CRP26.
Nuts contain a host of nutrients that can benefit the cardiovascular system, including fiber; vitamins and minerals, such as potassium, calcium, magnesium and tocopherols; phytochemicals, such as phytosterols and phenolic compounds; and other bioactive compounds, such as resveratrol and arginine. Walnuts are unique, in that they are a source of the omega-3 fatty acid, alpha linolenic acid. Tree nuts and walnuts are also high in total antioxidants.
An assessment of data from the Iowa Women’s Health Study reported strong and consistent reductions in CVD and coronary heart disease death, with increasing nut/peanut butter consumption27. A recent pooled analysis of four U.S. studies showed that subjects in the highest intake group for nut consumption had about a 35% reduced risk of CHD incidence28, 29, 30, 31.
The first metabolic feeding trial on nuts was conducted in 1993, in which 20% of energy intake came from walnuts. Total cholesterol and LDL-C decreased 12% and 18%, respectively, in the normocholesterolemic subjects studied32. Greil and Kris-Etherton have reported that, since then, over 25 clinical studies have been conducted evaluating the effects of nut consumption on serum lipids and lipoproteins. The most studied nuts have been walnuts and almonds33. These investigations have evaluated lipids, lipoproteins and apolipoproteins and have consistently shown cholesterol-lowering effects.
More recently, the effects of nuts on other emerging CVD risk factors have been evaluated in clinical trials. In mildly hypercholesterolemic subjects, walnuts and walnut oil containing ALA significantly reduced CRP levels by 75%, in addition to other inflammatory biomarkers, including tumor necrosis factor-alpha, IL-6 and IL-1β34.
Recent data reports that nut consumption can reduce the risk of hypertension35. A prospective cohort of 15,966 participants from the Physicians’ Health Study I, who were free of hypertension at baseline, was followed. During 237,585 person-years, 8,423 new cases of hypertension occurred. Compared to subjects who did not consume nuts, hypertension rates decreased as nut consumption increased. For example, multi-variable adjusted hazard ratios for hypertension ranged from 0.97 for those who consumed nuts once to twice a month down to only 0.82 for those consuming nuts at least seven times per week. Of interest, in a secondary analysis stratified by body mass index, there was an inverse relation between nut intake and hypertension in lean subjects, but not in overweight or obese subjects. This data suggests that nut consumption is associated with a lower risk of hypertension.
Growth in the demand for cocoa and chocolate products has grown in the last few years, due to favorable reports about heart-health benefits. For the scientist, the interest lies in the array of plant-derived antioxidants--particularly, flavonoids and anthocyanidins and their sub-classes (for example, catechins and proanthocyanins), which have numerous beneficial cardiovascular properties.
Mink, et al., have recently published the results of a large prospective study in post-menopausal women utilizing USDA databases to examine the associations between flavonoid intake and CVD mortality36. Specific subclasses of flavonoids (i.e., flavanones) and specific foods, including chocolate, were found to be associated with a reduced risk of CVD mortality.
Over the past decade, a number of human dietary intervention trials with flavanol-containing cocoa products have provided direct evidence in support of their cardiovascular benefits and potential cardioprotective effects. Reviews of these studies have reported that the acute consumption of cocoa can protect LDL particles from oxidation ex vivo and improve platelet reactivity, endothelial function and insulin sensitivity37, 38.
The results of a recent meta-analysis of five randomized, controlled studies comparing cocoa intakes in a total of 173 subjects demonstrated that systolic and diastolic BP were -4.7mmHg and -2.8mmHg lower, respectively, in high-cocoa consumers compared with cocoa-free controls39. Given that BP is a recognized cardiovascular risk factor, the demonstration that the consumption of flavanol-containing cocoa can reduce BP within the range of 3-5mmHg is notable.
Insights into Antioxidants
In 2000, the Institute of Medicine defined a dietary antioxidant as “...a substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiological function in humans.” Since oxidative stress is common in chronic degenerative disease, dietary antioxidants may have a protective effect. Every dietary plant contains numerous types of antioxidants with different properties.
Well-known antioxidants include a number of enzymes and other substances, such as vitamin C, vitamin E and beta-carotene (which is converted to vitamin A), and lycopene. There are also polyphenols, which include phenolic acids (cinnamic acids, benzoic acids).
These antioxidants have properties similar to those of the flavonoids and anthocyanidins, which were described earlier as being capable of inhibiting LDL oxidation, thrombosis and inflammation40, as well as improving endothelial function36 and, thus, reducing CVD risk. Abundant in richly colored red, blue and purple fruits and vegetables, anthocyanins decrease total and LDL cholesterol and show additional atherosclerotic benefits of transporting excess cholesterol from peripheral tissues to the liver for biliary excretion41.
