"Cardiovascular disease, a variety of conditions that affect the heart, is the world’s number one health threat,” says Trisha Sugarek MacDonald, BS, MS, Sr. Director of R&D, Bluebonnet Nutrition Corporation. “Moreover, it will likely remain so because of the impact of COVID-19 on the cardiovascular system and our nation’s people, as discussed by the American Heart Association, the leading global volunteer organization dedicated to fighting heart disease and stroke for all.” Sugarek MacDonald references points made by Donald M. Lloyd-Jones, M.D., Sc.M., FAHA, President of the American Heart Association and Chair of Department of Preventive Medicine at Northwestern University Feinberg School of Medicine in Chicago, who said: “Research shows that COVID-19 can cause heart and vascular damage directly. But the indirect effects of the pandemic can affect overall cardiovascular health as well, because most heart disease and stroke deaths are preventable with appropriate medical treatment and healthy lifestyle behaviors. We’d made tremendous progress in those areas over the last two decades but have seen much of that progress go out the window since COVID-19 hit.”

Looking at the reasons for this, Sugarek MacDonald says, “You may have guessed that the shutdowns, lockdowns, and fear of contracting COVID in the healthcare setting have all taken their toll. Why? Because more than ever, people are engaging in unhealthy eating behaviors, consuming greater amounts of alcohol, exercising less, and not making time for their annual healthcare checkups. These actions have thwarted our best efforts to drive home the message that people need to engage in healthier practices to reduce the risk of morbidity and mortality from cardiovascular diseases.”

While COVID has been a primary focus in the health arena, it isn’t beating CVD out for that number one spot: “In fact, COVID-19 is now officially ranked as the second leading cause of death in the U.S., as per the Peterson-KFF Healthy System Tracker,” Sugarek MacDonald notes. The tracker shows average daily deaths in the United States in September 2021, with COVID-19-related deaths sitting at 1,899, and deaths from CVD sitting at 2,078. Worthwhile context, here, is that while CVD is a group of conditions, SARS-COV-2 is one single disease—but clearly, maintaining immune health and heart health is a top priority.

Digging into the science connecting heart health and the immune system, Jay Levy, Sales Director, Wakunaga of America, points to a 2019 study in the journal Vascular Biology that noted a connection. “These systems ‘talk’ to each other via cytokines, hormones, and neurotransmitters—a conversation that maintains a balance that benefits both,” Levy explains. “This balance, however, can be altered by numerous physical or psychological stressors leading to the onset of inflammation, endothelial dysfunction, and tissue damage. How does this happen? Evidence suggests that cholesterol particles can build up along the inner walls of arteries (the endothelium) and trigger the release of immune molecules called NLRP3 inflammasomes. These molecules can cause inflammation and promote blood vessel injury, leading to certain cardiac events like a stroke or heart attack. This chronic type of inflammation, which is triggered by the immune system, can also contribute to high blood pressure (hypertension), a leading cause of heart attack and stroke.”

It’s not all bad news, though. “The good news is that, according to the National Heart, Lung and Blood Institute, adopting heart-healthy lifestyle changes can lower your risk,” says Levy. “That should include a heart-healthy diet, regular exercise and taking supplements clinically shown to support cardiovascular health. According to new proposed guidelines, however, a heart-smart lifestyle should not include a daily dose of baby aspirin—especially if you’re over age 60 and have never had a heart attack, stroke, or stent and don’t suffer from significant atherosclerosis. On the other hand, recent studies do support the use of supplements to enhance cardiovascular health.”

There’s plenty of information on heart health available—in fact, you can turn to the February 2021 issue of WholeFoods for a detailed dive on the category. This year, we’re looking at what’s new in terms of research, products, trends, and more in the market. Check out the list below to get the latest—and find out what’s next.

Aged Garlic Extract (AGE): Levy points to AGE as an option that can support heart health—“Recent research conducted at the David Geffen School of Medicine at UCLA on people with type 2 diabetes reports that supplementing with Kyolic Aged Garlic Extract (AGE) reduces multiple factors that increase the risk of atherosclerosis. This matters since people with type 2 diabetes are at a significantly higher risk of dying from cardiovascular disease. These studies found that Kyolic AGE improves endothelial function, lessens the progression of coronary calcification, decreases the amount of unstable low-attenuation (soft) plaque, and reduces left ventricular myocardial mass—an important marker used to predict a future heart attack.”

Aiming to double-down on heart health support, Levy adds, “Wakunaga recently launched Kyolic Omeg-AGE Formula 152, a new and unique multi-system supplement that focuses on supporting optimal cardiovascular, skeletal, and immune health. This one-of-a-kind formula starts by combining the heart and immune benefits of Kyolic AGE with the cardiovascular-supporting properties of EPAX Omega-3s. Omeg-AGE then adds a synergistic blend of nutrients, including vitamins D3, K2, E, and B complex, that have been clinically shown to support heart, bone, and immune health. Together, these ingredients provide users with a comprehensive and convenient way to level up their overall health, especially when paired with a healthy diet and exercise routine. This new supplement provides a broad array of cardiovascular, immune, and bone benefits based on recent clinical findings. It’s a real game changer for anyone trying to improve their overall health.”

