By Mike Montemarano, Associate Editor06.02.20
Cardiovascular disease (CVD) remains the leading cause of death in the U.S. despite significant strides made to provide people with the means to prevent related health issues like heart attacks, strokes, heart failure, arrhythmia, and heart valve problems.
According to the American Heart Association, 80% of all CVD cases and related morbid outcomes can be prevented in those at risk through interventions in medicine, nutrition, lifestyle, smoking habits, and exercise. Still, CVD maintains its rank as the number-one killer of Americans, costing healthcare systems about $1 billion every day and killing hundreds of millions each year. According to the Centers for Disease Control and Prevention (CDC), more than half of those living in the U.S. have at least one CVD risk factor.
Despite the growing body of nutritional science surrounding the functions that foods and dietary supplements might play in maintaining cardiovascular health, no significant decreases in heart disease rates have been achieved in most populations over the past several decades. That fact, compounded with an aging population, means that heart disease is slated to become an even greater social burden, and an even greater stress point on the capacities of healthcare systems around the globe.
For these reasons, it’s no surprise that the heart health segment of the nutritional market remains a dynamic, crowded, and competitive segment for dietary supplements and functional foods alike.
Experts characterize it as extremely difficult for new products and ingredients to enter the arena shared by a wide variety of omega-3s, dietary fibers, plant sterols, antioxidants, vitamins, minerals, and more, making up a massive chunk of the estimated $122 billion supplements market. Not only is the market flooded with some of the most well-established and scientifically-substantiated products, but the criteria to receive approvals for any heart health marketing claim by government agencies for a supplement is extremely rigorous.
In today’s climate, consumers seeking out supplements to maintain cardiovascular health are hoping to find time-tested products with the greatest wealth of scientific substantiation, market research suggests.
Traceability, third-party verification, and high manufacturing standards are especially important to the viability of products in this space, given that many of these products are used concurrently with traditional western medicine for serious health issues. Preliminary trials without serious significance don’t cut it in the eyes of consumers seeking lifelong solutions. Additionally, there is a shift occurring in which the benefits offered by dietary supplements are beginning to appeal to younger demographics who are taking a more proactive approach to CVD and its precursors.
In addition to specific needs, it appears that consumers are looking for nutritional solutions to cardiovascular health that are more holistic than ever before.
A survey conducted by Lycored found that 67% of consumers improved their diet in order to protect their cardiovascular health, which scored higher than all other options, including increasing exercise levels. Additionally, 59% agreed with the statement “I believe in a holistic approach to cardiovascular wellness, including physical, mental, and nutritional elements.” This figure rose to 65% among consumers based in the U.S. only.
Sharing a similar sentiment to a Mintel study from last year that suggested consumers are seeking foods and supplements in all categories to enhance mood and mitigate stress levels, people are responding well to the idea of alleviating stress as part of their cardio-protective regimen. Among consumers Lycored surveyed, 95% said they found the idea of being able to “calm your heart” appealing, and 35% said they would be more likely to buy a product for cardiovascular health if its packaging included the word “calm,” indicating a sense that popular opinion attributes the ubiquitously rising stress levels seen in the U.S. with cardiovascular health outcomes.
Stress is likely the most palpable cardiovascular risk factor people experience on a day-to-day basis, thereby making it an important point of communication for conscious consumers. While more research is needed to determine how stress contributes to CVD, it clearly has an impact on the behaviors considered risky, such as smoking, drinking, nutritional intake, and exercise.
At the forefront of consumer education has been the American Heart Association (AHA), perhaps one of the leading organizations providing freely available reports and regimens to allow consumers to take more control over their cardiovascular health outcomes. Additionally, AHA has armed many consumers in the fight against CVD risk by identifying the myriad of risk factors that extend well beyond cholesterol, many of which can be addressed in part through nutraceutical intervention. The organization is also more inclined than most to take a proactive, authoritative stance on the widespread nutritional research that it evaluates.
Consumer surveys suggest people are seeking out nutraceuticals for cardiovascular health maintenance in a way that is intuitive, scientifically bound, and trustworthy. This, fueled by the sheer prominence of CVD as the still-growing and leading cause of death in the U.S. is reason enough for consumers to continue viewing blood pressure, cholesterol reduction, inflammation modulation, and other CVD issues as the primary drivers for their dietary supplement purchases. These condition-specific needs, which become more prevalent among older demographics as more serious health issues arise, allow for more nuance in the types of demands that work best for each consumer, calling for more specialized formulations and innovations.
Omega-3s
Omega-3s have long been among the most popular supplements supporting cardiovascular health to date. The most potent source of omega-3s is oil extracted from marine species such as fish, krill, and algae, each of which provide unique profiles of EPA and DHA.
Omega-3 long-chain fatty acids have been extensively researched for decades, with consistent results showing they can be efficacious in reducing LDL cholesterol, arrhythmias, thrombosis, lipoprotein levels, growth rates of arterial plaque, and even blood pressure (slightly). It has also been shown that omega-3s can modulate the body’s inflammatory response beneficially, which researchers believe is tied to better cardiovascular health outcomes. According to Greg Lindsey, vice president of corporate marketing for Wiley Companies, over 40,000 studies and 4,000 human clinical trials to date have examined the potential benefits of fish oil.
“Consumers are becoming much more educated about all nutritional supplements, which is a very good thing for manufacturers and suppliers focused on delivering the highest quality products,” Lindsey said. “This includes researching beyond advertising claims, to gain a much better understanding of quality and purity.”
The sheer bulk of statistical significance has grown immensely over recent years, with large-scale, population-based trials such as REDUCE-IT, ASCEND, and a study published in the British Medical Journal in March which found statistically significant improvements in CVD outcomes in over 450,000 people with and without pre-existing conditions.
“Consumers are taking a 360-degree approach to their health and are seeking out supplements to help close the gaps. From managing symptoms to preventative measures, consumers are most definitely engaged with heart health foods and supplements,” said Kate Pastor, senior vice president of sales at Aker BioMarine, which specializes in omega-3 supplements formulated with krill oil sourced from Antarctica.
“Regarding the product itself, consumers are becoming more discerning and knowledgeable about their ingredients,” she added. “They want to know where the product is coming, how it was produced, if it’s third-party verified, and more. Consumers are interested in traceability and sustainability, and have trust and confidence in products that are made in the USA.”
As more research abounds in the role that inflammation has on cardiovascular and other conditions, this will likely enhance understanding of the benefits that fish oil provides.
“Chronic inflammation is a common denominator and link between chronic conditions, including cardiovascular health, diabetes, Alzheimer’s disease, arthritis, auto-immune conditions, periodontal disease, and more,” said Gretchen Vannice, director of nutrition education and research at Wiley Companies. “It’s the flashing red light indicator on the dashboard, warning of compromised health status. Inflammation interferes with the body’s ability to regain homeostasis, or a healthy state.”
In spite of the extensive research which had mixed results at times, in part due to the huge variety in dosages, population variants, and strengths of methodologies employed in omega-3 studies over the years, the exact biological mechanisms by which omega-3 fatty acids benefit the heart and reduce triglycerides is elusive at this time.
Researchers are also reaching conclusions on what they would consider an optimal daily intake of omega-3s necessary to prevent an apparent deficiency.
“In 2009, low intake of omega-3s was attributed to up to 96,000 preventable deaths in the U.S., second only to high salt intake,” Vannice said. “Ten years later, a validated predictive model of disease risk (completed by a group from Harvard School of Public Health, Tufts School of Nutrition Science and Policy, Brigham and Women’s Hospital Department of Cardiovascular Medicine, and more) reported that the lack of EPA and DHA omega-3s in our diet is costing the U.S. $12.74 billion a year for cardiovascular disease and type 2 diabetes care.... What’s more, these findings above are calculated at an intake of 250 mg of EPA and DHA per day; that’s the minimum amount generally considered to prevent frank deficiency.”
Meanwhile, a medical-grade fish oil-derived EPA, icosapent ethyl (branded as Vascepa) is undergoing trials as a drug candidate for CVD, with researchers from the UCI School of Medicine projecting that it could tentatively prevent 70,000 cardiovascular-related deaths per year.
For those who object to fish oil for whatever reason, there has also been a rising trend in obtaining the essential EPA and DHA from algae, which is how omega-3s enter the bodies of various fish species from which oil is derived.
