Risk Factors for Cardiovascular Disease
The American Heart Association (AHA) has made significant efforts over the last several years to educate the public on the risk factors that lead to heart disease. These comprise the mantra that almost every American can recite by rote: eat well, exercise more, don't smoke and drink in moderation. This advice is rooted in the epidemiology and etiology of cardiovascular disease and stroke. The landmark Framingham Heart Study of the last century was highly instrumental in teaching the medical community that the three key risk factors for heart disease are (in order) elevated cholesterol levels, high blood pressure and diabetes.

It can be argued that the present understanding of cardiovascular risk factors is overly biased by the findings of the Framingham Heart Study, particularly the rather simplistic, and now mostly obsolete, view that total cholesterol was the only concern. More recently, however, the very high level of risk associated with obesity, low-grade inflammation (as measured by the inflammatory marker c-reactive protein) and poor physical fitness (as measured by resting pulse rate) have gained widespread medical acceptance as recognized risk factors for cardiovascular disease.

Nutraceutical Interventions
More than any other disease, the etiology of cardiovascular disease reveals many risk factors that are amenable to nutraceutical intervention. The scientific literature shows that several ingredients marketed for use in dietary supplements address each of these. The ability for nutraceuticals to positively influence cardiovascular risk factors should be recognized as an enormous opportunity to nutraceutical companies.

Cholesterol Reduction: Cholesterol-lowering drugs still represent the largest slice of the cardiovascular and stroke pharmaceutical category. In fact, the two most successful pharmaceutical products of all time are cholesterol-lowering drugs. Due to the large amount of government- and privately-funded research done in the field of lowering cholesterol, there are myriad well understood approaches to cholesterol reduction.

At the risk of oversimplifying, it can be stated that the goal of cholesterol management is to lower low-density lipoprotein (LDL) cholesterol and elevate high-density lipoprotein (HDL) cholesterol. Cholesterol is obtained from food, but the body also manufactures it. As a result, total cholesterol management requires control of both dietary and genetic sources.

Phytosterols, soy protein and oat fiber hold the most prominent place among cholesterol-lowering products in the nutraceuticals industry. The science linking them to cholesterol reduction has led to approved health claims by FDA. Per 21 CFR 101.81 (soluble fiber), 21 CFR 101.82 (soy protein) and 21 CFR 101.83 (plant sterol/stanol esters), formulators using these products appropriately can use the health claim "may reduce the risk of heart disease."

Niacin is a special case. Like oat fiber, soy protein and phytosterols, niacin science has conveyed sufficient evidence to FDA to warrant cholesterol-lowering claims. In this case, niacin is considered a drug and is available only by prescription. However, niacin is also a vitamin, and as such is permitted in foods and dietary supplements. In principle, niacin could be dosed at a sufficiently high level to affect cholesterol levels, while still being marketed as a dietary supplement. To this ambiguity, the AHA recommends that niacin be taken only by prescription to lower cholesterol and then only as a pharmaceutical.

All other nutraceuticals that seek to intervene in cholesterol management must abide by structure/function claims that exclude mention of any disease (i.e., heart disease) or modification of any known disease biomarkers (i.e., cholesterol). The most widely used nutraceutical ingredients for cholesterol management are garlic, fish oil and policosanol.

Garlic extracts have been widely studied for lowering cholesterol. Results of well-controlled clinical trials have been mixed, but the weight of the evidence strongly suggests that if the active principles in garlic (allicin and alliin) can be protected from stomach acids, strong effects on cholesterol can be obtained.

While no cholesterol-lowering claims can be made for fish oils rich in docosahexaenoic acid (DHA) and eicosapentaenoic (EPA), results of epidemiological and intervention studies are such that the AHA recommends consumption of two servings of "fatty" fish per week. High omega 3 fatty acid fish oil extracts are widely available and generally make up an important part of the nutraceutical cholesterol-lowering arsenal.

Policosanol is a somewhat ambiguous nutraceutical ingredient that shows promise as a cholesterol-lowering agent. Policosanols extracted from plant waxes are widely used by nutraceutical manufacturers for cholesterol management, although the mechanism of action is not well understood.

In the category of "emerging" cholesterol-lowering nutraceuticals there are several promising candidates. These include black tea extracts, krill oil, novel soy protein fractions, polymethoxylated flavones (PMFs), avocado soy unsaponifiables (ASU) and tocotrienols.

Black tea contains theaflavins, which are oxidized catechins that form when green tea is converted into black tea. Certain of these theaflavins have exhibited potent inhibition of the enzyme squalene epoxidase, a key enzyme involved in the body's synthesis of cholesterol.

Krill oil has recently emerged as a dietary supplement for lowering cholesterol. This is because a study published in late 2004 showed dramatic effects on cholesterol levels at doses of 1-3 grams per day of krill oil.