Aronia: “One product that has been growing in awareness and respect is aronia (Aronia melanocarpa), also known as chokeberry,” says Melanie Bush, VP of Science and Research, Artemis International, Inc. “Researchers conducted a recent meta-analysis (Hawkins et al., 2020) and sought out to analyze all of the existing clinical studies on aronia’s influence on blood pressure and cholesterol in order to determine if the results had true clinical relevance. The conclusion was that with only six-to-eight weeks of supplementation with aronia extract, there was a significant reduction in systolic blood pressure and total cholesterol, especially in people over 50 years old who tend to need it most. This type of significant effect with a natural, berry-based dietary supplement makes it a viable option for consumers who are looking for alternatives or adjuncts to pharmaceuticals. Lowering blood pressure and cholesterol is extremely relevant to overall cardiovascular health status. Consumers have an inherent understanding that berries are a ‘good for you’ option for the diet, but this new research shows that concentrated bioactives from aronia berries can have targeted functional benefits for specific health outcomes. Much like elderberry has become the hero ingredient for immune support, aronia is the new hero in the heart health category.”

Bush is hoping for more research on aronia—and on berries in general. “While the observed cardiovascular-supporting health benefits of aronia are now well-defined, more research into the mechanisms of action of the bioactives would help to better understand how it is having these effects, and whether other dark berries high in flavonoids like anthocyanins and proanthocyanidins would have similar benefits. Darkly pigmented berries as a category remains a top influencer of human health across multiple categories, but the impact of aronia on heart health parameters is perhaps one of the most relevant for consumers as we navigate through 2022.”

Cannabidiol: CBD is entering the heart health arena. “It’s clear that our endocannabinoid system relates to heart health,” shares Stuart Tomc, VP Business Development, Science, Regulatory, and Education, CV Sciences. “CV Sciences conducted a 60-day clinical study of overweight but otherwise healthy participants, and found that +PlusCBD 15mg Extra Strength formula significantly improved HDL cholesterol and cardiovascular health.” The study, which, at press time, had not yet been peer-reviewed, found that CBD activated AMPK; altered cholesterol chemical activity; and altered metabolites, mRNA transcripts, and proteins consistent with activation of cholesterol biosynthesis, transport, and storage. The researchers concluded: “Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.”

Looking to the future, Tomc predicts: “At CV Sciences, we expect that new research will arise, and inspire consumers to utilize hemp CBD extracts to help support healthy stress responses and a healthy heart. While we are confident in the findings of our own study, more research is needed.” Tomc says the company is advocating for that research, and advocating for FDA to create and enforce regulation to ensure the safety and quality of all CBD.

CoQ10: “Very few ingredients have the 70 years of significant clinical research to support heart health like CoQ10 offers,” shares Scott Steinford, President, CoQ10 Association. “From heart failure to heart health, CoQ10 has demonstrated the ability to offer improvement. Studies continue to occur, with less frequency as they are often repeating the same conclusions and outcomes. Meta-analysis studies of CoQ10 therapy against a popular pharmaceutical heart health product, Entresto, demonstrates CoQ10 as an equivalency, or better, treatment. More studies need to happen.” And personalized information on this ingredient is getting easier and easier to access. Steinford notes: “More consumers are seeking personal information regarding CoQ10 lab tests. Lab pricing for these tests have decreased to approximately $100 per test. At-home CoQ10 blood tests, such as that offered by Life Extension, are now being offered for as little as $59. Increasing awareness of one’s CoQ10 levels will provide continued improvements in both the adoption and compliance of this ingredient for heart health.”

French Maritime Pine Bark: Branded as Pycnogenol, this supplement hits at heart health through circulation. “Good blood circulation factors into many components of our overall health, including our heart health, respiratory health, sexual health, and cognitive health,” notes Sébastien Bornet, VP Global Sales & Marketing at Horphag Research. “Supporting circulatory health from an early age can deliver long-term benefits—especially in the realm of heart health. At Horphag Research, we continue to invest in research demonstrating Pycnogenol French maritime pine bark extract’s ability to maintain healthy circulation by increasing vasodilation of blood vessels, thus improving blood flow from the heart through the entire body. Our latest study showcasing Pycnogenol’s ability to improve blood flow, published in 2020, not only found Pycnogenol’s ability to improve erectile dysfunction symptoms, but participants also reported additional cardiovascular benefits, including a 20% reduction of LDL cholesterol in the diabetes participant group, a 14% improvement of LDL cholesterol in the ED-only participant group, and a 22% improvement of serum glucose in the diabetes participant group.”

This approach may be particularly appealing, Bornet suggests, due to the fact that it can impact multiple facets of health: “Consumers are approaching heart health with a wider lens, and they are looking for natural solutions that support the entire body by working on the circulatory system. This is because the circulatory system carries nutrients and oxygen from the heart to all cells in the body. Our latest research shows the potent circulatory and endothelial nitric oxide enhancing benefits of Pycnogenol and builds on a comprehensive catalog of research examining its benefits for circulation and heart health. The sooner you take a proactive approach to your circulatory health, the better it will be for your overall health, including heart health.”

Homocysteine and Folate 

There are many factors in heart health—blood pressure, calcification, diet. One factor: homocysteine, a common amino acid found in the bloodstream, and a topic at the 13th International Conference on One-Carbon Metabolism, B Vitamins, and Homocysteine, held in September 2021. “A reduction of homocysteine level is important for cardiovascular protection,” explains Lorena Carboni, Scientific Communications Specialist with Gnosis by Lesaffre. “Two meta-analyses concluded that ischemic heart disease risk could be reduced by 16% with a 3 μmol/L decrease in homocysteine levels and by 11% with a 25% decrease in homocysteine levels. Recent studies showed that risk of cardiovascular diseases have been increased with increase in plasma concentration of homocysteine. Increased homocysteine is medically termed as hyperhomocysteinemia (HHcy). HHcy causes damage to the vascular endothelium, leading to inflammation in the blood vessel, which in turn leads to atherogenesis which may results in ischemic injury. Hence, HHcy is a risk factor for cardiovascular diseases, mainly may cause coronary artery disease due to the formation of atherosclerotic plaque blocking the coronary artery which supplies oxygenated blood to the heart. In some cases stroke may lead to cardiovascular diseases as the brain is exposed to most of the plasma constituents including homocysteine, as it has its effect on hypothalamus, which controls the contractility of heart."