Scientists have been lab-growing certain strains of algae for higher EPA and DHA content, making algal omega-3s increasingly more viable. Fish oil remains the most popular for supplements, infant formulas, and other formulations. While algae oil hasn’t been the subject of extensive studies at nearly the same prevalence as fish oil, several studies have compared its efficacy to fish oil, suggesting that nutritional equivalence can be achieved, and that the bioavailability components are also equivalent. In addition to algae oil having a more neutral flavor profile, appealing to those who can’t stand a fishy aftertaste, algae oil also appeals to vegetarians and vegans.
In other news, and in part of the push to integrate omega-3s into the dietary aspirations of consumers, OmegaQuant recently established an omega-3 testing kit which health practitioners can use in a partnership with Standard Process, so that practitioners can enable patients to evaluate their status in omega-3s, omega-6s, and trans fats all at once with a finger prick sample.
“Nutritional assessment tools, such as vitamin D or Omega-3 Index tests, can help provide a nutritional baseline for consumers,” Pastor said. “The Omega-3 Index is the percent of long-chain omega-3 fatty acids, (EPA and DHA) and the Omega-3 Index test measures the levels of these nutrients in our red blood cells. Industry experts are seeing this test as a long-term and constant marker of omega-3 status and a way to determine your risk level for heart disease.”
Pastor said that another driver in the growth of omega-3s in the heart health space will be offering consumers the ability to customize the supplements they use for heart health applications, due to the highly nuanced nature of demands for heart health formulations.
“In addition to customizable solutions, we are seeing an increased awareness and interest in proactive heart health care among younger demographics,” Pastor said. “While some consumers with pre-existing heart conditions are working to manage or reduce risks, others are following more proactive approaches to their health by changing their lifestyles and taking simple steps to being a healthier version of themselves while they are still healthy; and this is a combination of exercise, diet and supplementation.”
CoQ10
Coenzyme Q10 (CoQ10) is a fat-soluble, vitamin-like substance that is produced within the body, and is also found in many foods. It has been well-established that age and certain medical conditions such as the use of statins can deplete CoQ10 from the body, and researchers have been keen to understand the best way in which this beneficial nutrient can be introduced into the body for those who are deficient in it. CoQ10 is a potent antioxidant, and plays a major role in the production of cellular energy. People have been taking CoQ10 supplements in their bioactive form, ubiquinol, for many decades.
One of the most pivotal studies propelling CoQ10’s growth in the heart health segment, published in the Journal of the American College of Cardiology, established a low level of myocardial CoQ10 related to the severity of heart failure in 420 patients, the largest study of its kind to date.
“CoQ10 remains the dietary supplement most recommended by cardiologists,” said Scott Steinford, CoQ10 Association executive director at large. “The efficacy of CoQ10 is supported by scientific, clinical, and anecdotal evidence. Statins also are a driving contributor to CoQ10 supplementation since statins significantly reduce CoQ10 levels. It is theorized that many of the more serious statin side effects are a result of CoQ10 depletion.”
Patients in the study with moderate to severe heart failure were then administered 100 mg of CoQ10 three times daily, or a placebo. After 16 weeks they were evaluated with a six-minute walk test, and levels of N-terminal pro-B type natriuretic peptide, and a follow-up period monitoring any major outcomes.
The study found a 43% decrease in cardiovascular death in the CoQ10 group compared to the placebo group, and only 15% of the CoQ10 group experienced major adverse cardiovascular events compared with 26% of the placebo group by the study’s conclusion.
As the CoQ10 market continues to grow, the most prominent trade group associated with providing centralized industry guidelines, and information to the public, is the CoQ10 Association.
Over the past 15 years, CoQ10 has gone from a relatively niche place in the dietary supplements market, to one of the most-consumed dietary supplements in the U.S., and is now a household name in terms of dietary supplements beneficial to the heart. It has grown steadily (20% CAGR since 2000), and most analysts believe that trend will continue as cardiovascular health remains one of the most important categories across the dietary supplements market.
CoQ10 is largely considered to hold preventive benefits; numerous studies have found a positive correlation between CoQ10 deficiencies and CVD, cardiovascular mortality, stroke patients, and more. It is often also prescribed by doctors in conjunction with statins, due to evidence from statin recipients who repeatedly confirm that it mitigates some of the uncomfortable side effects associated with the cholesterol-lowering medication, though no large-scale studies have clinically supported this yet. It holds antioxidant properties, and as a nutrient, is responsible for the body’s production of ATP molecules, the basic source of energy in cellular function.
What puts CoQ10 at an advantage, compared to other nutritional supplements, is the fact that its biological mechanism is so well-understood at the molecular level, Steinford said. Its energy carrier function allows it to continually go through an oxidation-reduction cycle, by accepting electrons, and its role in the functions of both the mitochondria and muscle cells are clear. Additionally, a wide host of precursors to CoQ10 deficiency are well-understood, and CoQ10 levels can be tested with a wide array of effective methodologies. It is critical to mitochondrial respiration, improves tolerance to statins and myalgia symptoms, and may reduce the size of a myocardial infarction if/when individuals on statin therapy have an event.
As of late, it appears that the biggest ongoing developments in the CoQ10 space will be innovations in improving its bioavailability. Oral delivery of CoQ10 is extremely challenging due to the fact that it is insoluble in water, and has limited absorption in the digestive tract. Products can be formulated to be self-emulsifying, but much of the absorption also hinges on physiological characteristics of the individuals. Cross-examinations have found that certain formulations, such as softgels and liquid-filled capsules, may have three- to four times the efficiency of CoQ10 absorption in significant groups of
study participants.
Vitamin K2
Vitamin K2 has been shaking up the cardiovascular health segment since studies on its ability to improve arterial stiffness came back with positive results, signifying that it functions much more holistically and differently than K1. To put it simply, vitamin K1 functions in the liver to prevent blood clotting, whereas K2 is highly active in tissues outside the liver, including the bones and, as very recent studies continue to show, the cardiovascular system. It works for the heart both as an inhibitor of vascular calcification, and as a highly potent antioxidant.
NattoPharma, the makers of a proprietary vitamin K2 in MK-7 form, MenaQ7, has been the driver of all research confirming K2’s health benefits, as well as dosage-finding and safety studies on healthy volunteers, hemodialysis patients, and as a potential oral anticoagulant treatment. Kate Quackenbush, NattoPharma’s director of communications, shared some of the groundbreaking research which has propelled its flagship product into the heart health sphere.
“[Consumers] want to know that the products they are investing in deliver true health benefits,” Quackenbush said. “An efficacious product has to start with clinically validated raw materials, and MenaQ7 is the only vitamin K2 as MK-7 clinically proven to impact heart and bone health.”
Vitamin K2’s primary application, before its cardiovascular benefits were proven, was to improve bone health by ensuring that calcium binds to the bone mineral matrix, but another aspect of that process involves inhibiting a calcium buildup on arterial walls, according to the research. A study from the New England Journal of Medicine (Rosenhek, et al., 2000) suggested that calcification in the arteries can contribute to the shortening of life expectancies by as much as 10 years.
It’s a challenge to ensure that vitamin K2 is formulated and encapsulated effectively, Quackenbush said. There are many variabilities and applications at hand that manufacturers must consider when putting any products containing MenaQ7 to the stability “stress test.”
“Some K2 suppliers are claiming that they are the ‘only stable solution on the market,’ inferring that others are not,” Quackenbush said. “In fact, it is misleading to suggest that an encapsulated product will be stable in every application and testing by NattoPharma and other third parties show that stability rates vary depending on the application. In truth, no encapsulation is ‘one size fits all.’ However, NattoPharma’s CryoCap microencapsulation technology has demonstrated stability in a myriad of environments, against mild minerals, more aggressive mineral mixes, and even very aggressive products, such as chelates.”
While observational data had long suggested a positive link between vitamin K2 intake and cardiovascular longevity, evidence from a 2015 trial conducted by Maastricht University showcased its ability to reduce age-related arterial stiffness caused by calcification, and even promote unprecedented levels of vascular elasticity in 244 postmenopausal women. Not only did this propel vitamin K2 into many individuals’ approaches to cardiovascular longevity, but it substantiated that arterial hardening is not an age-related condition; in most cases, the cause is a nutrient deficiency.
Further studies, at the same dosage of 180 mcg of MenaQ7, found similar benefits for arterial stiffness and the promotion of arterial flexibility.
“In 2018, a one-year clinical trial with healthy men and postmenopausal women was completed by the expert researchers at VitaK (sponsored by NattoPharma),” Quackenbush said. “This study also demonstrated that 180 mcg daily of MenaQ7 Vitamin K2 as MK-7 improved vascular health, as measured by lower levels of inactive Matrix Gla Protein (MGP). This study is currently under peer review for publication.”
