Heart health ingredient winners and losers

Heart health ingredient winners and losers

Combating cardiovascular disease has been one of the most successful medical and public health interventions of the last 50 years. The spillover to functional food ingredients and complementary and alternative medicine (CAM) represents some of this industry's greatest successes, and a few inglorious failures.

According to a 2004 report from the World Health Organization, coronary heart disease, stroke and other cerebrovascular diseases, combined, were responsible for 13 million deaths worldwide, equal to 22 percent of all deaths.1 Closer to home, the U.S. Centers for Disease Control (CDC) put the 2006 number at 631,636 deaths and 26 percent.2 What is important, however, is the decline from earlier years. CDC prevalence statistics for the U.S. have the age-adjusted death rate from these diseases peaking in the 1950s, declining more than 60 percent since then.3-5

The classic role for Complementary and Alternative Medicine (CAM) is to front-run those areas in which medicine has not yet succeeded. For coronary and vascular heart disease, the situation tends to be reversed. Medical successes are so strong that they are able to pull, as trailing alternatives, CAM options that do have the additional benefit of being available without a prescription and with – one hopes – fewer side effects. Key CAM therapeutic approaches exist for lipid management, arrhythmia, artery health, inflammation, hypertension and homocysteine management.

Successful heart health ingredients

Fiber, phytosterols, soy protein, potassium and calcium lead the way with FDA-approved health claims, followed closely by FDA qualified health claims for fish oil; nuts; olive oil; and the B vitamins B6, B12 and folic acid. However, some of these ingredients that had reached or neared "significant scientific agreement" are being requestioned.

In 2007, the FDA set in motion a process to review the soy-protein health claim, which reads in part, "25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease." The American Heart Association supported revoking this health claim.6 The FDA has also proposed that the phytosterols claim to lowering cholesterol absorption be held to a higher standard requiring at least 2 g/day and only as incorporated into food, thus excluding popular dietary supplements that contain only 0.8g/day, the amount currently needed to justify the label health claim.7

Fish oil and nuts evidence appears to be going against the trend of revisiting claims because of newer evidence. The preponderance of evidence is that omega-3 fatty acids EPA and DHA reduce the risk of coronary heart disease deaths by 20-30 percent. Deaths from other causes are reduced to a lesser degree. The largest study enrolled 11,324 subjects to get either 0.85 g/day of omega-3 fatty acids or placebo for 42 months. Heart attack deaths were reduced by 20 percent. While the mechanism(s) is not certain, coronary heart disease is in part clearly a chronic inflammatory condition as tissues are in a cycle of damage and repair. Omega-3 fatty acids are known to be anti-inflammatory, by favoring less inflammatory prostaglandins and leukotrienes.8 Beneficial effects appear to also include reducing risk of arrhythmia.

Flaxseed oil, albeit another omega-3 fatty acid source, does not fare as well as the longer-chain omega-3s found in fish oil. The question has been whether alpha-linolenic acid, or ALA, can have a heart-health benefit either directly or as an adequate precursor to EPA and DHA. The answer is "maybe." Conversion to the longer chain-length fatty acids is inefficient – estimated at 10 to 15 percent. A review of flaxseed clinical trials found that while whole flaxseed or extracted flaxseed lignans significantly lowered total and LDL-cholesterol, flaxseed oil did not.9 On the plus side, numerous epidemiological studies connect higher dietary ALA intake to lower risk of cardiovascular disease. The Dietary Reference Intakes set Adequate Intake of ALA at 1.6g/day for adult men and 1.1g/day for adult women.10

Tree nuts evidence for walnuts, almonds, pecans and hazelnuts come from epidemiological studies such as those evaluating Mediterranean-style diets, plus clinical trials and compositional analysis.11-14 Nuts rich in proanthocyanidins  (PACs) have some of the same cardio-beneficial results as seen with other proanthocyanidin-rich foods such as dark chocolate and red wine.13,14 Given that most of the PACs are contained in the removable, oft-discarded, bitter-tasting skins, there is a potential raw material here for a supplement ingredient.      