What does this have to do with folate? "Folate is an important regulator of Hcy metabolism and helps to maintain normal plasma homocysteine concentrations," Carboni says. "Increase in homocysteine is associated with low levels of vitamin B6, B12, and folate. Hence vitamin supplement with vitamins B6, B12, and folate may reduce the risk of cardiovascular diseases. Clinical studies report evidence that folate supplementation can reduce cardiovascular disease risk by lowering homocysteine levels.

“At the 2021 conference,” Carboni continued, “Guéant et al. presented a study pointing out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes. The group performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay. Patients with CVD outcomes were assessed for vitamin B12, folate, HHcy, methylmalonic acid, and next-generation clinical exome sequencing. HHcy was related to vitamin B12 and/or folate deficiency in 55%, mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11%, and renal failure in 26% of the studied patients. HHcy was the single vascular risk retrieved in almost 9% of patients. 60% of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L. No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after nearly four years of follow-up.”

Carboni further explains that HHcy has a genetic component: A particular morph of a gene involved in folate metabolism impairs the conversion into the biologically active form of folate. Gnosis by Lesaffre offers Quatrefolic, the biologically active form of folate, allowing those taking it to bypass the conversion, raise folate levels, and decrease homocysteine levels. The ingredient is clinically backed: "Quatrefolic has been tested (in conjunction with our partners) for cardiovascular impact, including the normalization of Hcy. The most recent was in 2016, when Mazza et al. published a multicenter randomized clinical trial examining nutraceutical approaches to lowering homocysteine levels in hypertensive subjects at low cardiovascular risk. One-hundred and four patients were sequentially randomized to receive a combination nutraceutical called Normocis400 containing 400 mcg folate-6-5-methyltetrahydrofolate glucosamine salt (as Quatrefolic), 3 mg vitamin B6, 5 mcg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment. What is particularly noteworthy about this study is the effectiveness of Quatrefolic in normalizing homocysteine levels at a 400 mcg/day dose in this product versus the control group at a much higher dose (5 mg/daily)."

Carboni’s take: “Over the last few years, we have worked to raise the knowledge and awareness of active forms of folate as many studies using those forms of folate have been published, illustrating the wide range of benefits of folate supplementation. At Gnosis by Lesaffre, we believe awareness can only be improved through clear communication based in science and through scientific advisory. If we can increase consumer awareness of folate’s impact beyond pregnancy, we believe they would whole-heartedly be interested, particularly as consumers have been more conscientious of their health and the importance of taking proactive measures to secure it, especially after the pandemic.”
Notoginseng: “This fall, we were able to publish the results of our clinical trial, 'Randomized, Placebo-controlled, Triple-blind Study to Determine the Effect of Farlong Ginseng Plus NotoGinseng Extract on Cholesterol and Blood Pressure,' in Current  Nutraceuticals Journal by Bentham Science,” says Jing Struve, CEO & Executive Director of Farlong Pharmaceutical. She explains: “The findings of this study demonstrated that Farlong NotoGinseng (Farlong Ginseng Plus Panax Notoginseng extract) supplementation was well tolerated and may have a positive influence on reducing CVD risk by improving blood pressure and HDL-C. Sponsored by Farlong Pharmaceutical, the primary objective was the difference in serum LDL-C from baseline to week 12 between Farlong NotoGinseng and placebo after 12 weeks of supplementation. The secondary objectives were the difference in serum LDL-C, blood pressure, triglycerides, HDL-C, total cholesterol and endothelial vasodilation as measured by the EndoPAT from baseline to week eight and week 12 between Farlong NotoGinseng and placebo. The results showed a significant decrease in serum LDL-C in Farlong NotoGinseng group from baseline to week eight. LDL Cholesterol is sometimes called the ‘bad’ cholesterol because a high LDL level can lead to a buildup of cholesterol in the arteries. There was a slight increase in serum HDL-C following 12 weeks of supplementation with Farlong NotoGinseng. HDL (high-density lipoproteins) cholesterol is the ‘good’ cholesterol. Notably, there were significantly more participants supplemented with FNG (17.5%) who had improvements in all three CVD risk factors (high LDL-C and systolic blood pressure and low HDL-C), compared to 5% of those on placebo at week 12. It is possible that if left unaddressed, these participants may progress to a disease state, and even a small reduction in cholesterol is clinically meaningful in populations at risk for developing cardiovascular diseases.”

Looking forward, Struve speculates: “As clinical trials are completed and studies are published, more and more consumers are realizing the benefits from healing with natural substances instead of toxic chemicals. They are able to see studies and the positive results they produced, which furthers their confidence in natural medicine. More and more health care practitioners are using Panax Notoginseng to replace patients’ blood pressure pills gradually with good success. With the new research, studies and products, I believe more people will turn to natural medicine to both help prevent and treat illnesses and ailments.” Farlong is looking to continue boosting knowledge and awareness: The company is working on the design for a new clinical trial in 2022, Struve says, surrounding memory and cognitive function.

Omega-3s: Omega-3 fatty acids have been a major player in this space for a long time—and they’re not slowing down: “There is so much new research on EPA and DHA omega-3s—200 new articles are published each month, according to what we’re tracking for our clinical studies database,” shares Ellen Schutt, Executive Director of GOED, “although not all are on heart health. For heart health specifically, we’re still seeing secondary analyses from major clinical trials such as VITAL, which continue to support the need for EPA and DHA omega-3s to reduce cardiovascular risk. A publication in Progress in Cardiovascular Diseases addressed the question of whether there is more benefit from EPA only versus a combination of EPA and DHA; the conclusion remains that EPA monotherapy is no more effective than a combination of EPA and DHA. One scientific question right now is about the risk of atrial fibrillation (A-Fib) with increased omega-3 intake, which was the topic of two meta-analyses this year. The situation is complicated—not all studies report A-Fib occurrences, the epidemiological data to date has been positive, and more research needs to be done on absolute risk and the overall risk-benefit ratio. GOED is working to convene a scientific consensus panel on this topic in 2022.”