NattoPharma has been supporting several studies since then as researchers attempt to develop a more layered understanding of the mechanisms at play behind K2’s cardioprotective benefits, and any other beneficial properties it may hold.
MenaQ7 was shown in a study to boost nitric oxide (NO), improving NO-dependent endothelial function.
“Endothelial dysfunction has been associated with many health issues, including being a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis, a disease of the arteries characterized by the development and deposition of plaques and by vascular inflammation of fatty material on the inner walls,” Quackenbush said. Given the fact that endothelial function determines cardiovascular health, researchers hypothesized that the positive effects of vitamin K2 intake on cardiovascular mortality could be linked to the vitamin K-dependent regulation of endothelial function. The study concluded that low dose of vitamin K2 as MK-7 (as MenaQ7 from NattoPharma) could provide benefits for cardiovascular health, playing an important role in the regulation of endothelial function.
Another two studies published in Nephron linked vascular calcification, and vascular and arterial stiffness to MGP, a vitamin K-dependent protein. It was additionally found in this research, based on the results of 83 chronic kidney disease (CKD) patients, that inactive MGP levels in blood plasma were associated with increased vascular calcification, and that this vitamin K-dependent protein may be an early marker for vascular calcification in CKD patients.
Evidence that vitamin K2 may be especially helpful for those with kidney issues came in a study published by the Journal of the American Society of Hypertension, Quackenbush said. In this study, an 8-week regimen of oral MenaQ7 supplementation improved arterial stiffness among a group of renal transplant recipients, about half of whom had a subclinical vitamin K deficiency at the beginning of the trial.
“No other compound (drug or vitamin) has been shown to impact arterial calcification the way vitamin K2 as MK-7 has been shown. NattoPharma’s clinical work is so substantial that it has earned the attention of the medical community, which is now in process with its own trials that are using MenaQ7 Vitamin K2 as MK-7 as the source material as a possible therapy for patients whose conditions present symptoms of intense calcification,” Quackenbush said.
“These trials include The VitaK-CAC Trial, which is examining the effects of MenaQ7 on coronary artery calcification (CAC) ... The second study underway is BASIK2, a prospective study looking at the effect of MenaQ7 on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS ... Both trials are listed on clinicalstudies.gov. The final patients in VitaK have completed the trial, so now it is about the reading, coding, and analyzing more than 140 coronary scans. We are very excited for the potential of this study and the impact of its results.”
What’s next on the horizon for NattoPharma and stakeholders in the vitamin K2 industry, in addition to the cardiovascular research, will be studies examining its anti-inflammatory properties. Studies on high-purity natural vitamin K2, still in the in vitro stages, show that it has the potential to inhibit gene expression and production of pro-inflammatory markers TNF-a, IL-1a, and IL-1b.
Additionally, Quackenbush said that NattoPharma is spearheading efforts to establish a K2-specific recommended daily intake (RDI), in an “effort to help correct a global deficiency.” K2 is highly scarce in Western diets, which contain very little of the fermented foods in which it occurs naturally.
“More recent research has confirmed different bioavailability/activity between K1 and K2, and additional biological functions of K2 due to different side chains. Further, all epidemiological and interventional studies showed that only K2 was cardio-protective or has a beneficial effect on the arteries. This has not been considered in the forming of dietary recommendations.”
Plant Sterols & Stanols
Mounting substantial evidence that plant sterols and stanols—the key difference between the two being that one is saturated and one is not—could protect the heart by lowering LDL cholesterol absorption in the human body spurred FDA into approving certain cardiovascular health-related claims for this ingredient, as well as Generally Recognized As Safe (GRAS) status. This has provided a platform for many foods containing these substances. On a molecular level, plant sterols and stanols are very similar to both HDL and LDL cholesterol, and essentially “get in the way” of real cholesterol to prevent it from entering the bloodstream.
“First and foremost, consumers are looking for products that deliver real, proven benefits. Ingredients like plant sterols, which have an FDA-authorized health claim, give consumers confidence in their efficacy. They also give brands an opportunity to build a compelling story around time-tested ingredients,” said Pam Stauffer, global marketing programs manager for Cargill Ingredients. “Backed by more than 50 years of clinical research, plant sterols have been shown to help lower cholesterol. In its review, the FDA said: ‘…there is significant scientific agreement that diets that include plant sterol esters and plant stanol esters may reduce the risk of coronary heart disease.’ Consumers can’t easily ‘see’ the benefits of a heart health supplement, a reality that makes it all the more important for brands to rely on ingredients with a proven track record. Plant sterols are one of those options. “
Clinical studies have led the way for national health agencies’ cholesterol guidelines to report that eating 2 grams of plant sterols per day can reduce LDL cholesterol anywhere from 6% to 15%. These sterols can present themselves as highly available in nearly every functional food, supplement, and even beverage application when formulated correctly. The growing prevalence of chronic diseases related to high cholesterol levels has made plant sterols one of the leading “fortifying” ingredients in the functional foods category.
Because this ingredient is so bioavailable and easily formulated into food products, plant sterols are perhaps one of the easiest heart-healthy ingredients for consumers to include in their diets, knowing that the results will be effective regardless of whether they are taken in the form of a dietary supplement or naturally-occurring.
Magnesium
Despite the fact that magnesium plays a critical role in over 300 human biological functions, the most recent data from the National Health and Nutrition Examination Survey (NHANES) suggest that most Americans receive well below daily recommended intake. Not only is there disparity in magnesium intakes along lines of ethnicity, but it appears that magnesium intake decreases on average with increased age.
Additionally, certain digestive issues that affect nutrient absorption can further exacerbate magnesium deficiencies, which are already highly prevalent. Certain chemicals in food also further interfere with the body’s ability to absorb magnesium, and careful formulations must be made to ensure that the magnesium found in supplements remains bioavailable for consumers.
Magnesium is extensively studied, with evidence pointing to correlations between magnesium deficiencies and the development of CVD, hypertension, type 2 diabetes, and other conditions. It is often used in adjuvant treatments for cardiac arrhythmias and myocardial infarctions.
In recent news, a 2018 meta-analysis appearing in the British Medical Journal reported that 42% of patients hospitalized for adverse cardiovascular incidents were deficient in magnesium, and magnesium deficiencies correlate with hypertension, cardiomyopathy, strokes, and a wide range of cardiovascular injuries and events at significant rates.
Additionally, a 2015 review in the World Journal of Diabetes identified that most but not all diabetic subjects evaluated were experiencing magnesium deficiency, and acknowledged magnesium supplementation as a “possible public health strategy to reduce diabetes risk in the population.”
Last year, a review in the Journal of the American Heart Association went so far as to recommend the addition of calcium and magnesium into drinking water as part of a public health strategy to lower blood pressure levels across the population at large. Their findings came from evidence that the population of a coastal area in Bangladesh, in which the inhabitants there relied on groundwater or pond water as their main water source due to seawater intrusion, had lower blood pressure on a population-based level due to the high amounts of calcium and magnesium in their water supply, even in spite of the fact that the water supply was also salinated. The blood pressure levels of those who drank salinated water were surprisingly, and almost counterintuitively, a full 1.26 mmHg lower than those who drank freshwater.
Fibers
Dietary fibers’ ability to modulate cholesterol levels, frequently conducted in comparison to plant sterols, continues to become more evident with research also supporting a wide range of other attached health benefits. Dietary fibers on the whole are advantaged among other supplements and functional foods promising protective effects on the heart, as they have the added benefits of supporting gut health, one of the leading growth and research engines in today’s nutritional landscape.
The gut microbiome is still a wide-open frontier in terms of understanding related health benefits, but it is becoming increasingly clear that optimizing gut health is associated with positive cardiovascular outcomes. Consumers are clamoring for fibers due to their applications in digestive health and cholesterol modulation, as more research comes online indicating that dietary fibers may contribute to improving blood pressure, blood glucose levels, a host of metabolic conditions, and even sleep and mood. Researchers consistently call for further investigation into the clearly-established reciprocity between the gut microbiome and nutrition, anticipating that a wide range of biological mechanisms can be identified.
Additionally, there is a huge diversity in the lineup of natural products from which dietary fiber can be sourced, and that number grows incrementally as agencies such as FDA give new fibers the go-ahead for health claims.