Cranberries, which are particularly rich in flavonoids, have been reported to decrease plasma oxidized LDL concentrations, increase antioxidant capacity and HDL cholesterol42. Similar CVD protective effects can be seen in resveratrol (the polyphenol from grapes), stilbenes, lignans and other flavonoids (of which there are over 6,000).
Brighenti, et al., reported a significant inverse relationship between total antioxidant capacity of the diet and inflammatory markers, including CRP and soluble intercellular cell adhesion molecule-1 in 243 non-diabetic subjects43. The relationship was strongest for subjects with hypertension. The correlation with inflammatory proteins could be one of the mechanisms explaining the protective effects against CVD of antioxidant-rich foods. This could be of particular significance for subjects with high BP.
Plant sterols, phytosterols, are cholesterol- like compounds that are found mostly in vegetable oils, nuts and legumes. There are about 44 sterols known to exist in plants. The phytosterols available to the food industry are mostly derived from vegetable oils, such as corn and soy, or from tall oil. Plant sterols are naturally present in Western diets in amounts similar to those for dietary cholesterol (about 170-358mg/day) 44.
More than 40 years of investigation in animals and humans has shown that plant sterols can reduce total and LDL cholesterol concentrations. Several investigations of normocholesterolemic to mildly hypercholesterolemic subjects have shown that consumption of margarine enriched with esterified plant sterols effectively lowers plasma total and LDL cholesterol concentrations by some 10 and 15%, respectively45. LDL cholesterol was also lowered with reduced-fat spreads containing plant sterol esters (compared to reduced-fat spreads that did not) consumed as part of an NCEP Step I diet by men and women with mild-to-moderate primary hypercholesterolemia. Additionally, total cholesterol values were lowered 6%, the ratio of total to HDL cholesterol decreased 8.1%, and triacylglycerol concentrations decreased by 10.4%46.
Phytosterols interfere with the uptake of both biliary and dietary cholesterol from the intestinal tract in humans. The serum cholesterol-lowering effects of phytosterols are believed to be associated with an inhibition of cholesterol absorption resulting from the higher affinity of phytosterols than of cholesterol for micelles47.
The results of intervention trials, along with data from epidemiological investigations, support that the regular consumption of omega-3s, fiber, grains, as well as nut-based ingredients, phytosterols, cocoa flavanols and other antioxidants, can favorably affect the vascular environment and may help to maintain, and even promote, cardiovascular health and reduce the incidence of stroke. The food industry has the opportunity to positively impact the health of the consumer through the development of tasty products utilizing these well-studied bioactives. NS
On the Web: NUTRITIONAL INGREDIENT TRENDS
* www.NutraSolutions.com -- Type in “Ingredients for Health Reference” in the keyword search field and scroll down to Cardiovascular Health for commercially available ingredients addressing this issue
* http://astor.som.jhmi.edu/~esg/TALKS/PointEstimation.ppt#257,2,Point Estimation -- A PowerPoint presentation discussing how to interpret and convey disease risks statistically
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Healthy with HeartAs research in the heart-healthy ingredients arena continues to grow, so do new product introductions. In the U.S. last year, Mintel’s Global New Products Database (GNPD) shows an impressive 158 new food and drink products launched with functional, cardiovascular claims to December 23, 2008; the number was 78 in 2007.
The most popular categories included: breakfast cereals, with 30 new entries (up from 16 last year); bakery, with 28 (an increase from only nine one year ago); 27 new entries in beverages (up from six in 2007); and snacks, with 19 new introductions (compared to 11 last year).
“Prepared Foods’ 2008 R&D Trends Survey: Functional Foods” reported a continued high interest in cholesterol reduction and cardiovascular health as targets for product development. When those surveyed were given a list of 27 ingredients, antioxidants (as a category), omega-3 fatty acids and fiber were ranked first, second and fourth as being of “most” interest for product development efforts in the next two years.
Capitalizing on consumers’ increasing awareness of the multitude of different “healthy for your heart” ingredients, food manufacturers are introducing products with two or more bioactives. “Mission Plus! Life Balance Flour Tortillas” contain antioxidants and DHA omega-3 fatty acids, which are stated to be “important for brain, eye and heart health.” CocoaVia Milk Chocolate Almond Bars are promoted as “heart-healthy snacks …formulated to help reduce bad cholesterol and promote healthy circulation. It contains natural plant sterols, as well as other fortifiers (such as vitamins B6, B12, folic acid, and antioxidant vitamins C and E). Corazonas Hearth Healthy Squeeze of Lime Wholegrain Tortilla Chips contain 3g fiber per serving and plant sterols. PistachiOats Heart Healthy Cookies are claimed to be the first heart-approved cookies--the name suggests a combination of nuts and fiber from oats. The company claims the cookies feature an antioxidant-rich recipe that can help reduce cholesterol, prevent the narrowing of arteries and reduce the risk of cardiovascular and heart disease.