Dr. Bill Harris, President, Fatty Acid Research Institute (FARI), pointed to two specific studies. One, published in Nature Communications, is from the FORCE – Fatty Acids & Outcomes Research – Consortium. “FORCE is comprised of researchers around the world that have gathered data on blood fatty acid levels in large groups of study subjects (or cohorts) and have followed those individuals over many years to determine what diseases they develop,” Dr. Harris explains. “These data are then pooled to get a clearer picture of these relationships than a single cohort can provide. The current study focused on omega-3 levels and the risk for death during the follow-up period, and it is the largest study yet to do so. Specifically, this report is a prospective analysis of pooled data from 17 separate cohorts from around the world, including 42,466 people followed for 16 years on average during which time 15,720 people died. When FORCE researchers examined the risk for death from any cause, the people who had the highest EPA+DHA levels (i.e., at the 90th percentile) had a statistically significant, 13% lower risk for death than people with EPA+DHA levels in the 10th percentile. When they looked at three major causes of death—cardiovascular disease, cancer, and all other causes combined—they found statistically significant risk reductions (again comparing the 90th vs 10th percentile) of 15%, 11%, and 13%, respectively. The range between the 10th and 90th percentile for EPA+DHA was (in terms of red blood cell membrane omega-3 levels, i.e., the Omega-3 Index) about 3.5% to 7.6%. From other research, an optimal Omega-3 Index is 8% or higher. In the new paper, the authors noted that these findings suggest that omega-3 fatty acids may beneficially affect overall health and thus slow the aging process, and that they are not just good for heart disease.”

The second study: “Michael McBurney’s paper in AJCN, from the Framingham Offspring Study, showing that a low Omega-3 Index is on par as a risk factor with smoking when it comes to predicting risk for death from any cause over the next ~10 years,” Dr. Harris summarizes. Beyond the importance of the findings, the study feeds into one of FARI’s goals: “We believe that the medical community needs to become more aware of the usefulness of measuring the Omega-3 Index in caring for patients,” Dr. Harris explains. “To do that, we have to show the extent to which a low Omega-3 Index is like OTHER risk factors, which doctors are used to measuring and fixing (usually with drugs). Our paper noted above comparing the risk prediction for a low Omega-3 Index with smoking is the first step. Our next steps will be to do the same with the other classic risk factors for heart disease: LDL (or ‘bad’) cholesterol, high blood pressure, diabetes, and obesity. If we can show that the Omega-3 Index is as important as these standard factors are, then hopefully more doctors will demand to know their patients’ Omega-3 Index values.”

GOED is keeping an eye on what’s coming out, and working to contextualize it. “GOED published two letters to the editor during 2021,” Schutt adds. “One was an update to its 2019 publication linking omega-3 dosage to improved cardiovascular outcomes. The new publication incorporated two newer studies, STRENGTH and OMEMI, that did not find a benefit for omega-3 intake. GOED’s revised analysis showed a continued benefit for EPA and DHA supplementation.”

While GOED stands by EPA and DHA themselves, Schutt adds, more research is looking into source—krill vs. fish vs. algae—and she hopes it’ll have an impact: “We hope that all this ongoing research will help consumers understand how important EPA and DHA are for cardiovascular health, and that dietary supplements are a reasonable, cost-effective and accessible strategy for supporting heart health.”

And Dr. Harris hopes the research will be inspirational. “I can only hope that more and more people will be motivated to get their Omega-3 Index measured and then take action to optimize it. It is one of the easiest risk factors to modify—just consume more long-chain omega-3s EPA and DHA from cold-water fish or dietary supplements. It’s that simple.”

Persimmon: This one isn’t new—in fact, it’s old: “Persimmon leaves have been an essential part of traditional medicine in Asia for centuries, dating back to the Ming Dynasty in China,” says Abdul Alkayali, VP, Sales & Marketing, Longevity by Nature. As of this year, the company is offering Persimonal, a botanical extract of persimmon leaves, containing high concentrations of cardioprotective polyphenols: “Persimonal is rich in bioactive compounds such as flavonoids (Quercetin, Kaempferol and Rutin) that support cardiovascular health as well as other polyphenols, tannins, terpenoids, carotenoids, organic acids, and vitamins that studies have shown to reduce oxidative stress that can damage DNA, cells and tissues. Research has linked oxidative stress to many health conditions, including cardiovascular disease, high cholesterol, high blood pressure and chronic inflammation. Our Persimonal is sourced from our pristine farms in Guilin, a city in Guangxi Province, China, that is renowned for its persimmons.”

And while 2021 saw the product’s introduction, next year may see a big update: Alkayali tells WholeFoods that there are numerous ongoing studies with persimmons to further explore its mechanisms of action and validate its wide range of benefits for human health. Longevity by Nature intends to continue to monitor the research.