Compiled with the fact that ultra-processed foods are under increased scrutiny as a culprit for several adverse cardiovascular conditions, it’s apparent that opportunity is abound for food manufacturers to incorporate better grains into their products and be met with positive results. The fears consumers have of the negative health outcomes associated with refined carbohydrates, including high blood pressure, insomnia, weight gain, and more, will likely be a major driving factor for companies to formulate new and existing products with more whole grains in lieu of “empty” grains which have been stripped of all bran, fiber, and nutrients.
Recent research highlights include a study from the Ireland-based APC Microbiome Institute which found that oat beta-glucan, while marginally less effective at lowering cholesterol, didn’t wield many of the side effects that high plant sterol intakes caused in mice, including weight gain and changes in gut microbiota.
A 2014 meta-analysis demonstrating cholesterol-lowering effects after eating 3 grams of oat beta-glucan daily quickly put this fiber on the map. Its beneficial effect on gut microbiota compounded with an apparent lack of side effects, may allow the fiber to inhabit many supplement and functional foods spaces formerly dominated by other ingredients.
In an international study this year led by Monash University in Australia, researchers believe they’ve established a link between low prebiotic fiber intake and elevated blood pressure, signifying that mechanisms in the gut microbiome may be able to significantly impact hypertension, but more research is needed.
Antioxidants, Flavonoids & Inflammation
Research resoundingly suggests that reactive oxygen species generated during excessive oxidative stress are associated with the pathophysiology of cardiovascular disorders. During oxidative stress, the body fails to maintain normal physiological function. Antioxidant supplementation is believed to scavenge free radicals and other toxic radicals within the body, which can benefit the heart by eliminating precursors to metabolic syndrome. Some of the most common antioxidants believed to benefit cardiovascular function include CoQ10, beta-carotene, lycopene, quercetin, resveratrol, vitamin C, and vitamin E.
Metabolic syndrome, categorized not only by health conditions but by a number of biomarkers including C-reactive protein and other compounds, has a correlation with cardiovascular disease, as well as cancer, mental health disorders, and other conditions.
Oxidative stress, viewed as an imbalance between reactive oxygen species and their elimination by protective mechanisms, is widely viewed as a precursor to chronic inflammation. On that note, perhaps the largest study of its kind on the role that chronic inflammation, or at least a pro-inflammatory diet, has on incidences of metabolic syndrome, was published this year. It found that among 150,000 participants, those who scored high on Dietary Inflammatory Index assessments (meaning they ate high levels of pro-inflammatory foods) had higher incidences of criteria meeting metabolic syndrome.
Pycnogenol, a patented French maritime pine back extract, contains a variety of flavonoids. As one of the most-used flavonoid-rich ingredients in dietary supplements, many studies on its benefits show that certain flavonoids can optimize vascular relaxation, as well as improve blood pressure, platelet activity, and perhaps even endothelial function. One study on Pycnogenol found that in a group of 48 diabetic individuals, Pycnogenol achieved blood pressure reductions in over 58% of participants, allowing them to reduce the dosages of their blood pressure medications by 50%.
This year, one of the largest meta-analyses on flavonoids in relation to cardiovascular morbidity and adverse events attempted to determine through a collection of cohorts amassing millions of participants how routine consumption of flavonoid-rich green and black teas would effect cardiovascular health outcome. The data showed that each cup increase in tea consumption, to a certain endpoint, was associated with an average 4% lower risk of CVD mortality, a 2% lower risk of CVD events, a 4% lower risk of stroke, and a 1.5% lower risk of all-cause mortality.
Another rising star in the natural antioxidants arena has been black seed oil, which is steeped in ancient history as a traditional remedy to a host of ailments. It presents many challenges in supplement form stemming from the fact that certain processing is required to achieve meaningful concentrations of thymoquinone, the main active compound of this ingredient, which in and of itself has stability challenges that must be addressed in order to maintain its potency. This year, TriNutra, the makers of Thymoquin, successfully developed a black seed oil standardized to 3% thymoquinone, and numerous studies it conducted suggest it may have clinical potential in inflammation, reducing oxidative stress biomarkers, and other metabolic conditions such as type 2 diabetes. A clinical study published in the journal Food Science and Nutrition Research found that ThymoQuin was able to reduce systolic blood pressure by over 11%, and diastolic by over 12% among a group of 19 otherwise healthy adults suffering from hypertension. Significant drops in blood pressure occurred after just two days of supplementation.
The Plant-Based Revolution
Many market researchers believe that when it comes to preventive approaches to heart health, consumers by and large are more apt to seek out foods and beverages in lieu of pills. The fact that more consumers are structuring their diet around certain health conditions than ever before means that fortified foods with heart health claims are likely to see some growth in the years ahead. New windows of opportunity continue to open for functional food specialists, as research reveals previously unconfirmed or unknown benefits and risks.
The plant-based revolution has gripped the attentions of many health conscious consumers, and has been a centerpiece in the cardiovascular health market for foods and dietary supplements alike. The role that a transition to plant-based diets may play in cardiovascular health appears to be resoundingly positive, and cardiovascular health is a strong motivator alongside sustainability and animal welfare concerns for those who maintain or are transitioning to veganism.
A recent population-based cohort study, for example, published in the Journal of the American Heart Association, classified diets into four different indexes: healthy plant-based, less healthy plant-based, pro-vegetarian, and high animal food intake. It found that participants with the highest adherence to an overall plant-based or pro-vegetarian diet could reduce their risk of CVD, cardiovascular mortality, and all-cause mortality by up to 32%. Especially beneficial were plant-based diets high in nutrient-dense plant foods and lower in refined carbohydrates. They found, however, that more research is needed to investigate whether the quality of plant foods within the framework of an overall plant-based diet is associated with CVD and all-cause mortality.
One explanation, according to research published in The Journal of Nutrition, could be that plant-based diets reduce the concentrations of a number of biomarkers associated with severely overweight and obese people. In a study on the blood results of 831 women randomly selected from the Nurses’ Health Study II, lower concentrations of leptin, insulin, hsCRP, and higher levels of hsCRP, adiponectin, and sOB-R (which are inversely associated with obesity) were seen in individuals who scored highly on a questionnaire indexing their intake of healthful dietary plants.
Consumers have apparently been responding to the science. According to the Plant Based Foods Association, U.S. retail sales of plant-based foods grew 11.4% over the course of 2019, leaving many other food products sourced from animals in the dust. Mintel reported that between 2012 and 2018, food products using the term “plant-based” on packaging grew by 287%.
Recent developments in the plant-based arena include the ongoing dilemma over FDA’s potential decision to allow soy protein products to come with an attached claim that they may reduce the risk of heart disease. Soy protein has been and continues to be a major component in a number of plant-based meat alternatives, and sports nutrition products, and heart health claims may have been a major driver. This health claim was first approved in 1999, but FDA proposed revoking the approval of this claim in 2017, citing concerns that studies originally evaluated to determine soy protein’s efficacy in lowering LDL cholesterol had inconsistent results.
In a 2017 statement, Susan Mayne, then-director of the FDA Center for Food Safety and Applied Nutrition (CFSAN), said the relationship between soy protein and heart disease “does not meet the rigorous standard for an FDA-authorized health claim.” FDA will review the former 46 trials, though the agency has not confirmed whether it will be incorporating novel evidence which has come online since the revoking of the claim was proposed. This includes a meta-analysis of the studies previously evaluated by the FDA from the University of Toronto, in which researchers asserted that soy protein can reduce LDL cholesterol by 3-4% based on evidence that FDA is known to be considering.
Another culprit targeted at increasing rates for adverse heart health effects by the functional foods segment is salt. The CDC suggests that 90% of Americans consume too much salt, an excess of which is known to lead to high blood pressure. Meanwhile, it appears that companies are keen on providing low-sodium “salternatives” which could help address these issues. Potassium chloride has been a leading ingredient as a seasoning alternative, seeing prevalent use in the better-for-you snacking category. Not only does potassium rank relatively close on a saltiness index to sodium itself, but it is also known to be beneficial to cardiovascular function, and most Americans, according to the American Heart Association, have intakes well below the recommended 4,700 mg per day.
As the roles of functional foods and dietary supplements become clearer to consumers, physicians, and researchers, the heart health category will maintain its business and dynamism moving forward. Many ingredients play major roles in mitigating risk and promoting optimal function of the heart, and the 60,000 miles of arteries, veins, and capillaries inside the human body. Mounting evidence for alternatives to pharmaceutical intervention are becoming more legitimized and recommended by the medical community. Resoundingly, heart-conscious consumers will continue seeking out personalized solutions across a widening demographic range. While no product is a silver bullet, optimal combinations of supplements and dietary interventions allow each individual to take proactive measures to combat the number-one killer in the U.S.