Ingredients short of FDA approval

"Fair to middling" and "muddling through" convey so-so quality, perhaps moving in a better direction. These terms aptly describe the state of many of the ingredients buttressed by structure/function claims but short of a FDA-approved health claim or qualified health claim.

Hypertension is a good example of medicine leading and alternative medicine options following. Uncontrolled hypertension increases risk of stroke. This disease disproportionately affects African-Americans compared to the rest of the U.S. population. Despite the myriad choices of blood pressure-lowering medications, current estimates are that 60 million Americans are hypertensive and an additional 60 million prehypertensive. And, given the aging of baby boomers and the nationwide increase in obesity, those numbers are not decreasing anytime soon.

For the prehypertensive, there are promising nonpharmalogical approaches. Increasing potassium and calcium intake from foods has a modest but consistent effect, as does fish oil. Not as well known but also with consistent evidence are coenzyme Q10 and PACs, a subset of plant-derived polyphenols. From a review of 12 clinical trials, coQ10 in amounts of 60 to 225mg/day resulted in average decreases of 15.6 and 8.7mm/Hg for diastolic and systolic blood pressure, respectively. All 12 trials showed a decrease.15 Clinical trials conducted with dark chocolate, but also with Concord grape juice, and other PAC-rich foods, demonstrate a 4 to 8mm/Hg decrease in blood pressure.16 The apparent mechanism for PACs is one of vasodilatation mediated through increased nitric oxide concentration in arteries, but there may also be a direct inhibition of endothelin-1, a vasoconstrictor peptide.17,18

Pantethine is on the radar as an up-and-coming dietary supplement for lipid management. Pantethine is an S-S linked dimer of two pantothenic acid (vitamin B5) molecules. Seventeen published clinical trials testing doses in the range of 600 to 1,200mg/day resulted in lipid changes on the order of 12 percent decrease for total cholesterol, 13 percent decrease for LDL cholesterol, 19 percent decrease for triglycerides and a 10 percent increase for HDL cholesterol [unpublished review]. Most of this data dates back to trials conducted in Japan before 1990, but a recent trial in the U.S. replicated the findings. With 120 subjects randomized to either placebo or pantethine at 600mg/day for eight weeks followed by a second eight week period at 900mg/day, LDL cholesterol was lower as soon as two weeks and remained significantly lower than the control group through the end of the study.19 The mechanism is not entirely understood, but pantethine is a precursor molecule for the synthesis of coenzyme A, a cofactor in dozens of enzymatic pathways, including many involved in fatty acid and carbohydrate metabolism.

Niacin is a curious case, as it is a vitamin, dietary supplement or prescription medication depending on dose. Prescription doses range from 500-3,000mg/day. As doses increase there is a progressively larger decrease of serum triglycerides and LDL cholesterol, and an increase in HDL cholesterol (the "good" cholesterol). Although supplements companies sell niacin at doses overlapping the lower end of the prescription range, both the American Heart Association and the National Cholesterol Education Program advise against substituting nonprescription for prescription niacin.20,21 One concern is that people who are self-administering may not be aware of the potentially serious side effects. Furthermore, a supplement form known as inositol hexanicotinate and sold as a "flush-free" niacin does not have supportive clinical evidence that it lowers blood lipids.22

Red yeast rice (RYR) is a special case. This dietary supplement may contain "monacolin" compounds either chemically identical or similar to lovastatin, the generic drug name for Mevacor, the first prescription statin drug. Statins inhibit cholesterol synthesis in the liver. The operative words for RYR products are "may contain." There is no standardized specification. Depending on how the rice is fermented with Monascus purpureus yeast, the end product can contain anywhere from a physiologically functional amount to just traces of lovastatinlike compounds. Some suppliers are suspected of spiking inactive RYR with pure lovastatin. The dilemma is compounded by the fact that the FDA considers RYR with monacolins illegal, while RYR without monacolins is not illegal (just not functional).23,24    