Probiotics: Best known for their digestive support functions, probiotics are expanding—and have now reached heart health. Kaneka is offering Floradapt Cardio, which has shown lipid modification effects in clinical trials, according to Sid Shastri, M.Sc., Director of Marketing at Kaneka Probiotics. “Floradapt Cardio is one of only a few commercial probiotic strains with established lipid modification effects,” he says. “One of its primary mechanisms is its high BSH (Bile Salt hydrolase) enzyme production. This ability to copiously produce BSH is not a trait shared by probiotics, in general. So, merely taking any probiotic for a cardiovascular benefit may be similar to taking any mineral supplement—likely there will be no effect. Floradapt Cardio is the product of nearly a decade of studies, which include safety, in-vitro, as well as clinical trials. Our researchers demonstrated that Floradapt Cardio enabled significant reductions in lipid biomarkers like LDL-Cholesterol (p < 0.001), Total Cholesterol, Triglycerides, and oxidized LDL. The Fuentes study showed drops of 14+% in LDL-C and 16% in Triglycerides. It’s well established that LDL-C is a risk factor for CVD and a primary target for lipid-lowering therapies. Our data also very significant reductions in Oxidized LDL (p <0.001), which is not seen in other cardiovascular probiotics.”

Looking more closely at BSH, Shastri explains: “Not commonly known is that only about 15-30% of circulating cholesterol comes from diet. The rest is synthesized by the liver or recirculated in our bile salts. Bile is the digestive fluid made by the liver and stored in the gall bladder. Upon the ingestion of food, this digestive liquid is released in the duodenum. It is comprised of cholesterol, conjugated bile acids, phospholipids, bile pigments and electrolytes. Floradapt Cardio deconjugates bile salts into bile acids, thereby increasing the excretion of cholesterol. This deconjugation activity comes from an enzyme called Bile Salt Hydrolase (BSH), which is produced in maximum amounts by our Floradapt Cardio strains. Once bile salts are deconjugated, the bile acids are rendered less soluble and thus they are led to their excretion.”

Consumers are aware of the concept of heart-health probiotics, and are looking for them, Shastri says: “Probiotic applications for cardiovascular health are still in the early adopter stage. In a recent review from Lumina Intelligence, there were only nine Probiotic products available for cardiovascular health. Furthermore, the fastest growth in customer engagement in the period of December 2017 to July 2020 was recorded by probiotics positioned to support cholesterol. The total number of reviews was up by 2567%. Customer engagement is clear indication that people will welcome a probiotic recommendation for heart health. Furthermore, in a report dated November 4, 2021 called USA Report, Lumina scanned a total of 1,729 e-commerce probiotic products that were targeted for specific health benefits. Surprisingly, 60 products alluded to cardiovascular benefit (right after Digestion, Immunity, Gut, Wellbeing, and Women’s Health). This consumer data clearly demonstrates that consumers are searching for probiotic products that will impact their cardiovascular concerns.”

Looking to the future, Shastri foresees combination formulas—he points to Floradapt Cardio plus Red Yeast Rice Extract, which were shown in a 2021 study to work well together—and a domino effect, as consumers see the probiotic in products. Kaneka has more Floradapt Cardio studies underway, and the publication of those studies, Shastri feels, will provide more visibility—and, thus, more interest in probiotics for heart health.

Vitamin K2: Not just vitamin K, but vitamin K2 specifically, has seen quite a bit of research in the past 12 months. Elise Kaiser, VP Sales, Americas, with NattoPharma – Gnosis by Lesaffre pointed to no fewer than five studies considering the impact of K2 on heart health. One cross-sectional study, published in March 2021 in the Kaohsiung Journal of Medical Sciences, found evidence that statins—a cholesterol medication—may enhance calcium accumulation in the arterial wall by inhibiting vitamin K-dependent proteins involved in vascular protection. A review paper published in Nutrients examined the evidence connecting K2 to Alzheimer’s disease pathogenesis, and concluded that K2 has the potential to slow the progression of the disease and contribute to its prevention. A July 2021 study found that K2 could improve cardiovascular risks for nicotine users, noting that smokers have a higher atherosclerotic burden, which can be reduced by K2. A November 2021 study published in Nephrology Dialysis Transplant looked at an experimental kidney failure animal model and found that K2 and phosphate binders could be a useful therapy for chronic kidney disease patients by inhibiting vascular calcification. And on top of that, a November 2021 review published in Open Heart illustrated evidence supporting the need for a K2 RDI due to K2’s role in cardiovascular health. Plus, a new clinical trial was registered, which will look at the impact of 1mg of K2 daily on arterial stiffness and cardiovascular events over the course of 1.5 years. (Full descriptions of these studies can be found at the bottom of this article.)
“The evidence continues to build, confirming that vitamin K2 as MK-7 provides safe and effective cardiovascular benefits,” Kaiser says. “This is an argument that NattoPharma – Gnosis by Lesaffre has been making for decades. It is gratifying to see how our research has fed into other universities and institutes examining K2’s potential for cardiovascular health and other areas. Firstly, vitamin K2 delivers cardiovascular protection by activating a specific K-dependent protein—Matrix Gla Protein (MGP)—which helps the body inhibit calcium from depositing in arteries and soft tissues where it is the primary plaque component, impeding the free flow of blood. And this mechanism has now been linked to other areas of health, such as brain health and the progression of Alzheimer’s. The study of K2’s impact in patient populations that express intense calcification as a symptom of their condition provides insight on K2’s impact on calcification and ultimately as a potential therapy for these patient populations that should support its use as a proactive lifestyle measure for healthy populations seeking to protect their cardiovascular health. As this research grows, we hope to see vitamin K2 considered a proactive lifestyle measure. It is imperative to begin taking vitamin K2 early to provide a healthy bone and cardiovascular foundation as we age. Waiting until our senior years when the damage is done is not a prudent or viable strategy.”