According to the American Heart Association, 80% of all CVD cases and related morbid outcomes can be prevented in those at risk through interventions in medicine, nutrition, lifestyle, smoking habits, and exercise. Still, CVD maintains its rank as the number-one killer of Americans, costing healthcare systems about $1 billion every day and killing hundreds of millions each year. According to the Centers for Disease Control and Prevention (CDC), more than half of those living in the U.S. have at least one CVD risk factor.
Despite the growing body of nutritional science surrounding the functions that foods and dietary supplements might play in maintaining cardiovascular health, no significant decreases in heart disease rates have been achieved in most populations over the past several decades. That fact, compounded with an aging population, means that heart disease is slated to become an even greater social burden, and an even greater stress point on the capacities of healthcare systems around the globe.
For these reasons, it’s no surprise that the heart health segment of the nutritional market remains a dynamic, crowded, and competitive segment for dietary supplements and functional foods alike.
Experts characterize it as extremely difficult for new products and ingredients to enter the arena shared by a wide variety of omega-3s, dietary fibers, plant sterols, antioxidants, vitamins, minerals, and more, making up a massive chunk of the estimated $122 billion supplements market. Not only is the market flooded with some of the most well-established and scientifically-substantiated products, but the criteria to receive approvals for any heart health marketing claim by government agencies for a supplement is extremely rigorous.
In today’s climate, consumers seeking out supplements to maintain cardiovascular health are hoping to find time-tested products with the greatest wealth of scientific substantiation, market research suggests.
Traceability, third-party verification, and high manufacturing standards are especially important to the viability of products in this space, given that many of these products are used concurrently with traditional western medicine for serious health issues. Preliminary trials without serious significance don’t cut it in the eyes of consumers seeking lifelong solutions. Additionally, there is a shift occurring in which the benefits offered by dietary supplements are beginning to appeal to younger demographics who are taking a more proactive approach to CVD and its precursors.
In addition to specific needs, it appears that consumers are looking for nutritional solutions to cardiovascular health that are more holistic than ever before.
A survey conducted by Lycored found that 67% of consumers improved their diet in order to protect their cardiovascular health, which scored higher than all other options, including increasing exercise levels. Additionally, 59% agreed with the statement “I believe in a holistic approach to cardiovascular wellness, including physical, mental, and nutritional elements.” This figure rose to 65% among consumers based in the U.S. only.
Sharing a similar sentiment to a Mintel study from last year that suggested consumers are seeking foods and supplements in all categories to enhance mood and mitigate stress levels, people are responding well to the idea of alleviating stress as part of their cardio-protective regimen. Among consumers Lycored surveyed, 95% said they found the idea of being able to “calm your heart” appealing, and 35% said they would be more likely to buy a product for cardiovascular health if its packaging included the word “calm,” indicating a sense that popular opinion attributes the ubiquitously rising stress levels seen in the U.S. with cardiovascular health outcomes.
Stress is likely the most palpable cardiovascular risk factor people experience on a day-to-day basis, thereby making it an important point of communication for conscious consumers. While more research is needed to determine how stress contributes to CVD, it clearly has an impact on the behaviors considered risky, such as smoking, drinking, nutritional intake, and exercise.
At the forefront of consumer education has been the American Heart Association (AHA), perhaps one of the leading organizations providing freely available reports and regimens to allow consumers to take more control over their cardiovascular health outcomes. Additionally, AHA has armed many consumers in the fight against CVD risk by identifying the myriad of risk factors that extend well beyond cholesterol, many of which can be addressed in part through nutraceutical intervention. The organization is also more inclined than most to take a proactive, authoritative stance on the widespread nutritional research that it evaluates.
Consumer surveys suggest people are seeking out nutraceuticals for cardiovascular health maintenance in a way that is intuitive, scientifically bound, and trustworthy. This, fueled by the sheer prominence of CVD as the still-growing and leading cause of death in the U.S. is reason enough for consumers to continue viewing blood pressure, cholesterol reduction, inflammation modulation, and other CVD issues as the primary drivers for their dietary supplement purchases. These condition-specific needs, which become more prevalent among older demographics as more serious health issues arise, allow for more nuance in the types of demands that work best for each consumer, calling for more specialized formulations and innovations.
Omega-3s
Omega-3s have long been among the most popular supplements supporting cardiovascular health to date. The most potent source of omega-3s is oil extracted from marine species such as fish, krill, and algae, each of which provide unique profiles of EPA and DHA.
Omega-3 long-chain fatty acids have been extensively researched for decades, with consistent results showing they can be efficacious in reducing LDL cholesterol, arrhythmias, thrombosis, lipoprotein levels, growth rates of arterial plaque, and even blood pressure (slightly). It has also been shown that omega-3s can modulate the body’s inflammatory response beneficially, which researchers believe is tied to better cardiovascular health outcomes. According to Greg Lindsey, vice president of corporate marketing for Wiley Companies, over 40,000 studies and 4,000 human clinical trials to date have examined the potential benefits of fish oil.
“Consumers are becoming much more educated about all nutritional supplements, which is a very good thing for manufacturers and suppliers focused on delivering the highest quality products,” Lindsey said. “This includes researching beyond advertising claims, to gain a much better understanding of quality and purity.”
The sheer bulk of statistical significance has grown immensely over recent years, with large-scale, population-based trials such as REDUCE-IT, ASCEND, and a study published in the British Medical Journal in March which found statistically significant improvements in CVD outcomes in over 450,000 people with and without pre-existing conditions.
“Consumers are taking a 360-degree approach to their health and are seeking out supplements to help close the gaps. From managing symptoms to preventative measures, consumers are most definitely engaged with heart health foods and supplements,” said Kate Pastor, senior vice president of sales at Aker BioMarine, which specializes in omega-3 supplements formulated with krill oil sourced from Antarctica.
“Regarding the product itself, consumers are becoming more discerning and knowledgeable about their ingredients,” she added. “They want to know where the product is coming, how it was produced, if it’s third-party verified, and more. Consumers are interested in traceability and sustainability, and have trust and confidence in products that are made in the USA.”
As more research abounds in the role that inflammation has on cardiovascular and other conditions, this will likely enhance understanding of the benefits that fish oil provides.
“Chronic inflammation is a common denominator and link between chronic conditions, including cardiovascular health, diabetes, Alzheimer’s disease, arthritis, auto-immune conditions, periodontal disease, and more,” said Gretchen Vannice, director of nutrition education and research at Wiley Companies. “It’s the flashing red light indicator on the dashboard, warning of compromised health status. Inflammation interferes with the body’s ability to regain homeostasis, or a healthy state.”
In spite of the extensive research which had mixed results at times, in part due to the huge variety in dosages, population variants, and strengths of methodologies employed in omega-3 studies over the years, the exact biological mechanisms by which omega-3 fatty acids benefit the heart and reduce triglycerides is elusive at this time.
Researchers are also reaching conclusions on what they would consider an optimal daily intake of omega-3s necessary to prevent an apparent deficiency.
“In 2009, low intake of omega-3s was attributed to up to 96,000 preventable deaths in the U.S., second only to high salt intake,” Vannice said. “Ten years later, a validated predictive model of disease risk (completed by a group from Harvard School of Public Health, Tufts School of Nutrition Science and Policy, Brigham and Women’s Hospital Department of Cardiovascular Medicine, and more) reported that the lack of EPA and DHA omega-3s in our diet is costing the U.S. $12.74 billion a year for cardiovascular disease and type 2 diabetes care.... What’s more, these findings above are calculated at an intake of 250 mg of EPA and DHA per day; that’s the minimum amount generally considered to prevent frank deficiency.”
Meanwhile, a medical-grade fish oil-derived EPA, icosapent ethyl (branded as Vascepa) is undergoing trials as a drug candidate for CVD, with researchers from the UCI School of Medicine projecting that it could tentatively prevent 70,000 cardiovascular-related deaths per year.
For those who object to fish oil for whatever reason, there has also been a rising trend in obtaining the essential EPA and DHA from algae, which is how omega-3s enter the bodies of various fish species from which oil is derived.
Scientists have been lab-growing certain strains of algae for higher EPA and DHA content, making algal omega-3s increasingly more viable. Fish oil remains the most popular for supplements, infant formulas, and other formulations. While algae oil hasn’t been the subject of extensive studies at nearly the same prevalence as fish oil, several studies have compared its efficacy to fish oil, suggesting that nutritional equivalence can be achieved, and that the bioavailability components are also equivalent. In addition to algae oil having a more neutral flavor profile, appealing to those who can’t stand a fishy aftertaste, algae oil also appeals to vegetarians and vegans.