A modified soy ingredient from Japan, c-terminal soy protein hydrolysate bound to phospholipids, has shown a great deal of promise, according to the scientific literature. It potently sequesters cholesterol from bile acids, preventing the reuptake of circulating cholesterol, whether from dietary source or coming directly from the liver. At doses of 3 grams per day, this unique nutraceutical shows great promise in cholesterol maintenance, lowering LDL cholesterol and elevating HDL cholesterol.

PMFs are abundant phytochemicals found in citrus that are now commercially available in the dietary supplement industry as extracts. They have very recently shown impressive anticholesterolemic activity at numerous points in cholesterol biosynthesis and absorption in animal models. While still very much an "emerging" nutraceutical, PMFs are particularly interesting because they are found in citrus pulp, which is an abundant and inexpensive byproduct of citrus juicing.

Another intervention involves taking another common agricultural byproduct, in this case the "unsaponifiable" fraction of soybean and avocado oils or ASU for short. This interesting mixture has undergone extensive clinical testing in France and shows very promising results for cholesterol management. Like policosanols, there is some ambiguity when it comes to pinning down the mechanism of action or even the exact chemical makeup of ASU, but the clinical data are compelling, and like policosanol, is worthy of further investigation.

Tocotrienols are phytochemicals found abundantly in palm oils and are structurally similar to vitamin E. They have a very significant effect on cholesterol synthesis in vitro. Compared to statins, which directly inhibit HMG-CoA reductase, tocotrienols reduce the actual level of HMG-CoA reductase by increasing HMG-CoA reductase degradation and decreasing the efficiency of HMG-CoA reductase mRNA translation.

Hypertension: The second major cardiovascular disease risk factor is high blood pressure, or hypertension. While hypertension is considered a disease, no claims for lowering blood pressure have been approved by FDA for nutraceutical products, although there are a few promising candidates.

Most of these nutraceuticals act by inhibiting angiotensin converting enzyme (ACE). There are a number of specific peptides that inhibit ACE, including a specific casein hydrolysate with an interesting published clinical trial. Sesamin, found in sesame oil, has been shown to have positive effects on lowering blood pressure in both animal models and human intervention studies.

Gamma-aminobutyric acid (GABA) has long been implicated in blood pressure lowering, and a recent study has at last shown an effect on blood pressure when using appropriate doses of GABA in an animal model.

Finally there is green tea. Green tea catechins have been shown to inhibit ACE in vitro and have long been a putative anti-hypertensive. In addition, green tea contains the unique amino acid L-theanine, which has been shown to have anti-hypertensive effects in animals. Currently, L-theanine is commercially available in synthetic form.

Circulation: In the last several years, a number of dietary supplements have been introduced that seek to address nitric oxide (NO) levels. NO's role as a signaling molecule in cardiovascular health won three U.S. researchers the 1998 Nobel Prize in Medicine. Interestingly, two of these Nobel laureates have introduced "signature" dietary supplements targeting this intervention. These interventions seek to elevate NO levels by providing arginine and arginine precursors, which is the substrate by which the enzyme endothelial nitric oxide synthase (eNOS) makes NO. Dietary ingredients, which upregulate eNOS include mixed tocopherols, flavonoids, such as those found in pine bark and grape seed, as well as ellagic acid, which is abundant in pomegranate. DHEA (dehydroepiandrosterone) has also been shown clinically to increase expression of the eNOS gene, permitting more eNOS to be made by the body.

Inflammation: One of the major advances in the understanding of heart disease over the past few years relates to the effect of low-grade inflammation on heart health. As a result, it is increasingly becoming standard practice to test for c-reactive protein (a biomarker for inflammation). This is a prominent risk factor among diabetics, who have a much higher propensity toward heart disease. There are numerous interventions that have been implicated in reducing c-reactive protein. These include vitamin C, vitamin E and omega 3 fatty acids from fish or krill oil. While anti-inflammatory drugs that specifically inhibit the inflammatory enzyme cox-2 may actually increase the risk of heart disease, general anti-inflammatory nutraceuticals like white willow bark have no negative side effects in relation to the heart.

Heart Energy: The heart is our strongest muscle. Like all muscles it requires large amounts of the basic energy currency adenosine triphosphate (ATP). Nicotinamide adenine dinucleotide (NADH) and co-enzyme Q10 (CoQ10) are essential components of the mitochondrial manufacture of ATP. CoQ10 is also a potent antioxidant (important in preventing oxidation of LDL cholesterol) and a membrane stabilizer. CoQ10 is obtained from dietary sources, but it is also biosynthesized in the liver using the same pathway as cholesterol. As a result, CoQ10 levels can be depleted by HMG-CoA reductase inhibitors (e.g., by "statin" drugs). CoQ10 has been an approved heart failure drug in Japan for the last 30 years.