Kaiser says that the work in this area is far from finished. “One of the most critical ways for consumers to address their K2 deficiency is to have a K2-specific RDI established. This research—specifically the recent K2 cardio review paper published in November 2021—is an essential foundational piece for two reasons: First, for clinicians to understand the K2 impact. For example, where statins are concerned, CoQ10 supplementation is typically recommended by practitioners prescribing statins because the medication is known to deplete CoQ10 levels in the body. No such recommendation exists for vitamin K2 at this point. Second, compiling this type of research into comprehensive review papers helps put into perspective the regulatory bodies responsible for considering and eventually approving a change in RDI.”

Moreover, Kaiser adds, we may not even know how much K2 can do just yet: “There are 17 K-dependent proteins in the body. We have only scratched the surface of K2’s potential with its activation of these proteins, and we are excited to see what new benefits will be uncovered through our continued commitment as the K2 leader in research and development. We have done this in support of our research partners, primarily by providing our MenaQ7 Vitamin K2 as MK-7 as the source material for clinical studies (22+ published human clinical trials with more currently underway) or providing support through research grants.”

Fresh Thinking on Cholesterol Tests, Processed Foods, and Fat 

“There are two critically important things everyone should know about immediately,” says Jonny Bowden, Ph.D., CNS, aka the Nutrition Myth Buster. “One, the old ‘HDL-LDL’ test is obsolete. Two, the biggest risk factor for heart disease is not cholesterol but a metabolic condition called insulin resistance, which most people don’t even know about.”

What does Dr. Bowden mean by this? “We’ve been using the old ‘good cholesterol/ bad cholesterol’ test for decades, but it’s as dated and irrelevant as the instruction manual for a Commodore 64 computer. People should insist on the modern cholesterol tests, which are known by different names depending on the lab you use: Advanced Lipid Profiling, the NMR particle test, the Cardio-IQ panel, or LabCorp’s LP-IR test. Those are the tests that actually give you good information about risk. The HDL-LDL test needs to be retired permanently. Cholesterol—particularly what’s known as LDL cholesterol—does not cause heart disease, and neither does saturated fat. We’ve seen that in at least a half dozen studies just in the last decade. And once you realize that cholesterol and fat aren’t the culprit, then the dietary guidelines crumble like a house of cards.”

What, then, is the culprit? Food products that come in boxes—”processed food in general, and sugar and seed oils in particular,” Dr. Bowden opines. Sugars and starch cause insulin resistance, which, he says, is a top cause of health issues, and entirely reversable: “Insulin resistance syndrome (pre-diabetes) affects 88% of Americans and underlies not just heart disease, but a host of chronic diseases including diabetes and obesity. It’s also significantly related to every major medical co-morbidity for COVID. Insulin resistance shows up years before your doctor says, ‘Mrs. Jones, your blood sugar and A1C are a little high, let’s put you on some Metformin,’ or ‘Your cholesterol is high, let’s get you on a statin.’ And we can reverse, treat or prevent insulin resistance with diet, exercise and intermittent fasting. One study we reference in the new, revised edition of our book, The Great Cholesterol Myth, estimates that if we wiped out insulin resistance, we could prevent 42% of all heart attacks.”

Dr. Bowden has two hopes for the future: First, that people will insist on modern cholesterol tests, and won’t accept prescriptions otherwise. Second: “That if people like me do our jobs well and educate the public about the real cause of insulin resistance, people will stop fearing fat and start paying attention to sugar and starch. That’s what really causes insulin resistance. Fat—including saturated fat and tropical oils and all the rest of the stuff we’ve been told to avoid—is not the problem. Just as the country started awakening to some of the inequalities and prejudices that are baked into our system, we need to awaken that conventional medicine is stuck in some ancient paradigms that don’t serve us anymore. Dietary guidelines have been pushing the foods that make us fat, sick, tired, and depressed. Hippocrates, the father of medicine, said 'Let food be they medicine.' We need to get back to that basic principle. And we need to eat real food—food you could hunt, fish, gather or pluck—including all the fat it naturally comes with.”

Dr. Bowden offers a five-day introduction to intermittent fasting on his site, jonnybowden.com, to help people fight insulin resistance.
What Now? 

Looking to the future, Sugarek MacDonald predicts greater awareness—and more action: “Cardiovascular health will be top of mind in 2022, and consumers will need to be more aware that making healthier lifestyle changes is necessary for positive change. If consumers jumpstart their lifestyles with healthier practices, the seeds of change will be planted.” WF

ONLINE EXCLUSIVE: In Kaiser's words, the latest studies on vitamin K2:

  • March 2021 – Further evidence that statins contribute to vascular calcification; highlights importants/need for Vitamin K2
A new cross-sectional clinical study published in Kaohsiung Journal of Medical Sciences1 adds to the evidence that statins, a heavily prescribed cholesterol medication, may enhance calcium accumulation in the arterial wall by inhibiting vitamin K-dependent proteins involved in vascular protection.

Statins are first‐line drugs in the prevention and treatment of established atherosclerotic cardiovascular disease. Paradoxically, intensive statin therapy has been shown to increase vascular calcification and accelerate its progression. The aim of the study, “Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?”, was to find a putative relation between statin use, coronary calcification, and the vitamin K-dependent proteins as a possible mechanism mediating statins’ pro-calcification.

“According to the study, statins negatively influence vitamin K status. To that end, supplementation with Vitamin K2, which has been shown to effectively improve vitamin K status and activate extrahepatic K-dependent proteins, might prove beneficial for statin users,” says Dr. Hogne Vik, chief medical officer with NattoPharma – Gnosis by Lesaffre.

(Ref: 1 Zhelyazkova-Savova MD, Yotov YT, Nikolova MN, Nazifova-Tasinova NF, Vankova DG, Atanasov AA, Galunska BT. “Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?” Kaohsiung J Med Sci. 2021 Feb 26. Online ahead of print.)
  • June 2021 – New cardio-specific clinical trial in a specific patient population uses the highest dose of K2 as MK7 to date
A new 1.5-year clinical trial using MenaQ7® Vitamin K2 as MK-7 was registered on ClinicalTrials.gov. The trial will examine the cardiovascular impact in a patient population and will use the highest dosage of K2 as MK-7 to date: 1mg daily.