In other news, and in part of the push to integrate omega-3s into the dietary aspirations of consumers, OmegaQuant recently established an omega-3 testing kit which health practitioners can use in a partnership with Standard Process, so that practitioners can enable patients to evaluate their status in omega-3s, omega-6s, and trans fats all at once with a finger prick sample.
“Nutritional assessment tools, such as vitamin D or Omega-3 Index tests, can help provide a nutritional baseline for consumers,” Pastor said. “The Omega-3 Index is the percent of long-chain omega-3 fatty acids, (EPA and DHA) and the Omega-3 Index test measures the levels of these nutrients in our red blood cells. Industry experts are seeing this test as a long-term and constant marker of omega-3 status and a way to determine your risk level for heart disease.”
Pastor said that another driver in the growth of omega-3s in the heart health space will be offering consumers the ability to customize the supplements they use for heart health applications, due to the highly nuanced nature of demands for heart health formulations.
“In addition to customizable solutions, we are seeing an increased awareness and interest in proactive heart health care among younger demographics,” Pastor said. “While some consumers with pre-existing heart conditions are working to manage or reduce risks, others are following more proactive approaches to their health by changing their lifestyles and taking simple steps to being a healthier version of themselves while they are still healthy; and this is a combination of exercise, diet and supplementation.”
CoQ10
Coenzyme Q10 (CoQ10) is a fat-soluble, vitamin-like substance that is produced within the body, and is also found in many foods. It has been well-established that age and certain medical conditions such as the use of statins can deplete CoQ10 from the body, and researchers have been keen to understand the best way in which this beneficial nutrient can be introduced into the body for those who are deficient in it. CoQ10 is a potent antioxidant, and plays a major role in the production of cellular energy. People have been taking CoQ10 supplements in their bioactive form, ubiquinol, for many decades.
One of the most pivotal studies propelling CoQ10’s growth in the heart health segment, published in the Journal of the American College of Cardiology, established a low level of myocardial CoQ10 related to the severity of heart failure in 420 patients, the largest study of its kind to date.
“CoQ10 remains the dietary supplement most recommended by cardiologists,” said Scott Steinford, CoQ10 Association executive director at large. “The efficacy of CoQ10 is supported by scientific, clinical, and anecdotal evidence. Statins also are a driving contributor to CoQ10 supplementation since statins significantly reduce CoQ10 levels. It is theorized that many of the more serious statin side effects are a result of CoQ10 depletion.”
Patients in the study with moderate to severe heart failure were then administered 100 mg of CoQ10 three times daily, or a placebo. After 16 weeks they were evaluated with a six-minute walk test, and levels of N-terminal pro-B type natriuretic peptide, and a follow-up period monitoring any major outcomes.
The study found a 43% decrease in cardiovascular death in the CoQ10 group compared to the placebo group, and only 15% of the CoQ10 group experienced major adverse cardiovascular events compared with 26% of the placebo group by the study’s conclusion.
As the CoQ10 market continues to grow, the most prominent trade group associated with providing centralized industry guidelines, and information to the public, is the CoQ10 Association.
Over the past 15 years, CoQ10 has gone from a relatively niche place in the dietary supplements market, to one of the most-consumed dietary supplements in the U.S., and is now a household name in terms of dietary supplements beneficial to the heart. It has grown steadily (20% CAGR since 2000), and most analysts believe that trend will continue as cardiovascular health remains one of the most important categories across the dietary supplements market.
CoQ10 is largely considered to hold preventive benefits; numerous studies have found a positive correlation between CoQ10 deficiencies and CVD, cardiovascular mortality, stroke patients, and more. It is often also prescribed by doctors in conjunction with statins, due to evidence from statin recipients who repeatedly confirm that it mitigates some of the uncomfortable side effects associated with the cholesterol-lowering medication, though no large-scale studies have clinically supported this yet. It holds antioxidant properties, and as a nutrient, is responsible for the body’s production of ATP molecules, the basic source of energy in cellular function.
What puts CoQ10 at an advantage, compared to other nutritional supplements, is the fact that its biological mechanism is so well-understood at the molecular level, Steinford said. Its energy carrier function allows it to continually go through an oxidation-reduction cycle, by accepting electrons, and its role in the functions of both the mitochondria and muscle cells are clear. Additionally, a wide host of precursors to CoQ10 deficiency are well-understood, and CoQ10 levels can be tested with a wide array of effective methodologies. It is critical to mitochondrial respiration, improves tolerance to statins and myalgia symptoms, and may reduce the size of a myocardial infarction if/when individuals on statin therapy have an event.
As of late, it appears that the biggest ongoing developments in the CoQ10 space will be innovations in improving its bioavailability. Oral delivery of CoQ10 is extremely challenging due to the fact that it is insoluble in water, and has limited absorption in the digestive tract. Products can be formulated to be self-emulsifying, but much of the absorption also hinges on physiological characteristics of the individuals. Cross-examinations have found that certain formulations, such as softgels and liquid-filled capsules, may have three- to four times the efficiency of CoQ10 absorption in significant groups of
study participants.
Vitamin K2
Vitamin K2 has been shaking up the cardiovascular health segment since studies on its ability to improve arterial stiffness came back with positive results, signifying that it functions much more holistically and differently than K1. To put it simply, vitamin K1 functions in the liver to prevent blood clotting, whereas K2 is highly active in tissues outside the liver, including the bones and, as very recent studies continue to show, the cardiovascular system. It works for the heart both as an inhibitor of vascular calcification, and as a highly potent antioxidant.
NattoPharma, the makers of a proprietary vitamin K2 in MK-7 form, MenaQ7, has been the driver of all research confirming K2’s health benefits, as well as dosage-finding and safety studies on healthy volunteers, hemodialysis patients, and as a potential oral anticoagulant treatment. Kate Quackenbush, NattoPharma’s director of communications, shared some of the groundbreaking research which has propelled its flagship product into the heart health sphere.
“[Consumers] want to know that the products they are investing in deliver true health benefits,” Quackenbush said. “An efficacious product has to start with clinically validated raw materials, and MenaQ7 is the only vitamin K2 as MK-7 clinically proven to impact heart and bone health.”
Vitamin K2’s primary application, before its cardiovascular benefits were proven, was to improve bone health by ensuring that calcium binds to the bone mineral matrix, but another aspect of that process involves inhibiting a calcium buildup on arterial walls, according to the research. A study from the New England Journal of Medicine (Rosenhek, et al., 2000) suggested that calcification in the arteries can contribute to the shortening of life expectancies by as much as 10 years.
It’s a challenge to ensure that vitamin K2 is formulated and encapsulated effectively, Quackenbush said. There are many variabilities and applications at hand that manufacturers must consider when putting any products containing MenaQ7 to the stability “stress test.”
“Some K2 suppliers are claiming that they are the ‘only stable solution on the market,’ inferring that others are not,” Quackenbush said. “In fact, it is misleading to suggest that an encapsulated product will be stable in every application and testing by NattoPharma and other third parties show that stability rates vary depending on the application. In truth, no encapsulation is ‘one size fits all.’ However, NattoPharma’s CryoCap microencapsulation technology has demonstrated stability in a myriad of environments, against mild minerals, more aggressive mineral mixes, and even very aggressive products, such as chelates.”
While observational data had long suggested a positive link between vitamin K2 intake and cardiovascular longevity, evidence from a 2015 trial conducted by Maastricht University showcased its ability to reduce age-related arterial stiffness caused by calcification, and even promote unprecedented levels of vascular elasticity in 244 postmenopausal women. Not only did this propel vitamin K2 into many individuals’ approaches to cardiovascular longevity, but it substantiated that arterial hardening is not an age-related condition; in most cases, the cause is a nutrient deficiency.
Further studies, at the same dosage of 180 mcg of MenaQ7, found similar benefits for arterial stiffness and the promotion of arterial flexibility.
“In 2018, a one-year clinical trial with healthy men and postmenopausal women was completed by the expert researchers at VitaK (sponsored by NattoPharma),” Quackenbush said. “This study also demonstrated that 180 mcg daily of MenaQ7 Vitamin K2 as MK-7 improved vascular health, as measured by lower levels of inactive Matrix Gla Protein (MGP). This study is currently under peer review for publication.”