Heart health ingredient failures

Homocysteine (HCys) lowering as a heart-health benefit is another perfectly good theory ruined by facts. Epidemiological studies linked low food folate intake and consequent low serum folate with increased risk for cardiovascular disease (CVD). Companies in search of a biomarker latched onto serum homocysteine, as this precursor to methionine increases when folate or vitamin B12 is low. Supplementing with folic acid increases serum folate by more than 100 percent and does in fact lower HCys by 10-30 percent.25,26 Predictions were that this decrease would reduce the risk of CVD events and deaths by 10 percent. Predictions are nice, but two meta-analyses concluded that in large intervention trials, there was no significant benefit for risk of CVD or all-cause mortality among subjects with prior history of vascular disease. Dosing in reviewed trials was 800-1,000mcg/day.26,27

The evidence for preventing strokes is a bit more complex. The HOPE 2 trial reported on 2,500mcg folic acid in patients with known cardiovascular disease. Over a five-year span, folic acid at this large amount led to a 2.2mmol/L decrease in homocysteine and a 25 percent decrease in the incidence of stroke.28 The results from the Vitamin Intervention for Stroke Prevention study were different: 2,500mcg folic acid per day for two years similarly lowered homocysteine by 2mmol/L but there was no effect on stoke, cardiovascular event or death.29 Researchers are considering whether benefits will require co-supplementing with vitamin B12 in addition to folic acid.

There is a tremendous amount of ongoing human research with folic acid, meaning frequent new findings, both positive and negative. The clinical trials clearinghouse website, www.clinicaltrials.gov, lists 500 clinical trials currently recruiting subjects, plus hundreds more completed but not yet analyzed or published. Over the past three years there has been an average of 200 clinical trial articles per year. Collectively, all this activity may lead to a revisiting of the 10-year-old FDA qualified health claim for B vitamins and vascular disease. The current UL of 1,000mcg/day may also be revisited and revised downward.26

When you have nails, everything looks like a hammer. Actually, the adage is "When you have a hammer, everything looks like a nail," but let's not go there. The nails in this analogy are oxidants and the hammers antioxidants. The oxidation theory of aging cites cumulative damage due to years of oxidation to organs that either have no means to repair themselves or lose cell replacement capacity due to cumulative DNA mutations. This theory, holding great initial promise, has come under attack in recent years.

For example, vitamin E had a very long run as an antioxidant nutrient with cardiovascular benefits. Major observational studies suggested 20-40 percent reductions in coronary heart disease risk for vitamin E supplements.30 Subsequent randomized trials reported no protective effects, which led the American Heart Association to withdraw its recommendation.31 A meta-analysis by Dr. Edgar Miller of Johns Hopkins concluded that for all-cause mortality, vitamin E intake lower than 200 IU/day might have a benefit, while more than 200 IU/day increased risk.32 A more recent Cochrane Systematic Review supported the conclusions of modestly increased risk.33 Schurks' meta-analysis for stroke risk reported a 22 percent increase for hemorrhagic stroke and a 10 percent decrease for ischemic stroke.34

"Eat less" is the refrain from Michelle Obama, Michael Pollan and the 2010 update of Dietary Guidelines for Americans. "Eat more" is the unspoken motto of the food industry, which wants to promise shareholders six percent growth despite a population with a less than two percent growth rate.

The above noted trends for continuing improvements in disease detection and treatment are opposed by counter-trends of increasing obesity and diabetes – both strongly causative for cardiovascular disease.

Some of the previously approved food and ingredient health claims may be reversed, and other ingredients either need more research support or are being conclusively shown to be not effective. Functional ingredients do well when the measurables are the widely accepted cardio-biomarkers of lipids or blood pressure. Everything else, for example an anti-inflammatory mixture, is likely to be asked to demonstrate real clinical outcomes.

David A. Mark, Ph.D., is president of dmark consulting, a Boston-area science consulting firm. His 25+ years of industry R&D experience includes functional foods, dietary supplements and medical nutrition products. www.dmarknutrition.com

Disclosure: Dr. Mark has as clients dietary supplements companies that market products aimed at the heart-health category.

Editor's picks for heart health

Fish oil
Lowers serum triglycerides, makes blood thinner so sudden heart attacks are avoided, and as a bonus, likely aids a host of other health conditions from cognitive to joints and even obesity.