The new multi-centre, placebo-controlled, randomized, open-label intervention clinical trial, “The Effect of Vitamin K2 Supplementation on Arterial Stiffness and Cardiovascular Events in PEritonial DIAlysis (VIKIPEDIA)”, will be conducted with Peritoneal Dialysis (PD) patients. The investigators at Aristotle University of Thessaloniki in Greece will study the effect of K2 supplementation (through normalization of dp-ucMGP) on arterial stiffness and the occurrence of cardiovascular events.

Chronic Kidney Disease (CKD) is a state of progressive vascular calcification and cardiovascular disease. End Stage Kidney Disease patients receive renal replacement therapy either by hemodialysis or by PD, according to lead researcher Stefanos Roumeliotis , MD, PhD. “Several studies have shown that hemodialysis patients have vitamin K depletion and accelerated vascular calcification ,and this finding led to the initiation of several randomized controlled trials exploring the effect of vitamin K2 supplementation on vascular calcification in hemodialysis patients.

“VIKIPEDIA is the first study to assess whether high dosage of Menaquinone-7 could improve arterial stiffness, mortality, cardiovascular disease, 24-hour ambulatory blood pressure and dialysis efficacy in patients with PD,” he explains. “MenaQ7® was chosen to be used in the study because the compound showed its efficacy to improve vitamin K status in many clinical trials with kidney patients.”

(Ref: https://clinicaltrials.gov/ct2/show/NCT04900610?term=peritoneal&cond=vitamin+k&draw=2&rank=1)
  • July 2021 – Review paper connects the cardio-protective mechanism of K2 to Alzheimer’s as a potential therapy
Nutrients published a new review paper that examines the body of evidence connecting vitamin K2 to factors involved in Alzheimer’s disease (AD) pathogenesis, concluding that this demonstrates K2 as having the potential to slow the progression of AD and contribute to its prevention.

In the review, “Vitamin K2 Holds Promise for Alzheimer’s Prevention and Treatment” [1], researchers from the Harvard Extension School and Pacific Northwest University considered the antiapoptotic and antioxidant effects of vitamin K2 and its impact on neuroinflammation, mitochondrial dysfunction, cognition, cardiovascular health, and comorbidities in AD. In their review, they also “examine the link between dysbiosis and vitamin K2 in the context of the microbiome’s role in AD pathogenesis,” they write. “Our review is the first to consider the physiological roles of vitamin K2 in the context of AD, and, given the recent shift in AD research toward nonpharmacological interventions, our findings emphasize the timeliness and need for clinical studies involving vitamin K2.”

“There is growing evidence for possible dietary risk factors in the development of AD and cognitive decline with age, such as antioxidants, omega-3s, dietary fats, and B vitamins. Moreover, research suggests that people with low levels of vitamin D are more likely to develop AD and other forms of dementia. We are gratified that Vitamin K2 is becoming a prominent part of this conversation, particularly as most of the world’s population expresses a K deficiency,” says Dr. Hogne Vik, NattoPharma Chief Medical Officer. “A 2018 paper [3] connected aortic stiffness with an increased risk of dementia in older adults. By activating matrix Gla protein (MGP), vitamin K2 as MK-7 is the only compound to date shown to impact arterial calcification.”

“NattoPharma’s branded Vitamin K2, MenaQ7, is the only K2 on the market clinically proven to impact cardiovascular health through its activation of MGP, and the only K2 patented for cardiovascular health. But it has also been shown to be anti-inflammatory in human cells and act as an antioxidant, improving endothelial function [5],” Dr Vik continues. “There are 17 K-dependent proteins in the body, and we have a strong understanding of a few, which contribute to blood clotting, bone health, and cardiovascular health. These findings shine a light on the importance of continuing our research to articulate the health benefits of activating additional proteins, and the impact that can have on the global population.”

(Ref: 1 Popescu A and German M. “Vitamin K2 Holds Promise for Alzheimer’s Prevention and Treatment.” Nutrients. 2021,13,2206.

3 Cui C, Sekikawa A, Kuller LH, Lopez OL, Newman AB, Kuipers AL, Mackey RH. “Aortic stiffness is associated with increased risk of incident dementia in older adults.” J Alzheimer’s Dis. 2018;66(1):297-306.

5 Bar A, Kus K, et al. Vitamin K2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR mice. Vascul Pharmacol. 2019 Aug 14: 106581. Doi: 1016/j.vph.2019.106581.)
  • July 2021 – Vitamin K2 could improve cardiovascular risks for nicotine users
Smokers are at increased risk of cardiovascular events as smoking influences cardiovascular disease, resulting in accelerated atherosclerosis and vascular calcification. As the exact mechanisms through which nicotine accelerates vascular disease is unknown, Cardiovascular Research is publishing a new study[1] that investigated the effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification. The study aimed to elucidate the underlying mechanisms of nicotine-induced VSMC calcification and examined vitamin K2 as a potential therapy. The study that was completed with the support of NattoPharma, as partner within the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant INTRICARE.

The researchers assessed vascular calcification of human carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed-tomography (µCT)-scanning. Calcification was present more often in carotid plaques of smokers compared to non-smokers, confirming a higher atherosclerotic burden. The difference was particularly profound, according to researchers, “for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. Using induced human primary VSMC in vitro, nicotine increased osteogenic gene expression (Runx2, Osx, BSP and OPN), extracellular vesicle (EV) secretion and subsequently increased calcification.”