NattoPharma has been supporting several studies since then as researchers attempt to develop a more layered understanding of the mechanisms at play behind K2’s cardioprotective benefits, and any other beneficial properties it may hold.
MenaQ7 was shown in a study to boost nitric oxide (NO), improving NO-dependent endothelial function.
“Endothelial dysfunction has been associated with many health issues, including being a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis, a disease of the arteries characterized by the development and deposition of plaques and by vascular inflammation of fatty material on the inner walls,” Quackenbush said. Given the fact that endothelial function determines cardiovascular health, researchers hypothesized that the positive effects of vitamin K2 intake on cardiovascular mortality could be linked to the vitamin K-dependent regulation of endothelial function. The study concluded that low dose of vitamin K2 as MK-7 (as MenaQ7 from NattoPharma) could provide benefits for cardiovascular health, playing an important role in the regulation of endothelial function.
Another two studies published in Nephron linked vascular calcification, and vascular and arterial stiffness to MGP, a vitamin K-dependent protein. It was additionally found in this research, based on the results of 83 chronic kidney disease (CKD) patients, that inactive MGP levels in blood plasma were associated with increased vascular calcification, and that this vitamin K-dependent protein may be an early marker for vascular calcification in CKD patients.
Evidence that vitamin K2 may be especially helpful for those with kidney issues came in a study published by the Journal of the American Society of Hypertension, Quackenbush said. In this study, an 8-week regimen of oral MenaQ7 supplementation improved arterial stiffness among a group of renal transplant recipients, about half of whom had a subclinical vitamin K deficiency at the beginning of the trial.
“No other compound (drug or vitamin) has been shown to impact arterial calcification the way vitamin K2 as MK-7 has been shown. NattoPharma’s clinical work is so substantial that it has earned the attention of the medical community, which is now in process with its own trials that are using MenaQ7 Vitamin K2 as MK-7 as the source material as a possible therapy for patients whose conditions present symptoms of intense calcification,” Quackenbush said.
“These trials include The VitaK-CAC Trial, which is examining the effects of MenaQ7 on coronary artery calcification (CAC) ... The second study underway is BASIK2, a prospective study looking at the effect of MenaQ7 on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS ... Both trials are listed on clinicalstudies.gov. The final patients in VitaK have completed the trial, so now it is about the reading, coding, and analyzing more than 140 coronary scans. We are very excited for the potential of this study and the impact of its results.”
What’s next on the horizon for NattoPharma and stakeholders in the vitamin K2 industry, in addition to the cardiovascular research, will be studies examining its anti-inflammatory properties. Studies on high-purity natural vitamin K2, still in the in vitro stages, show that it has the potential to inhibit gene expression and production of pro-inflammatory markers TNF-a, IL-1a, and IL-1b.
Additionally, Quackenbush said that NattoPharma is spearheading efforts to establish a K2-specific recommended daily intake (RDI), in an “effort to help correct a global deficiency.” K2 is highly scarce in Western diets, which contain very little of the fermented foods in which it occurs naturally.
“More recent research has confirmed different bioavailability/activity between K1 and K2, and additional biological functions of K2 due to different side chains. Further, all epidemiological and interventional studies showed that only K2 was cardio-protective or has a beneficial effect on the arteries. This has not been considered in the forming of dietary recommendations.”
Plant Sterols & Stanols
Mounting substantial evidence that plant sterols and stanols—the key difference between the two being that one is saturated and one is not—could protect the heart by lowering LDL cholesterol absorption in the human body spurred FDA into approving certain cardiovascular health-related claims for this ingredient, as well as Generally Recognized As Safe (GRAS) status. This has provided a platform for many foods containing these substances. On a molecular level, plant sterols and stanols are very similar to both HDL and LDL cholesterol, and essentially “get in the way” of real cholesterol to prevent it from entering the bloodstream.
“First and foremost, consumers are looking for products that deliver real, proven benefits. Ingredients like plant sterols, which have an FDA-authorized health claim, give consumers confidence in their efficacy. They also give brands an opportunity to build a compelling story around time-tested ingredients,” said Pam Stauffer, global marketing programs manager for Cargill Ingredients. “Backed by more than 50 years of clinical research, plant sterols have been shown to help lower cholesterol. In its review, the FDA said: ‘…there is significant scientific agreement that diets that include plant sterol esters and plant stanol esters may reduce the risk of coronary heart disease.’ Consumers can’t easily ‘see’ the benefits of a heart health supplement, a reality that makes it all the more important for brands to rely on ingredients with a proven track record. Plant sterols are one of those options. “
Clinical studies have led the way for national health agencies’ cholesterol guidelines to report that eating 2 grams of plant sterols per day can reduce LDL cholesterol anywhere from 6% to 15%. These sterols can present themselves as highly available in nearly every functional food, supplement, and even beverage application when formulated correctly. The growing prevalence of chronic diseases related to high cholesterol levels has made plant sterols one of the leading “fortifying” ingredients in the functional foods category.
Because this ingredient is so bioavailable and easily formulated into food products, plant sterols are perhaps one of the easiest heart-healthy ingredients for consumers to include in their diets, knowing that the results will be effective regardless of whether they are taken in the form of a dietary supplement or naturally-occurring.
Magnesium
Despite the fact that magnesium plays a critical role in over 300 human biological functions, the most recent data from the National Health and Nutrition Examination Survey (NHANES) suggest that most Americans receive well below daily recommended intake. Not only is there disparity in magnesium intakes along lines of ethnicity, but it appears that magnesium intake decreases on average with increased age.
Additionally, certain digestive issues that affect nutrient absorption can further exacerbate magnesium deficiencies, which are already highly prevalent. Certain chemicals in food also further interfere with the body’s ability to absorb magnesium, and careful formulations must be made to ensure that the magnesium found in supplements remains bioavailable for consumers.
Magnesium is extensively studied, with evidence pointing to correlations between magnesium deficiencies and the development of CVD, hypertension, type 2 diabetes, and other conditions. It is often used in adjuvant treatments for cardiac arrhythmias and myocardial infarctions.
In recent news, a 2018 meta-analysis appearing in the British Medical Journal reported that 42% of patients hospitalized for adverse cardiovascular incidents were deficient in magnesium, and magnesium deficiencies correlate with hypertension, cardiomyopathy, strokes, and a wide range of cardiovascular injuries and events at significant rates.
Additionally, a 2015 review in the World Journal of Diabetes identified that most but not all diabetic subjects evaluated were experiencing magnesium deficiency, and acknowledged magnesium supplementation as a “possible public health strategy to reduce diabetes risk in the population.”
Last year, a review in the Journal of the American Heart Association went so far as to recommend the addition of calcium and magnesium into drinking water as part of a public health strategy to lower blood pressure levels across the population at large. Their findings came from evidence that the population of a coastal area in Bangladesh, in which the inhabitants there relied on groundwater or pond water as their main water source due to seawater intrusion, had lower blood pressure on a population-based level due to the high amounts of calcium and magnesium in their water supply, even in spite of the fact that the water supply was also salinated. The blood pressure levels of those who drank salinated water were surprisingly, and almost counterintuitively, a full 1.26 mmHg lower than those who drank freshwater.
Fibers
Dietary fibers’ ability to modulate cholesterol levels, frequently conducted in comparison to plant sterols, continues to become more evident with research also supporting a wide range of other attached health benefits. Dietary fibers on the whole are advantaged among other supplements and functional foods promising protective effects on the heart, as they have the added benefits of supporting gut health, one of the leading growth and research engines in today’s nutritional landscape.
The gut microbiome is still a wide-open frontier in terms of understanding related health benefits, but it is becoming increasingly clear that optimizing gut health is associated with positive cardiovascular outcomes. Consumers are clamoring for fibers due to their applications in digestive health and cholesterol modulation, as more research comes online indicating that dietary fibers may contribute to improving blood pressure, blood glucose levels, a host of metabolic conditions, and even sleep and mood. Researchers consistently call for further investigation into the clearly-established reciprocity between the gut microbiome and nutrition, anticipating that a wide range of biological mechanisms can be identified.
Additionally, there is a huge diversity in the lineup of natural products from which dietary fiber can be sourced, and that number grows incrementally as agencies such as FDA give new fibers the go-ahead for health claims.
Compiled with the fact that ultra-processed foods are under increased scrutiny as a culprit for several adverse cardiovascular conditions, it’s apparent that opportunity is abound for food manufacturers to incorporate better grains into their products and be met with positive results. The fears consumers have of the negative health outcomes associated with refined carbohydrates, including high blood pressure, insomnia, weight gain, and more, will likely be a major driving factor for companies to formulate new and existing products with more whole grains in lieu of “empty” grains which have been stripped of all bran, fiber, and nutrients.