Probably the most underappreciated nutrient. This B vitamin both lowers LDL cholesterol and raises HDL cholesterol. At higher doses is classified as a bona fide drug.

Study published this month states pom juice consumption reduces blood pressure and hypertension, and "is convincingly a heart-healthy fruit." Tastes good, too.

Vitamin D and blood pressure

Vitamin D may lower blood pressure, but the effect is at most modest and the evidence is not consistent. According to a 2010 article, when large groups of people are tested, those with low blood levels of vitamin D are more likely to be hypertensive. Similarly, researchers who recruit healthy populations into multi-year studies find that those who had low vitamin D at the start were at greater risk of becoming hypertensive by the end of the study.35

Vitamin DWhile population studies appeared promising, placebo-controlled clinical trials in which subjects with hypertension were given vitamin D are less convincing. Dr. Miles Witham of the University of Dundee in Scotland pooled the results from eight published trials. On average, systolic and diastolic blood pressure decreased by 3.6 and 3.1mm/Hg, respectively. A weakness here is that the vitamin D dose used in the clinical trials may have been too low to have a significant impact.36

Authors of both reviews discussed several possible mechanisms by which vitamin D could affect blood pressure: excess fluid could be retained in blood because low vitamin D leads to a rise in renin and/or parathyroid hormones; vitamin D may be needed to maintain artery flexibility; or, increases in hypertension and decreases in vitamin D are both inversely correlated to aging and obesity but the change in vitamin D may not be causative.35,36 Among the many lifestyle changes recommended in the NIH Seventh Report on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, increasing vitamin D intake is not one of them.37                 


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  8. Wang C, et al. N3 fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary prevention studies: a systemic review. Am J Clin Nutr2006;84:5-17.
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  17. Wallerath T, et al. Red wine increases the expression of human endothelial nitric oxide synthase : a mechanism that may contribute to its beneficial cardiovascular effects. J Am Coll Cardiol2003;41:471-478.
  18. Corder R, et al. Endothelin-1 synthesis reduced by red wine. Nature2001;414:863-64.
  19. Rumberger JA, et al. Pantesin, an active derivative of vitamin B5, used as a nutritional supplement, significantly lowers cardiovascular (CV) disease markers in low to intermediate CV risk North American subjects: a triple-blind placebo/diet controlled study. Experimental Biology 2010 (abstract).
  20. American Heart Association. Cholesterol lowering drugs.
  21. National Cholesterol Education Program. Nicotinic acid. National Heart, Lung and Blood Institute website.
  22. Benjo AM, et al. Accumulation of chylomicron remmants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment. Atherosclerosis 2006;187:116-122.
  23. Liu J, et al. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chinese Med 2006;1:4-17.
  24. FDA press release, August 9, 2007: FDA warns consumers to avoid red yeast rice products promoted on internet as treatments for high cholesterol products found to contain unauthorized drug.
  25. Yang Q, et al. Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutritional Examination Survey (NHANES) 2003-2006. Am J Clin Nutr 2010;91:64-72.
  26. Smith DA, et al. Is folic acid good for everyone? Am J Clin Nutr 2008;87:517-533.
  27. Bazzano LA, et al. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006;296:2720-26.
  28. Saposnik G, et al. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE-2 trial. Stroke 2009;40:1365-72.
  29. Toole JF, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. JAMA 2004;291:565-575.
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  31. Kris-Etherton PM, et al. AHA science advisory: antioxidant vitamin supplements and cardiovascular disease. Circulation 2004;110:637-641.
  32. Miller ER, et al. Meta-analysis: high dosage vitamin E supplementation may increase all-cause mortality. Annals Intern Med 2005:142:37-46.
  33. Bjelakovic G, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2008;16;(2):CD007176.
  34. Schürks M, et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomized controlled trials. BMJ 2010;4;341:c5702.
  35. Ullah MI, et al. Does vitamin D deficiency cause hypertension? Current evidence from clinical studies and potential mechanisms. Int J Endocrin 2010:Article ID 579640.
  36. Witham MD, et al. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens 2009;27:1948-54.
  37. National Institutes of Health: Seventh Report on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. 2003. 
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