Marketing Heart Health Products to Consumers
Constant media attention has consumers of all ages aware of the cardiovascular risks they face in the immediate or distant future. There is an undisputed need for innovative nutraceutical solutions, but not at the expense of two keys to consumer confidence: proven efficacy and safety.

In the 1990s, consumers witnessed many herbal supplements come and go. The situation is not much different today, as many consumers remain confused by marketing and media messages associated with health and ingredient claims. Shoppers want the straight story: Does garlic really reduce cholesterol levels? Is vitamin E safe for long-term use?

These are the types of issues being addressed by consumer research firms like Iconoculture, Minneapolis, MN. The consumer values tracked by Iconoculture are central to understanding marketplace trends and health, and more specifically, cardiovascular health consumers. Values drive consumer behavior and, when properly identified, help marketers, advertisers and industry professionals understand why consumers behave as they do. Some of the values that are key to consumer heart health include:

Security: Consumers want to know that they and their loved ones can safely take a supplement.

Trust: Consumers want a brand and a story that have earned their trust. Period.

Purity: More consumers are reading labels and questioning ingredients and their origins.

Quality: Educated consumers realize that nutritional supplements can vary dramatically in their efficacy because of differences in ingredient quality.

Integrity: Consumers are becoming wise to companies that do not deliver on their promises, whether they are issues with brand identity, questionable claims or manufacturing processes.

Expertise and Excellence: Bombarded with products in an industry where everyone is an "expert," shoppers need to know precisely how a product sets itself apart from the crowd.

Challenges to Consider
As has been stressed previously, cholesterol, hypertension and circulation fall under the umbrella of disease management, according to FDA, and are therefore not appropriate targets for dietary supplements. As a result, marketers of dietary supplements must be very cognizant of FDA's structure/function rules. While the science supporting the various ingredients discussed in this article is compelling, it must be recognized that the quality of science available to support these nutraceuticals for heart health is not of sufficient quality to warrant direct claims for the prevention, treatment, cure or mitigation of heart disease. This presents a challenge to marketers, who must convey their products' putative heart health benefits without direct mention of them.

Further complicating the issue is the fact that while many physicians are amenable to recommending dietary supplements for their patients, they must offer tangible benefits and good values when compared to traditional pharmaceuticals. This makes the marketing of nutraceuticals targeted at hypertension particularly problematic. The existing drug regimens for mild to moderate hypertensives include thiazide-derivative diuretics and ACE inhibitors, which are highly effective, extremely inexpensive and have very low incidence of side effects.

Finally, like an increasing number of nutraceutical categories, there is an intellectual property "minefield" in heart health. It is safe to say that the majority of the interventions discussed in this article are covered by one or more patents. It is the responsibility of any marketer to ensure its proposed intervention does not infringe on any of these patents.

Future Opportunities
The real power of the cardiovascular health market lies in finding creative ways to speak to the consumer values addressed previously.

Security and Trust: Be straight with the consumer. Deliver easy-to-understand ingredient and safety information and claims. Avoid hype that offends people who've done their homework. Simply put, avoid far out claims and treat consumers like the smart, aware and critical consumers they are. Maintain consumer trust once you've earned it. Even if your product or ingredient is not in question, tell consumers why it's known to be safe and effective. A proactive approach is the best way to maintain consumer trust.

Expertise and Excellence: If your product is a known safe alternative to others, say so! Consumers shying away from prescription, OTC and questionable nutrition products gravitate toward options they can use with confidence.

Quality: Don't just tell consumers your ingredients and products are of high quality. Tell them exactly how you are committed to safe and effective products. Give consumers and retailers an "insider's view" of your research and development, quality assurance and quality control measures. Provide detailed information about ingredient selection and safety and efficacy testing. (Those not concerned will bypass the details.)

Purity: What is in your product is just as important, if not more so, than what's not in it. Call out where you have avoided excipients, for example.

Integrity: Does your corporate conscience embody integrity and trust? Marry a commitment to science and performance with a dedication to trust, safety and consumer confidence. If you've lost consumer trust, own up. Be forthright with an immediate public apology before you dig your brand into a crater of lost loyalty.

The market potential for nutraceutical products that can positively influence known cardiovascular disease risk factors cannot be overstated. Medical doctors understand the importance of controlling these risk factors (i.e., cholesterol, obesity, hypertension) very well, and presenting all of the evidence to support nutraceutical interventions represents enormous opportunity. The nutraceuticals industry has the same tools available to it that "big pharma" does, such as the "gold standard" randomized, double-blind, placebo-controlled clinical trial and other potent interventions. It is our challenge to use them. Indeed, it is our responsibility.

About the authors: Michael Yatcilla is the vice president of Research & Development for Natrol, Chatsworth, CA. He can be reached at 818-739-6000; E-mail: myatcilla@natrol.com. Jennifer Haid is senior consumer analyst at Iconoculture, Minneapolis, MN. She can be reached at 612-642-2222.

*References furnished upon request.*