Recent research highlights include a study from the Ireland-based APC Microbiome Institute which found that oat beta-glucan, while marginally less effective at lowering cholesterol, didn’t wield many of the side effects that high plant sterol intakes caused in mice, including weight gain and changes in gut microbiota.
A 2014 meta-analysis demonstrating cholesterol-lowering effects after eating 3 grams of oat beta-glucan daily quickly put this fiber on the map. Its beneficial effect on gut microbiota compounded with an apparent lack of side effects, may allow the fiber to inhabit many supplement and functional foods spaces formerly dominated by other ingredients.
In an international study this year led by Monash University in Australia, researchers believe they’ve established a link between low prebiotic fiber intake and elevated blood pressure, signifying that mechanisms in the gut microbiome may be able to significantly impact hypertension, but more research is needed.
Antioxidants, Flavonoids & Inflammation
Research resoundingly suggests that reactive oxygen species generated during excessive oxidative stress are associated with the pathophysiology of cardiovascular disorders. During oxidative stress, the body fails to maintain normal physiological function. Antioxidant supplementation is believed to scavenge free radicals and other toxic radicals within the body, which can benefit the heart by eliminating precursors to metabolic syndrome. Some of the most common antioxidants believed to benefit cardiovascular function include CoQ10, beta-carotene, lycopene, quercetin, resveratrol, vitamin C, and vitamin E.
Metabolic syndrome, categorized not only by health conditions but by a number of biomarkers including C-reactive protein and other compounds, has a correlation with cardiovascular disease, as well as cancer, mental health disorders, and other conditions.
Oxidative stress, viewed as an imbalance between reactive oxygen species and their elimination by protective mechanisms, is widely viewed as a precursor to chronic inflammation. On that note, perhaps the largest study of its kind on the role that chronic inflammation, or at least a pro-inflammatory diet, has on incidences of metabolic syndrome, was published this year. It found that among 150,000 participants, those who scored high on Dietary Inflammatory Index assessments (meaning they ate high levels of pro-inflammatory foods) had higher incidences of criteria meeting metabolic syndrome.
Pycnogenol, a patented French maritime pine back extract, contains a variety of flavonoids. As one of the most-used flavonoid-rich ingredients in dietary supplements, many studies on its benefits show that certain flavonoids can optimize vascular relaxation, as well as improve blood pressure, platelet activity, and perhaps even endothelial function. One study on Pycnogenol found that in a group of 48 diabetic individuals, Pycnogenol achieved blood pressure reductions in over 58% of participants, allowing them to reduce the dosages of their blood pressure medications by 50%.
This year, one of the largest meta-analyses on flavonoids in relation to cardiovascular morbidity and adverse events attempted to determine through a collection of cohorts amassing millions of participants how routine consumption of flavonoid-rich green and black teas would effect cardiovascular health outcome. The data showed that each cup increase in tea consumption, to a certain endpoint, was associated with an average 4% lower risk of CVD mortality, a 2% lower risk of CVD events, a 4% lower risk of stroke, and a 1.5% lower risk of all-cause mortality.
Another rising star in the natural antioxidants arena has been black seed oil, which is steeped in ancient history as a traditional remedy to a host of ailments. It presents many challenges in supplement form stemming from the fact that certain processing is required to achieve meaningful concentrations of thymoquinone, the main active compound of this ingredient, which in and of itself has stability challenges that must be addressed in order to maintain its potency. This year, TriNutra, the makers of Thymoquin, successfully developed a black seed oil standardized to 3% thymoquinone, and numerous studies it conducted suggest it may have clinical potential in inflammation, reducing oxidative stress biomarkers, and other metabolic conditions such as type 2 diabetes. A clinical study published in the journal Food Science and Nutrition Research found that ThymoQuin was able to reduce systolic blood pressure by over 11%, and diastolic by over 12% among a group of 19 otherwise healthy adults suffering from hypertension. Significant drops in blood pressure occurred after just two days of supplementation.
The Plant-Based Revolution
Many market researchers believe that when it comes to preventive approaches to heart health, consumers by and large are more apt to seek out foods and beverages in lieu of pills. The fact that more consumers are structuring their diet around certain health conditions than ever before means that fortified foods with heart health claims are likely to see some growth in the years ahead. New windows of opportunity continue to open for functional food specialists, as research reveals previously unconfirmed or unknown benefits and risks.
The plant-based revolution has gripped the attentions of many health conscious consumers, and has been a centerpiece in the cardiovascular health market for foods and dietary supplements alike. The role that a transition to plant-based diets may play in cardiovascular health appears to be resoundingly positive, and cardiovascular health is a strong motivator alongside sustainability and animal welfare concerns for those who maintain or are transitioning to veganism.
A recent population-based cohort study, for example, published in the Journal of the American Heart Association, classified diets into four different indexes: healthy plant-based, less healthy plant-based, pro-vegetarian, and high animal food intake. It found that participants with the highest adherence to an overall plant-based or pro-vegetarian diet could reduce their risk of CVD, cardiovascular mortality, and all-cause mortality by up to 32%. Especially beneficial were plant-based diets high in nutrient-dense plant foods and lower in refined carbohydrates. They found, however, that more research is needed to investigate whether the quality of plant foods within the framework of an overall plant-based diet is associated with CVD and all-cause mortality.
One explanation, according to research published in The Journal of Nutrition, could be that plant-based diets reduce the concentrations of a number of biomarkers associated with severely overweight and obese people. In a study on the blood results of 831 women randomly selected from the Nurses’ Health Study II, lower concentrations of leptin, insulin, hsCRP, and higher levels of hsCRP, adiponectin, and sOB-R (which are inversely associated with obesity) were seen in individuals who scored highly on a questionnaire indexing their intake of healthful dietary plants.
Consumers have apparently been responding to the science. According to the Plant Based Foods Association, U.S. retail sales of plant-based foods grew 11.4% over the course of 2019, leaving many other food products sourced from animals in the dust. Mintel reported that between 2012 and 2018, food products using the term “plant-based” on packaging grew by 287%.
Recent developments in the plant-based arena include the ongoing dilemma over FDA’s potential decision to allow soy protein products to come with an attached claim that they may reduce the risk of heart disease. Soy protein has been and continues to be a major component in a number of plant-based meat alternatives, and sports nutrition products, and heart health claims may have been a major driver. This health claim was first approved in 1999, but FDA proposed revoking the approval of this claim in 2017, citing concerns that studies originally evaluated to determine soy protein’s efficacy in lowering LDL cholesterol had inconsistent results.
In a 2017 statement, Susan Mayne, then-director of the FDA Center for Food Safety and Applied Nutrition (CFSAN), said the relationship between soy protein and heart disease “does not meet the rigorous standard for an FDA-authorized health claim.” FDA will review the former 46 trials, though the agency has not confirmed whether it will be incorporating novel evidence which has come online since the revoking of the claim was proposed. This includes a meta-analysis of the studies previously evaluated by the FDA from the University of Toronto, in which researchers asserted that soy protein can reduce LDL cholesterol by 3-4% based on evidence that FDA is known to be considering.
Another culprit targeted at increasing rates for adverse heart health effects by the functional foods segment is salt. The CDC suggests that 90% of Americans consume too much salt, an excess of which is known to lead to high blood pressure. Meanwhile, it appears that companies are keen on providing low-sodium “salternatives” which could help address these issues. Potassium chloride has been a leading ingredient as a seasoning alternative, seeing prevalent use in the better-for-you snacking category. Not only does potassium rank relatively close on a saltiness index to sodium itself, but it is also known to be beneficial to cardiovascular function, and most Americans, according to the American Heart Association, have intakes well below the recommended 4,700 mg per day.
As the roles of functional foods and dietary supplements become clearer to consumers, physicians, and researchers, the heart health category will maintain its business and dynamism moving forward. Many ingredients play major roles in mitigating risk and promoting optimal function of the heart, and the 60,000 miles of arteries, veins, and capillaries inside the human body. Mounting evidence for alternatives to pharmaceutical intervention are becoming more legitimized and recommended by the medical community. Resoundingly, heart-conscious consumers will continue seeking out personalized solutions across a widening demographic range. While no product is a silver bullet, optimal combinations of supplements and dietary interventions allow each individual to take proactive measures to combat the number-one killer in the U.S.