The pro-calcifying effects of nicotine were mediated by the free radical producing Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Additionally, the study showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels. Finally, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification.

(Ref: Petsophonsakul P, Burgmaier M, Willems B, Heeneman S, et al. “Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress and extracellular vesicle release in vascular smooth muscle cells.” Cardiovasc Res. 2021 Jul 17;cvab244. doi: 10.1093/cvr/cvab244. Online ahead of print.)
  • November 2021 – Vitamin K2 combined with phosphate binders could provide a useful therapy for CKD patients
Nephrology Dialysis Transplant has published findings from an experimental kidney failure animal model showing Vitamin K2, when combined with phosphate binders (PBs), could potentially be a useful therapy for chronic kidney disease (CKD) patients. NattoPharma, now part of Gnosis by Lesaffre, supported the study by providing MenaQ7® K2 as MK-7 as the source material and funding through a Norwegian Research Council grant.

The paper, "Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure", presents important evidence furthering the understanding of the role of vitamin K deficiency, specifically highlighting its potential as a cardiovascular therapy for an at-risk population, according to Prof. Leon Schurgers, Professor of Biochemistry of Vascular Calcification and Vice-Chair of Biochemistry at the Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, and corresponding author to this paper.

"CKD patients often express intense vascular calcification as a symptom of their condition. People with chronic kidney failure are often prescribed phosphate binders to reduce the absorption of dietary phosphate, to lower their serum phosphate which is a major risk factor for vascular calcification. However, PBs also bind vitamin K, thereby potentially aggravating vitamin K deficiency,” Schurgers explains. “This vitamin K binding by PBs may offset beneficial effects of phosphate level reduction on reducing vascular calcification. With this study, we wanted to assess whether combining PBs with K2 supplementation inhibited vascular calcification.”

The authors concluded: "In an animal model of kidney failure with vitamin K-deficiency, neither phosphate binder therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC. Our findings might provide a combination therapy to combat VC in CKD. These findings should be translated to human research.”

“While this is early research, it is still significant in furthering our understanding of the K2 mechanism and its potential for improving cardiovascular health for the global population, but specifically at-risk populations like those suffering from CKD,” explains Dr. Hogne Vik, Chief Medical Officer with NattoPharma – Gnosis by Lesaffre, which supported this study through funding and supplying the K2 used in the study. “K2 is the only known compound to date shown to impact vascular calcification. We are proud to continue driving our understanding of Vitamin K2, building on the already substantial body of evidence showing it is a safe and effective cardiovascular protector.”
  • November 2021 – Comprehensive narrative review paper summarizes K2 cardiovascular-support evidence for clinicians and scientists; lends to K2 RDI argument
Open Heart has published an important review paper from NattoPharma's long-time research partner, Maastricht University, and the Cleveland Clinic touting Vitamin K2's overlooked role in cardiovascular health, specifically identifying in the United States where K deficiency is significant.

The paper, "Vitamin K2, a Neglected Player in Cardiovascular Health: A Narrative Review"1, presents a thoughtful organization of data, which is desperately needed in the effort to petition for a K2-specific Recommended Daily Intake, according to Prof. Leon Schurgers, Professor of Biochemistry of Vascular Calcification and Vice-Chair of Biochemistry at the Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, and author to this paper.

"There is expanding preclinical and clinical data on vitamin K's cardiovascular benefits, with multiple ongoing clinical trials. To that end, there is a pressing need to organize our understanding of the pathophysiology, and efficacy of K2 intake as it relates to markers and outcomes of cardiovascular health," he explains. "As we point out, there is an alarmingly high prevalence of vitamin K deficiency and suboptimal recommended intake among the general population in the United States. And yet there is a growing body of evidence that supports the potential role of vitamin K2 in cardiovascular health."

This comprehensive narrative review aims to summarize the literature for scientists and clinicians. Divided into two major sections – I) the role of MGP in cardiovascular health, and II) the cardiovascular benefits of vitamin K2 dietary intake and supplementation – the authors first discuss the pathophysiological interplay between K2 and Matrix Gla Protein (MGP).

"By providing an organized framework of the available evidence, we then elucidate the association of vitamin K2 deficiency and MGP on the various markers cardiovascular health," the authors write. "In the second section, this review outlines the clinical impact of dietary and supplemental K2 intake on these outcomes, citing the data of its use as a novel and practical addition to our arsenal of cardioprotective therapies."

"This review covers the rapidly expanding evidence supporting the cardioprotective effects of vitamin K2 intake, mediated by activated MGP; a foundation of evidence NattoPharma and Maastricht have driven for decades, using our MenaQ7 K2 as the source material,” adds Dr. Hogne Vik, Chief Medical Officer with NattoPharma – Gnosis by Lesaffre, noting the breakthrough 3-year cardiovascular study published in 20152 and the 1-year cardiovascular study published in 20203.

The authors conclude: “Vitamin K2 supplementation appears safe and practical, and randomized clinical trials can investigate its use ... With evidence mounting, the definitive role of vitamin K2 supplementation in delaying progression of vascular and valvular calcifications remains the subject of multiple clinical trials. Nonetheless, vitamin K2 and MGP utility in various patient populations … grows commensurate with the data supporting its efficacy in improving cardiac function and decelerating arterial stiffness."

(Ref: 1 Hariri E, Kassis N, Iskandar J, et al. Vitamin K2—a neglected player in cardiovascular health: a narrative review. Open Heart 2021;8:e001715. doi: 10.1136/openhrt-2021-001715.


2 Knapen MHJ et al. Thrombosis and Haemostasis, 2015; 19;113(5).

3 Vermeer C and Vik H. Vascul Dis Ther. 2020, 5:1-4.)